Environmental and Health Assessment of Alternatives to Phthalates and to flexible PVC, Danish Environmental Protection Agency

Environmental and Health Assessment of Alternatives to Phthalates and
to flexible PVC

1. English summary (Summary)

2. Sammendrag (Sammenfattende artikel)

3. Introduction and approach
3.1 Background
3.2 Approach
3.2.1 Data search and substance selection
3.3 Properties information
3.3.1 Data collection
3.3.2 Estimation of exposure
3.3.3 Assessment
3.3.4 Combined assessment

4. Use patterns and substitutes
4.1 Use patterns of phthalates
4.1.1 Assessment of use of phthalate plasticisers
4.2 Selection of substitute substances
4.2.1 Assessed substitutes for phthalates - substances
4.2.2 Assessed substitutes for flexible PVC - materials
4.3 Proposed use pattern for substitutes
4.3.1 Substitution matrix for the 11 substances in tons
4.3.2 Substitution matrix for the two materials
4.4 Assessment of emission and exposure
4.4.1Considerations regarding specific uses of phthalates/substitutes
4.4.2 Worker and consumer exposure
4.4.3 Exposure in environment
4.4.4 Migration potential

6. Health and environmental assessment for materials
6.1 Polyurethane
6.1.1 Use, emission and exposure
6.1.2 Health assessment
6.1.3 Environmental assessment
6.2 Polyethylene (PE)
6.2.1 Use, emission and exposure
6.2.2 Health assessment
6.2.3 Environmental assessment

7. Combined Assessment of Use, Exposure and Effects
7.1 Chemical Hazard Evaluation
7.1.1 Data availability
7.1.2 Physical-chemical data
7.1.3 Humans
7.1.4 Environment
7.2 Risk evaluation
7.2.1 Working environment
7.2.2 Consumer exposure
7.2.3 Human exposure in environment/secondary poisoning
7.2.4 Aquatic ecosystems
7.2.5 Sediment
7.2.6 Groundwater, soil and microorganisms
7.3 Overview

8. Conclusion

9. Reference list

A. Appendix 1
B. Appendix 2
C. Appendix 3
D. Appendix 4

A total of 20 million tonnes of PVC is produced globally every year. Recent statistics from the Association of European Plastic Converters states that production in Western Europe is 4.2 million tonnes of rigid and 3.7 million tonnes of flexible PVC(EU Commission 2000)

Plasticisers are necessary to manufacture flexible PVC products and may in the product constitute from 15 to 60% (Gächter, Müller 1993) depending on the final application with a typical range between 35 - 45%. At present a range of phthalates constitute the vast majority of plasticisers for PVC (in 1997: 93%) and approximately 900,000 tonnes are used annually in Western Europe. Other plasticisers, in particular adipates, trimellitates, organophosphates and epoxidised soy bean oil can also be used in PVC, but constitutes only a fraction of the present total consumption (EU Commission 2000).

Five of the phthalates have been put on priority lists for risk assessment due to the potential for human health and environment effects, and some are already under assessment by the EU. In Denmark an action plan has been adopted to reduce the use of phthalates with 50% over the next 10 years. In Sweden the usage of the main phthalate DEHP (diethylhexylphthalate) is to be reduced, and in Germany the Umweltbundesamt recommends a phase-out of flexible PVC where safer alternative exist. It is therefore expected that the need for alternatives to the existing plasticisers will grow.

The present project is a general assessment of the use, exposure, and possible health and environmental effects of several alternative plasticisers and of two materials suggested for substitution of flexible PVC.

3.2 Approach

The DEPA has presented a list of substances and groups of substances for the study, which were suggested as possible alternatives to phthalate plasiticisers, and two materials suggested as alternatives to flexible PVC. A health and environmental assessment, including exposure, was requested. The list comprised:

Tabel 3.1 List of substances suggested as possible alternatives to phthalate plasiticisers

Substances	Groups of substances
Diethylhexyl adipate	Alkylsulphonic acid esters
O-acetyltributyl citrate	Butane esters
Di(2-ethylhexyl) phosphate	Polyester
Tri(2-ethylhexyl) phosphate	Epoxyester and epoxydized oils
Tri-2-ethylhexyl trimellitate	Benzoates
	Sebacates
Materials
Polyurethane
Polyethylene

In the following an overview of procedures and activities of the assessment is presented. A more detailed description is given in the introduction to the presentation of the result of each activity.

Figure 3.1 Overview of procedures and activities of the assessment.

3.2.1 Data search and substance selection

Identification of phthalate usage
The selection of example substances and materials were based on information on the present uses of phthalates, i.e. information from the industry and from The Danish Product Register (PR). Especially, the usage as plasticiser was emphasised.

Use estimation
The use of PVC and phthalates herein was taken from the report on mass balance of phthalates for Denmark from 1996 (Hoffmann 1996) and from the Inventory of the Industry (2000).

Preliminary data on substance properties
From a number of databases and other readily available information sources preliminary data collection on properties was performed on the five sub-stances and on a number of suggestions for additional substances as exam-ples for groups of substances. This information was compiled into data sheets and given a preliminary review.

Selection of substances for assessment
Based on the information on use pattern, volume, and the screening data, six substances were chosen as examples of their group and for this total of 11 substances a more comprehensive data collection took place.

3.3 Properties information

3.3.1 Data collection

Databases used
The data collecting includes searches for original literature in bibliographi-cal databases and searches in the following databases directed towards rele-vant toxicological and ecotoxicological properties.

Chemfinder, CHEMFATE, ENVICHEM, TOXALL
ECOTOX: Aquire, Terretox, Phytotox
Hazardous Substances Data Bank (HSDB)
Oil and Hazardous Material Technical Assistance Data System
International Uniform Chemical Information database (IUCLID)
Handbook of environmental data of organic chemicals ("Verschueren")
SAX's Dangerous properties of industrial materials

The most relevant reference sources from the listed database outputs have in addition been procured. In most cases these references are reviewed litera-ture and not the original sources. This means that the evaluated effects are not always described in detail but often in more general terms like 'slightly irritating' or 'moderately toxic'. A more precise evaluation is therefore not possible and also not a precise evaluation against the classification criteria in the Substance Directive (EU, 1967).

Quality assessment of data for the environmental hazards of chemicals is based on the procedures in Pedersen et al. (1995)

3.3.2 Estimation of exposure

Worst case
As a first step, a hypothetical worst case scenario was included for each sub-stance assuming a total change of all phthalate consumption to one single substitute. This number was also used in exposure calculation.

Substitution matrix
Estimation of exposure in a future substitution scenario was attempted by establishing a 'realistic' use pattern scenario for all the substitutes in PVC applications. This was performed with a substitution matrix showing the use pattern in use groups. From this matrix the maximum usage in tonnes for an application was used for the exposure calculation.

Exposure
The exposure was calculated for workers, consumers, humans exposed via the environment and the aquatic and terrestrial environment by using the EUSES programme (European Chemicals Bureau 1996) based on the EU Technical Guidance Document on risk assessment of chemicals (EU 1996).

3.3.3 Assessment

Where incomplete information on physical-chemical, toxicological or eco-toxicological properties was identified in data sheets a renewed information search was performed.

Health
The health assessment is based on available data from animal studies re-flecting all relevant exposure routes and toxicological effects. Observations in humans are included where available. These data are presented in the data sheets included in Appendix 1. In the data sheets the most significant test results are highlighted (marked with ¨) and these results are presented in chapter 5 along with an evaluation of each substance. Calculations using the EASE model are used to estimate the possible exposure from selected use scenarios in the work environment and to the consumer. The estimated ex-posure is compared to the doses and effects seen in the described animal studies and to the exposure levels and related effects observed in humans.

Environment
The environmental assessment is built around the exposure data provided by the EUSES for a number of compartments for which relevant ecotoxicologi-cal test data have been searched. These include test with algae, crustaceans and other invertebrates, fish, micro-organisms, and terrestrial organisms. Other test data have also been included where relevant. For each of these groups of organisms the data are presented in the datasheets provided in the appendix and the key data for the assessment are marked. A more detailed description of the key data is presented in chapter 5 along with a summary description of the substance data. The (eco)toxicolgical data are not entered into EUSES, because of a typical lack of the type of test data needed to comply exactly with EUSES. The risk is estimated by comparing predicted environmental concentrations (PEC) and predicted no-effect concentrations (PNEC).

The parameters on partitioning and degradation are also discussed under 'Environment'. These values also enter EUSES and influence the exposure calculations. These are octanol-water partition coefficient, bioconcentration factor (BCF), soil or sediment-water partition coefficient, and aerobic and anaerobic biodegradation.

3.3.4 Combined assessment

The sources of the data are given primarily in the data sheets in the report appendix and for core information also in the main report. The information includes peer reviewed original papers, databases, previous reviews and re-ports, books, and proprietary information from suppliers. The combined as-sessment is found in chapter 7.

It has been attempted to prioritise studies performed after standard test methods and guidelines for inclusion. In a number of cases the database IUCLID, which contains information submitted by the industry, is almost the sole data source. Again, standardised tests have been selected whenever possible.

The core physical-chemical properties considered are the hazardous proper-ties, such as corrosiveness, flammability etc.

The choice of properties for human toxicity has been based on the hazard indicators for humans as mentioned in CSTEE (2000), i.e. carcinogenicity, reproductive and developmental effects, mutagenicity, sensitisation and se-vere organ toxicity supplemented with assessment of acute and/or local ef-fects. For the environment the properties evaluated are the three core prop-erties of the hazard classification scheme of EU (Commission of the Euro-pean Communities 1993), i.e. persistence (biodegradation), bioaccumulation and acute toxicity to algae, crustaceans and fish of the chemical substance.

In addition to evaluating hazards, the risk is also assessed. For humans this is achieved by comparing the estimated dose of the substance in consumer and environmental exposure with existing or estimated acceptable daily dose (ADI). For the environment the environmental risk quotient is calculated from PNEC and estimated environmental concentrations.

Other important properties with respect to the potential use areas of the sub-stances and materials are the volatility and migratory properties. Compari-son of these properties will also be carried out, although no recommendation regarding technical uses will be made.

4.Use patterns and substitutes

4.1 Use patterns of phthalates

4.1.1 Assessment of use of phthalate plasticisers

Many polymer products need to be flexible and soft so they can take on a different shape and form depending on their application. This plastification is often conducted using plasticisers such as phthalates, adipates, trimelli-tates and citrates.

The major uses of flexible PVC in Western Europe is in the product groups of film and sheet, wire and cable, floor covering, extrusions, coated fabrics and plastisols (European Council for Plasticisers and Intermediates, 2000).

PVC plasticisers
According to the European Council for Plasticisers and Intermediates there are more than 300 different types of plasticisers of which about 50-100 are in commercial use (European Council for Plasticisers and Intermediates, 2000). The most commonly used plasticisers are phthalates.

In the Danish Product Register, close to 180 different plasticisers are registered in a wide range of products.

According to the European industry 95% of the plasticiser production is for PVC end-use. In Denmark phthalate in PVC contributes with 90% of the turnover of phthalates (Hoffmann, 1996).

Plasticisers are used in a wide range of products from toys, babycare items, medical devices, wall-coverings, electrical cables, automotive parts, pack-aging, coatings and in the manufacture of clothing and footwear.

Smaller quantities of plasticisers are also used in paints, rubber products, adhesives and some cosmetics. A small amount is used as denaturant in cosmetics such as "sun-tan oil".

In Denmark, phthalates are used as plasticisers in various PVC-products for medical utilities, packaging, cables, fittings, floor/wall covering, but there is still a an extensive, not specified, consumption of phthalates in plasticised PVC products (Hoffmann, 1996). This "Other application of PVC" covers e.g. the use of phthalates in plastisol (coating materials) and toys. Artificial leaders are e.g. produced by coating textile with plastisol. The plastisol con-sists of a PVC-resin, solvent and a plasticiser e.g. phthalates.

In Denmark, phthalates are used as plasticisers in non-PVC materials such as lacquer, paint, printing inks, adhesives, fillers and denaturants in cosmet-ics. The unspecified consumption of phthalates in non-PVC applications is small compared to the use in PVC (Hoffmann, 1996). Capacitors with di-electric fluid may contain phthalates (notably DEHP), but in Denmark most capacitors are dry and therefore without fluids. Another use of phthalates in non-PVC products is in ceramics for electronic products. It is assumed that the used amounts associated with these applications are relatively small in Denmark.

The use of phthalates as plasticisers a.o. in 1992 in Denmark was assessed in the Substance Flow Analysis (Hoffmann, 1996). This analysis indicates that the Danish distribution of the applications of phthalates in 1992 can be illustrated as in Figure 4.1.

Figure 4.1 The distribution of phthalates for applications in Denmark in 1992 (Hoffmann, 1996).

Figure 4.1 The distribution of phthalates for applications in Denmark in 1992 (Hoffmann, 1996).

As mentioned earlier, the use of phthalates in PVC-toys is included in "other applications of PVC". This amount is assumed equal to the use of DEHP for flexible PVC-toys. This includes phthalates used for toys for children both less and more that 3 years old ~ 380 ton/year. The use of phthalates are now banned for the former category.

It appears that the amount of phthalates within certain applications is de-creasing. This trend is illustrated in Table 4.1, where the development in the use pattern is listed.

Table 4.1 Development in the use pattern of phthalates in different applications in Denmark.

Application	Subapplication	Amount phthalate in 1992 in tonnes^a	Amount phthalate in 1994 in tonnes^b	Est. amount of phthalate in 2000 in tonnes^c	Trend
PVC	Medical utilities	240-350	240		increasing ^a
	Packaging	200-350	100		decreasing ^a
	Construction and installations: - cables - fittings - floor and wall covering
		3,000	3,500		constant ^a
		80	700		constant ^a
		1,500	2,000		increasing ^a
	other application	4190	3,100		^e
	Subtotal	9,200-9,500	9,640		^d
Non-PVC	Lacquer and paint	45-225	189^g	70	decreasing ^{a and c}
	Printing ink	90-270		50	decreasing ^{a and c}
	Adhesives	160-220	350^g	220	constant ^c
	Fillers	< 400		100	decreasing ^c
	Denaturants	< 5			?^a
	Other non-PVC applications e.g. in rubber, concrete and silicone	< 50^f			? ^a
Total		9,500-10,700	11,000

^{aHoffmann (1996)^b The Danish Plastics Federation (1996)^c Hansen and Havelund (2000)^d At the moment increasing globally and constant on the Nordic
market, but decreasing a little on the Danish marked.^eAccording to SFA (Hoffmann, 1996) consumption is decreasing but
according to the Danish Plastics Federation (1996) it might be increasing.^f The application "other applications" under non-PVC
-products in Hoffmann (1996) is estimated to cover as a maximum 50 tons.^g Inventory for the Consumption in 1994 made by FDLF for The Danish
EPA.
The trend shown in Table 4.1 for the non-PVC-products, is a
decline in the consumption of phthalates. Concerning the PVC-products the
general trend is difficult to deduce from Table 4.1. According to the
suppliers the overall consumption is at the moment increasing but within
the near future it is ex-pected to decline.
The consumption of phthalates
is slightly increasing in the EU as a whole, stagnant in northern Europe,
and decreasing slowly in Denmark (Hansen and Havelund, 2000).
4.2 Selection of substitute substances
In the following the background for the selection of the 11 substitutes
for phthalates is described. In Table 4.2 a total of 18 compounds are listed
that, in variable degree, all are potential substitutes for phthalates.

5 chemical compounds (substitutes), and
6 groups of substances.

Within each of the 6 groups, one specific substance has been
selected as marker for the group.
The primary source of information
is the industry and the initial information from The Danish Product
Register.
To get an impression of how the substitution will take
place selected indus-trial organisations have been contacted.
Suppliers and users of phthalates and/or have been contacted to give
an estimate of how a complete substitu-tion of phthalates 5 years
from here can be predicted.
The same substance will not substitute
phthalates in all applications. The substitution will within the
different applications take place by a distribution of substitutes.
Estimates of this distribution are given in the substitution matrix
in Table 4.5 and Table 4.6.
In Table 4.2, a short description of the
selection of substitutes for phthalates for various applications is
given.
Table 4.2 The plasticiser substitutes and suggestions for example
substances in the groups of plasticisers. Other possible substitutes are
shown in italics.

Group of

plasticiser

Name of substance

CAS No.

Adipate

Diethylhexyl adipate

103-23-1

Diisodecyl adipate

27178-16-1

Diisooctyl adipate

1330-86-5

Citrate

O-acetyltributyl citrate

77-90-7

Phosphate

Di(2-ethylhexyl) phosphate

298-07-7

Tri(2-ethylhexyl) phosphate

78-42-2

Mellitate

Tri-2-ethylhexyl trimellitate

3319-31-1

Alkylsulphonic acid esters

o-Toluene sulfonamide

Toluene ethylsulfonamide

88-19-7
8047-99-2

Butane esters

2,2,4-trimetyl-1,3-pentanediole diisobutyate (TXIB)

6846-50-0

Polyester

No suggestion from industry

-

Epoxyester and epoxydised oils

No suggestion from industry

-

Benzoate

Dipropylene glycol dibenzoate

27138-31-4

Diethylene glycol dibenzoate

120-55-8

Triethylene glycol dibenzoate

120-56-9

Sebacate

Dioctyl sebacate

122-62-3

Dibutyl sebacate

109-43-3

The Danish Product Register has conducted a search on these CAS No.s and
a general search to identify which CAS No.s are registered in Denmark as
plasticisers.
The result of the general search was that approx. 180
different substances are registered as plasticisers. These were screened
with respect to their uses, and only a minority was found to be relevant
substitutes for phthalates.
Reduction of the list in Table 4.2 has been
performed based on information from the industry, the result of
comprehensive information on use patterns from The Danish Product Register,
and assessment of the data availability regarding toxicological and
ecotoxicological information necessary for the assessment.
4.2.1 Assessed substitutes for phthalates -
substances
The plasticisers assessed are those for which most information is
expected to be available for the environmental and health assessment and
which have a use pattern involving high PVC volume and/or expected high
exposure of humans and/or the environment. The substances are listed in
Table 4.3.
Table 4.3 Substances used for the environmental and health
assessment.

Chemical group

Name of substance

CAS No.

Suggested by DEPA

Identified in Hansen and Havelund (2000)

Plasticiser according to the PR

Known actual application

Adipates

Diethylhexyl adipate

103-23-1

Compound

+

+

Broad application in PVC and non-PVC

Citrates

O-acetyl tributyl citrate

77-90-7

Compound

+

+

PVC, printing ink and concrete products

Phosphates

Di(2-ethylhexyl) phosphate

298-07-7

Compound

-

-

Broad application in PVC

Tri(2-ethylhexyl) phosphate

78-42-2

Compound

+

+

Paint, glue and adhesive

Mellitates

Tri-2-ethylhexyl trimellitate

3319-31-1

Compound

-

-

Broad application in PVC

Alkylsulphonic acid esters

O-toluene sulfonamide

88-19-7

Group

-

-

Substance proposed by suppliers

Butane esters

2,2,4-trimethyl1,3-pentandioldiisobutyrate
(TXIB)

6846-50-0

Group

+

+

Printing ink, paint, glue, adhesive and concrete
products.

Polyesters

Polyadipates

-

Group

-

-

Foils, substance proposed by Industry

Epoxy esters and epoxidized oils

Epoxidised soybean oil

8013-07-8

Group

+

+

Printing ink, paint, glue and adhesive

Benzoates

Dipropylene glycol dibenzoate

27138-31-4

Group

+

+

Glue, adhesive

Sebacates

Dioctyl sebacate

122-62-3

Group

+

+

Printing ink and glue

No specific substance to be used as a marker for
polyester-substitutes has been identified in PR or from suppliers. The
industry has emphasised that these substances may become important and
the branch organisation has suggested polyadipate as an example
substance. However, no information on health or environmental properties
has been identified on this substance or group during the present
project.
4.2.2 Assessed substitutes for flexible PVC -
materials
Polyethylene (PE) and polyurethane (PU) are both materials which
are identified as possible substitutes for flexible PVC in a number of
products and they thereby contribute to the overall substitution of
phthalates. The two materials polyurethane and polyethylene substitute the
PVC polymer as such and not only the plasticiser additive. Both materials
are polymers.
The two alternative materials PE and PUR

In this study low density polyethylene (LDPE) rather than high density
polyethylene (HDPE) is selected for the environmental and health
assess-ment, since it is expected that LDPE will substitute plasticised PVC
in the main uses in toys and garden hoses.
PU is expected to substitute
plasticised PVC in waterproof cloths, shoes, boots and waders, and PUR based
on the diphenylmethane-4,4'-diisocyanate (MDI) monomer is selected for the
environmental and health assessment.
LDPE and HDPE

Industrial polyethylenes are thermoplastics, which exist in different
ver-sions. Low-density versions (LDPE and Linear LDPE) are produced in
branched forms in a structure with long and short branches respectively.
LDPE is therefore only partly crystalline and the polymer is highly
flexible. Principal uses include packaging film, waste bags and soft type
plastic bags, tubes, agricultural mulch, wire and cable insulation, squeeze
bottles, house-hold items, and toys. LDPE has already substituted flexible
PVC in the majority of household packaging products, and the potential for
substitution is therefore greater for other product groups like toys.
High density versions (HDPE) are produced in linear forms which allow the
polymer chains to pack closely together. This structure results in a dense
and highly crystalline material of high strength and moderate stiffness.
Principal uses include bottles, pails, bottle caps, packaging, household
appliances, and toys. Because of the strength and stiffness HDPE is more
commonly used for industrial products compared to household products and
consumers in general are more likely to be exposed to LDPE than HDPE. LDPE
and HDPE are assumed comparable with regard to effects on environment and
health.
HDPE is used for toys of rigid materials, but the proportion of toys
manu-factured from LDPE compared to HDPE is not known. It has been suggested
that the two PE polymers have an equal share of toy market, and it is
as-sumed that LDPE may lead to higher exposures than HDPE.
Polyurethanes

Polyurethanes cover a broad range of synthetic resinous, fibrous, or
elasto-meric compounds belonging to the family of organic polymers made by
the reaction of diisocyanates with other difunctional compounds such as
glycols (polyols). Polyurethanes are one of the most versatile of any group
of plas-tics, capable of an almost infinite number of variations in
chemistry, struc-ture and application. Polyurethanes can be produced as a
foam, in solid form, as an elastomer, coating, adhesive or binder. Foamed
polyurethanes form about 90% by weight of the total market for
polyurethanes, but there is also a wide range of solid polyurethanes used in
many diverse applications.
By itself, the polymerisation reaction produces a
solid polyurethane. Polyu-rethane foams are made by forming gas bubbles in
the polymerising mixture, which is achieved by using a blowing agent.
MDI

MDI is one of the most important raw materials to make polyurethane.
MDI can be grouped into polymeric MDI, which in the form of foam is
being used for several heat protection materials, motor car seats, etc.,
and mono-meric MDI, being used for shoe soles, coating materials,
synthetic leather, etc.
Because of the health risks ascribed to
monomeric diisocyanates, much at-tention is paid to the physico-chemical
and toxicological properties of the monomer in situations where
substitution with a polyurethane is required.
MDI has a particularly low
vapour pressure compared to TDI (toluene diiso-cyanate), HDI
(hexamethylene diisocyanate) and IPDI (isophorone diiso-cyanate ) and is
under European legislation classified as harmful whereas the other
mentioned diisocyanates are classified as toxic. This often makes MDI a
better choice where it is technologically feasible.
MDI is already used
in the production of PU for waterproof clothes, shoes, boots and waders,
application areas, which are suggested for substitution of flexible PVC
in the substitution matrix, and is therefore selected to the health and
environmental assessment.
4.3 Proposed use pattern for substitutes
The Danish Product Register (PR) has been used to establish an
overview of the function of phthalates in chemicals until now. The
Register mainly con-tains information about chemicals and to a lesser
extent about materials.
The historical main use of phthalates in
Denmark, summarised in Table 4.1, forms the basis for the search for
relevant alternatives in the PR.
The most important function of
phthalate has until now been plasticising, but besides this function
phthalates had have the function of being denatur-ants in cosmetics
(Hoffmann, 1996).
The PR has conducted a search to identify the
plasticisers used in selected types of chemical products or materials.
The result is illustrated in Table 4.4 for the first 10 that are the
substances selected for the assessment. The Poly-ester was not included
due to lack of CAS no.
Table 4.4 The registered use of the selected substances as
plasticisers in the selected product groups. Data from the Danish
Product Register. The polyester plasticiser (polyadipate) was not
included due to lack of CAS no. Materials such as cables, profiles,
floor and wall covering are not covered by the PR.

CAS No.

Name

Fillers

Paint and lacquers

Adhesives

Printing inks

Plastic in Concrete

Rubber products

PVC packaging

103-23-1

Di(ethylhexyl) adipate

·

·

·

·

·

77-90-7

O-acetyl tributyl citrate

·

·

298-07-7

Di(2-ethylhexyl) phosphate

78-42-2

Tri(2-ethylhexyl) phosphate

·

·

·

·

3319-31-1

Tri-2-ethylhexyltrimellitate^a

88-19-7

Alkylsulfonic acid ester^a

6846-50-0

2,2,4-trimethyl 1,3-pentanediol diisobutyrate (butane ester)

·

·

·

·

· ^b

8013-07-8

Epoxidised soybean oil

·

·

·

·

·

27138-31-4

Dipropylene glycol dibenzoate

·

122-62-3

Dioctyl sebacate

·

a Not found in the Product Register.

b Unclear whether 'plast' is PVC
Not all substances are registered as plasticisers in the selected
products. This has to be seen in the light of the fact that the register
only contains informa-tion about substances classified dangerous to the
environment or the health. The result of the search is therefore as
mentioned earlier supplemented with industrial information about the
development of plasticisers not containing phthalates.
4.3.1 Substitution matrix for the 11 substances in
tons
By using the amounts found within the different applications in the
sub-stance flow analyse (Hoffmann, 1996) and the proposed %-distribution of
the alternatives in Table 4.5, the following "amount-substitution
matrix" shown in Table 4.6 within the different applications can be
established.
Table 4.5 Substitution matrix for the 11 substances with anticipated
share given in %.
Note: It is only relevant to ad up the figures horizontal and not
vertically because each row describe the substitution within one
application. One column rep-resents non-comparable figures.
Based on information from the industry, Table 4.6 represents the best
pres-ent estimate on substitution of phthalates within different types of
products. The dominating amount is for each substance marked in bold. The
informa-tion is primarily based on interviews with industry sources rather
than trade bodies, since only little overview information is available.
This
best present estimate has to be seen in the light of the situation in which
all phthalates in a product are substituted by only one substitute.
The
actual substitution five years from now, will presumably not be exactly as
illustrated in Table 4.6, but the information indicates in which areas the
substances might be used extensively and in which areas the use is expected
to be negligible.
It should be emphasised that a large portion of the
expected use is placed in "Other applications of PVC" (e.g. toys).

Another scenario is that one substance substitutes the phthalates 100%
within an application area (a 'worst worst case').
Table 4.6 Substitution matrix for the 11 substances (in tonnes)

Application

Tons phthalates per year (1992)

Diethylhexyl adipate, CAS no. 103-23-1

O-acetyltributylcitrate, CAS no. 77-90-7

Di(2-ethylhexyl)phosphat, CAS no. 298-07-7

Tri(2-ethylhexyl)phosphat, CAS no 78-42-2

Tri-2-ethyl trimellitate, CAS no. 3319-31-1

Toluene sulphonamide, CAS 88-19-7)

2,2,4-trimethyl 1,3-pentanediol diisobutyrate, CAS no.
6846-50-0

Epoxidised soybean oil, CAS no. 8013-07-8

Polyester

Dipropylene glycol dibenzoate, CAS no. 27138-31-4

Dioctyl sebacate, CAS no. 122-62-3

Other substanes and materials

Hospital sector

350

88

53

70

70

35

35

Packaging

350

53

53

70

35

18

53

35

35

Cables

3,000

90

750

900

840

30

120

30

240

Profiles

80

16

12

12

8

12

12

8

Floor and wall covering

1,500

450

300

300

150

150

150

Other application of PVC

4,190

838

251

838

838

838

42

545

Lacquer and paint

225

23

23

23

68

90

Printing ink

270

54

81

27

54

54

Adhesive

220

22

11

22

44

33

44

44

Filler

400

40

80

40

20

60

160

Other applications e.g. in the following products:

Rubber

50

25

25

Concrete

50

5

25

5

3

13

Silicone

50

50

Sum (max.)

10,735

1,704

554

2,040

2,245

1,854

30

465

251

93

204

110

1,190

4.3.2 Substitution matrix for the two materials
In view of the general phase out policy for PVC the substitution of
phtha-lates may obviously take place exchanging the PVC-material by other
mate-rials that do not need to be plastified with phthalates. However, PE
and PU cannot substitute flexible PVC across-the-board, but as seen in
substitution matrix Table 4.7 PE and PU are possible substitutents for
flexible PVC in different kinds of products:

PE will mainly substitute flexible PVC in toys
PU will mainly substitute flexible PVC in waterproof clothes,
shoes, boots and waders.

Using the same procedure as for the 11 substances, but with the
1994-inventory from The Danish Plastics Federation of the consumption
of plasti-cised PVC, a substitution matrix for the PVC-substituting
materials can be established as in Table 4.8
Table 4.7 Substitution matrix for selected flexible PVC products in
% of the total amount plasticised PVC (tonnes).

Application

Tons plasticised PVC

Ethylene-vinyl-acetate (EVA)

EPDM rubber

Polyethylene (PE)

Polypropylene (PP)

Cardboard and paper

Leather

Polyurethane (PUR)

Nylon

Neoprene rubber

Natural rubber

Wood

Other

Sum (100%)

Garden hose

450

60

30

10

100

Office supplies

3,500

75

20

5

100

Toys

1,130

30

30

30

10

100

Waterproof clothes

260

80

20

100

Shoes

200

20

50

5

20

5

100

Boots and waders

380

30

5

60

5

100

Sum

5,920

*

*

*

*

*

*

*

*

*

*

*

*

*

*: The vertical sum across different applications of PVC is not
relevant to cal-culate. It is only the horizontal sum within the same
application, which is relevant to calculate because it is describing
the situation within one spe-cific application and has to add up to
100%.
Table 4.8 Substitution matrix for alternative materials to flexible
PVC. The unit is tons.

Application

Tons plasticised PVC

Ethylene-vinyl-acetate (EVA)

EPDM rubber

Polyethylene (PE)

Polypropylene (PP)

Cardboard and paper

Leather

Polyurethane (PUR)

Nylon

Neoprene rubber

Natural rubber

Wood

Other

Sum (100%)

Garden hose

450

270

135

45

450

Office supplies

3,500

2,625

700

175

3,500

Toys

1,130

339

339

339

113

1,130

Waterproof clothes

260

208

52

260

Shoes

200

40

100

10

40

10

200

Boots and waders

380

114

19

228

19

380

Sum

5,920

609

135

339

2,964

700

215

422

10

19

268

239

5,920

As for the 11 substances, the information from the industry in
Table 4.8 rep-resents the most likely substitution of phthalates
within different types of PVC-products. The dominating amount for each
material is marked in bold.
Again, the substitution five years from
now, will presumably not be exactly as illustrated in Table 4.8, but
the information indicates in which areas the materials might be used
extensively and in which areas the use is expected to be negligible.

The worst case scenario is when one material substitutes the
plasticised PVC 100% within an application area.
As seen in Table 4.8,
polyethylene is most likely going to substitute 339 tons flexible PVC
in toys. With an average concentration of phthalates in soft-PVC toys,
similar to 34%, the 339 tons PVC represent 115 tons phthalates.

Polyurethane is, as shown in Table 4.8, the mayor substitute for PVC
in waterproof clothes. It is therefore of special interest to
undertake an EUSES-calculation on the 208 tons flexible PVC, which may
contain up to 100 tons phthalates.
4.4 Assessment of emission and exposure
Data compilation for substitution matrix

The qualitative information from suppliers of phthalates and the
alternative substances is based on an assumed complete substitution of
phthalate in the mentioned applications in the near future (a five year
perspective).
In Table 4.5 and Table 4.7 the qualitative information is
transferred to quantitative figures in percent. These figures form a
possible scenario for how the complete substitution can take place. It will
probably not corre-spond to the real situation in five years time, but it
illustrates where the use of a substance might be extensive and where the
use might be negligible. This overview is useful in connection with
evaluation of results from calcu-lations in EUSES and in connection with
priority of efforts of the environmental regulating authorities.
The 11
substances and the 2 materials in this project are regarded as the main
basis for the complete substitution for phthalates.
According to discussion
with the organisations listed in the Appendix, the most likely way to
substitute phthalates is illustrated in the following sub-stitution matrixes
Table 4.5 and Table 4.7.
Substitution matrix for the 11 substances in %

The consumption of phthalates within the relevant applications is
based on substance flow analyses covering the situation in 1992
(Hoffmann, 1996). In Table 4.5, the share of 11 substances for the
substitution of the phthalates within each application is estimated in
%.
According to the Danish Plastics Federation, flexible PVC is not used
in packaging, today. The actual consumption of phthalates for this
purpose is therefore estimated to be of minor importance.
The first five
substances are expected to substitute phthalates directly. The next six
are selected as markers for chemical groups from which substitutes are
expected to be identified in the near future. Meanwhile the six markers
are used to calculate a scenario for substitution of phthalate.
Other
substances and materials cover less important substitutions, conducted
by other means than the 11 substances. Examples could be substances not
covered by the 11 substances in Table 4.6, or new technology in the
produc-tion of the mentioned products. The new technology could be the
use of new materials without the need for plasticising with phthalates.

The point of origin of Table 4.5 is the Danish consumption of phthalates
in 1992 shown in Table 4.1 (Hoffmann, 1996). These data are selected
because they are the result of a comprehensive survey, and the studies
conducted later, confirm the amounts and the indicated development
trends within the different applications. For the non-PVC products a
decline in the use of phthalates has been identified (Hansen and
Havelund, 2000). For the PVC-products the suppliers expect a decline in
the near future.
The background for the ratios in Table 4.5 is
information gathered in con-nection with one of the substitution
projects initiated by the Danish Envi-ronmental Protection Agency. It is
the general impression among suppliers and users of phthalates that a
complete substitution will be possible for both PVC and non-PVC
products. Available substitutes for non-PVC products have been
identified earlier (Hansen and Havelund, 2000).
Table 4.9 Estimated use of the substitutes. These volumes are used
for consumer expo-sure

Name of substitute

Expected most relevant application

Expected used amount for the substitution in
tons per year

Di(2-ethylhexyl) phosphate, CAS No. 298-07-7

Cables

750

Tri(2-ethylhexyl) phosphate. CAS No. 78-42-2

Cables

900

Tri-2-ethylhexyltrimellitate, CAS No. 3319-31-1

Cables

900

Alkylsulfonic acid ester (toluene sulphonamide, CAS 88-19-7)

Cables

30

Diethylhexyl adipate, CAS No. 103-23-1

Floor and wall covering

450

Butane ester (2,2,4-trimethyl 1,3-pentanedioldiisobutyrate, CAS
No 6846-50-0)

Floor and wall covering

150

Epoxidised soybean oil (CAS No. 8013-07-8)

Lacquer and paint

70

o-Acetyl tributyl citrate, CAS No. 77-90-7

Toys

250

Dioctyl sebacate (CAS No. 122-62-3)

Printing ink

50

Polyester

Fillers

60

Dipropylene glycol dibenzoate (CAS No. 27138-31-4

Fillers

160

4.4.1 Considerations regarding specific uses of
phthalates/substitutes
Industrial processes

There is no synthesis of phthalates or substitutes for phthalates in
Denmark.
The synthesis of phthalates for the Danish market is at the moment
mainly conducted in Sweden. The identified substitutes are expected also to
be synthesised in countries outside of Denmark.
The main source to emissions
and exposures in Denmark is expected to be from formulation of products
containing plasticisers such as plasticised PVC, printing inks, adhesives
and fillers. For paints and lacquers there is also an emission and exposure
from the professional use of the products.
Based on the substitution matrix
focus in this investigation has been set on the use of the eleven substances
with known potential application the fol-lowing process:

Use of di(2-ethylhexyl) phosphate (CAS
No. 298-07-7), tri(2-ethylhexyl) phosphate (CAS No. 78-42-2),
tri-2-ethylhexyltrimellitate (CAS No. 3319-31-1) and alkylsulfonic
acid ester (toluene sulphona-mide, CAS No 88-19-7) in the production
of cables

Use of butane ester diethylhexyl adipate
(CAS No. 103-23-1), (2,2,4-trimethyl 1,3-pentanediol diisobutyrate,
CAS No 6846-50-0) in the pro-duction of floor and wall covering

Professional use of epoxidised soybean
oil (CAS No. 8013-07-8) con-taining lacquer and paint products

Use of o-acetyl tributyl citrate (CAS
No. 77-90-7) and dioctyl sebacate (CAS No. 122-62-3) in the
production of printing inks.

Use of polyester and dipropylene glycol
dibenzoate (CAS No. 27138-31-4) in the production of fillers.

In general, uses of the products are
regarded as diffuse and as minor sources to emission, but concerning
consumer exposure of the 10 substances there are relevant scenarios that
are described in Section 5.4.
Human exposure is estimated mainly to take
place in connection with:

Formulation process.
Uses of the products

To illustrate the potential human exposure
from the 10 well defined sub-stances a calculation in EASE, which is
based on the principles in the TDG has been conducted.
EASE calculates a
theoretical exposure of humans in the working environ-ment and private
consumers.
The input data takes point of origin in the scenarios in
Table 4.10, which is assessed to represent the most extensive exposure.
Table 4.10 Exposure scenarios of the 11 substances

Name of
substance

Scenarios

Working environment

Consumers

Diethylhexyl adipate

(CAS 103-23-1)

Production of follies to floor and wall coverings

Use of floor and wall coverings in bathrooms

o-acetyltributyl citrate

(CAS 77-90-7)

Production of printed papers

Daily use of printed papers

Di(2-ethylhexyl)phosphate

(CAS 298-07-7)

The well defined step in the production of cables which is the
exposure just after the extrusion of cables and before the cooling
in water

Contact with cables in a private house

Tri(2-ethyl)phosphate

(CAS 78-42-2)

The well defined step in the production of cables which is the
exposure just after the extrusion of cables and before the cooling
in water

Contact with cables in a private house

Tri-2-ethylhexyltrimellitate

(CAS 3319-31-1)

The well defined step in the production of cables which is the
exposure just after the extrusion of cables and before the cooling
in water

Contact with cables in a private house

o-Toluene sulphonamide

(CAS 88-19-7)

The well defined step in the production of cables which is the
exposure just after the extrusion of cables and before the cooling
in water

Contact with cables in a private house

2,2,4-trimethyl 1,3-pentanediol diisobutyrate (CAS 6846-50-0)

Production of follies to floor and wall coverings

Use of floor and wall coverings in bathrooms

Epoxidised soybean oil

(CAS 8016-11-3)

Professional painting in a room without ventilation

Stay in a painted house and conducting painting once a year

Polyester

Production of fillers

Stay in a bathroom with fillers

Dipropylene glycol dibenzoate

(CAS 27138-31-4)

Production of fillers

Stay in a bathroom with fillers

Dioctyl Sebacate

(CAS 122-62-3)

Production of printing inks

Half an hour interior reading in printed papers

To approach a situation five years from now the exposure calculation in
EUSES is therefore conducted for both the most likely situation
represented in bold figures and the 100%-scenario.
4.4.2 Worker and consumer exposure
Assessment of the exposure of humans in the working environment and
con-sumers has been conducted using the model Estimation and Assessment of
Substances Exposure Physico-chemical Properties (EASE), which is a part of
the model European Union System for the Evaluation of Substances (EUSES).
Limitations and uncertainties of the EASE

The equations in EASE are intended to provide a simple description of
con-sumer exposure. Most equations give a worst case estimation of exposure,
by assuming that all of the compound in the product is at once available for
intake and uptake. Intake and uptake themselves are modelled as simple
fractions.
Workers exposure

EASE provides a general-purpose predictive model for exposure
assessment in the workplace. The model predicts external exposure only: it
does not take into account absorption and bioavailability.
If reliable and
representative measured data are available these can be used to overwrite
the model results. The general-purpose model is called EASE (Estimation and
Assessment of Substance Exposure) which is described in details in Section
2.2 of the TGD.
EASE was specifically developed for the purpose of modelling
inhalation and dermal workplace exposure across a wide range of
circumstances.
EASE is an analogue model, i.e. it is based on measured data
which are as-signed to specific scenarios. The user can build scenarios by
choosing be-tween several options for each of the following variables:
physical proper-ties during processing (tendency to become airborne,
potential for dermal contact), use pattern and pattern of control. Numerical
ranges have been as-signed using measured data contained within the UK
National Exposure Database for inhalation exposure, and experimental data
and expert judge-ment for dermal exposure.
The data used to assign ranges
within the model are all 8-hour time weighted averages and the numbers
generated by the model are only valid when the exposures being assessed can
be related to such averages.
The output of EASE is numerical ranges of
concentrations or ppm. These are converted from ppm to kg.m-3 and can be
used as input for risk charac-terisation in which the exposure estimates are
compared to the results of the human effects assessment.
Consumer-exposure

The consumer, i.e. a member of the general public who may be of any
age, either sex, and in any stage of health may be exposed to chemical
substances by using consumer products.
A consumer product is one, which
can be purchased from retail outlets by members of the general public and
may be the substance itself, or a prepara-tion, or an article containing
the substance.
The EASE equations for consumer exposure can be used to
estimate exter-nal exposure substances used as or in consumer products.
Absorption or bioavailability is not taken into account by the equations
implemented in EASE.
The focus in EASE is on substances used indoors for a
relatively short pe-riod of time per event (such as e.g. a carrier/solvent
in a cosmetic formula-tion; a powder detergent).
The equations in the
model apply to both volatile substances and airborne particulates. It is
assumed the substance is released as a vapour, gas, or air-borne
particulates, and the room is filled immediately and homogeneously with
the substance. Ventilation of the room is assumed to be absent.
The
equations can also be adapted to estimate exposure arising from
'rea-sonably foreseeable misuse', i.e. when products are not used
according to the instructions, but as if they were other, allied products.

To adapt the equations, the values for the parameters used in the
equations are changed to reflect values foreseen in "reasonably
foreseeable misuse". For example, the volume of product or the area
of application is set to a dif-ferent value, reflecting reasonable
foreseeable misuse.
If a substance is released relatively slowly from a
solid or liquid matrix (e.g. solvent in paint, plasticiser or monomer in a
polymer, fragrance in furniture polish), the equation in EASE acts as a
worst case estimation, estimating the maximum possible concentration.
Dermal

The calculation in EASE has in this investigation been operating with
two scenarios concerning dermal exposure: A and B
Dermal A: a substance contained in a medium. This dermal scenario also
applies to

a non-volatile substance in a medium used without further dilution
(set dilution D=1), and
a non-volatile substance in a volatile medium.

The assumption behind the equations in the calculations is that all of
the substance on the skin is potentially available for uptake. This is the
case when the medium is well mixed or only present as a thin film on the
skin. The dermal equations apply for:

a non-volatile substance in a diluted product,
a non-volatile substance in a medium used without further dilution,
and,
a non-volatile substance in a volatile medium.

Dermal B: a non-volatile substance migrating from an article (e.g. dyed
clothing, residual fabric conditioner, dyestuff/newsprint from paper).
The
assumption behind the equation is that only part of the substance will
migrate from the article (e.g. dyed clothing, residual fabric conditioner,
dye-stuff/newsprint from paper) and contact the skin. The migration is
assumed to be slow enough to be represented by a constant migration rate
multiplied by the time of contact.
The exposure calculation will involve
estimating the amount of substance which will migrate from the area of the
article in contact with skin during the time of contact. Dyestuff amounts
in fabrics and paper are usually given as weight of product per unit area
(e.g. mg/m2).
Oral

The calculation concerning oral exposure has also been operating with
two scenarios: A and B.
Oral A: a substance in a product unintentionally
swallowed during normal use (e.g. toothpaste).
The exposure equations may
also be used to estimate exposures arising from ingestion of the
non-respirable fraction of inhaled airborne particulates.
The equations
may also be used to estimate exposures arising from ingestion of the
non-respirable fraction of inhaled airborne particulates.
Oral B: a
substance migrating from an article into food or drink (e.g. plastic film,
plastic-coated cups/plates).
It is assumed that the substance in a layer
of thickness of article (e.g. plastic film, plasticcoated cups/plates) in
contact with the food will migrate to the food. The migration rate is
assumed to be constant, and the migration rate multiplied by the contact
duration is the fraction of substance that is migrated to the food. The
equation can be used to give a conservative estimate of substance uptake
by a defined volume of food. The value of the migration rate will be
influenced by the type of food (e.g. fatty/dry/moist), the period of
exposure and the temperature at which it occurs. Consumer exposure level
will also be influenced by the proportion of contaminated food eaten.
Use pattern scenarios

Based contacts to the Danish industry and the substance flow analyse
(Hoffmann, 1996) relevant scenarios has been identified and are described
in section 4.3.
The background for choosing scenarios is the most likely
way of substitu-tion described by industrial actors and rendered in the
substitution matrix in Table 4.5. Within the substitution matrix the
application representing the largest estimated consumption of each
substitute is selected as the most relevant scenario. This application is
marked in bold figures in the substitu-tion matrix.
The input data for the
calculation are the substitution matrix and scenarios with the largest
estimated consumption substitute for phthalate plasticisers.
With point of
origin in the substitution matrix the substances are distributed in the
following most relevant application areas.
Plasticisers in the
"Cables"-application are expected to be:

Di(2-ethylhexyl) phosphate, CAS No. 298-07-7
Tri(2-ethylhexyl) phosphate. CAS No. 78-42-2
Tri-2-ethylhexyltrimellitate, CAS No. 3319-31-1
Alkylsulfonic acid ester (o-toluene sulphonamide, CAS No 88-19-7).

For the production of "floor and wall covering" the
following plasticisers are chosen:

Diethylhexyl adipate, CAS No. 103-23-1
Butane ester (2,2,4-trimethyl 1,3-pentanediol diisobutyrate, CAS
No 6846-50-0).

Concerning the production of lacquer and paint the focus is on:

Epoxidised soybean oil (CAS No. 8013-07-8).

In connection with printing ink the relevant substances are estimated
as:

O-acetyl tributyl citrate, CAS No. 77-90-7
Dioctyl sebacate (CAS No. 122-62-3).

The production of "fillers" is assumed to include:

Polyester
Dipropylene glycol dibenzoate (CAS No. 27138-31-4).

The scenarios in EASE for the consumer exposure are based on the
amounts for these uses and the exposure characteristics for the
application.
4.4.3 Exposure in environment

Substance parameters

For each substance the required input parameters molecular weight,
octanol-water partition coefficient, water solubility, vapour pressure and
physical state were fed to the model in accordance with the data search
and evaluation.

Two types of assessments were performed for each
substance substituting phthalates. One scenario simulates the best
educated guess for the future share that this particular substance would
gain in the market based on inter-views with the industry. The second
assessment simulates the hypothetical situation where only one of the
alternatives (100% substitution case) sub-stitutes the entire tonnage of
phthalates.
In the 100% substitution case it is chosen to base the
estimates on the most recent inventory of the phthalates in PVC and use
the sum used in 1992 (10,735 tons). In various applications substitutes
may be used in different volumes than the phthalates - if 1 kg new
substance can substitute 2 kg phthalate or vice versa. Since the available
information on this is very in-complete it has been decided not to try to
include such information in the calculations.
The physical parameters of
some of the compounds are out of the advised range in which EUSES
operates. In the cases where the physical parameters are out of the
pre-set range (e.g. logPow > 6) or unknown as melting and boiling point
sometimes are, it has been chosen to use the nearest maximum or minimum
value as suggested in EU TDG or use a worst case approach.
All results are
presented in the report with two significant digits rounded off from the
EUSES calculations with three significant digits (given in appen-dix).
The
assessment of emission to the environment and exposure of man and biota
from environmental concentrations of phthalate alternatives are based on
the procedures outlined in the EU TGD (EU Commission 1996). The actual
concentrations are calculated by using the PC program EUSES (European
Chemicals Bureau 1996), which is designed to provide decision support for
the evaluation of the risks of substances to man and the envi-ronment
based directly on the EU TGD.
In the present evaluation EUSES is operated
in three of the possible five modes. Parameters are entered for:

Environmental assessment,
Predators exposed via the environment and
Humans exposed via the environment.

EUSES will calculate concentrations and doses for the assessment on
three spatial scales: the local (point source), the regional (small and
densely in-habited country) and the continental (Europe). The default
regional scale has been changed to suit Danish conditions (see below). The
local and conti-nental scenarios are included in the calculations, but no
specific values have been entered.
The EUSES program calculates
environmental exposure based on 1) a physical scale where the use and
emission takes place, 2) the use and emis-sion pattern of the substance
and 3) on substance specific parameters. The specific parameters for each
substance are provided for each exposure esti-mation. To assist the
comparison between substances the physical dimen-sions of the scenario and
the overall industrial use and emission pattern has been set identical for
all substances.

Use and emission scenarios

The use and emission scenarios rely on the database of emission
scenario documents for a number of industrial uses included in EUSES. The
follow-ing settings have been used to represent the primary use of
phthalate alter-natives:

Emission input data

No.

Name

Industry category

11

Polymers industry

Use category

47

Softeners

Main category (production)

III

Multi-purpose equipment

Main category (formulation)

III

Multi-purpose equipment

Main category (processing)

IV

Wide dispersive use

Danish regional scenario

The physical dimensions of the regional scenario have been set at
values representative for Denmark, those changed are shown in Table 4.11
(a com-plete list of parameters can be found in the Appendix). The values
were taken from the evaluation of the SimpleBox Model for Danish
conditions (Miljostyrelsen 1995).
Table 4.11 Parameters of the EUSES model, which were adapted to Danish
conditions

Parameter

Value

Units

Fraction of EU production volume for region

0.05

[-]

Fraction connected to sewer systems

0.9

[-]

Environmental temperature

7.7

[^oC]

Volume fraction water in soil

0.4

[m3.m-3]

Weight fraction of organic carbon in soil

0.025

[kg.kg-1]

Number of inhabitants of region

5.30E+06

[eq]

Wind speed in the system

5

[m.s-1]

Area of regional system

4.30E+04

[km2]

Area fraction of water of the regional system

0.011

[-]

Area fraction of natural soil

0.332

[-]

Area fraction of agricultural soil

0.647

[-]

Area fraction of industrial/urban soil

0.01

[-]

Suspended solids concentration of regional system

17.7

[mg.l-1]

Net sedimentation rate

8.22

[mm.yr-1]

Average annual precipitation

735

[mm.yr-1]

Fraction of rain water infiltrating soil

0.46

[-]

Calculate dilution from river flow rate

No

Mixing depth of grassland soil

0.05

[m]

Mixing depth agricultural soil

0.2

[m]

4.4.4 Migration potential
A key parameter in comparing various plasticisers is their potential
for mi-grating out of the PVC polymer. Only few data has been identified
on mi-gration potential for the substitutes. The information on migration
potential will be used in the expert assessment process, but is not used
in the exposure calculation model.
To determine the total migration
potential various reference methods are used which all are available as
CEN standards (ENV 1186-1 - ENV 1186-12). Several new standards in this
area are in preparation.
In general the methods are divided in two
categories: Migration from plastic to an oily extractant and migration
from plastic to an aqueous solution.
To determine the total migration
potential using the two groups of methods either a double sided test
(total submergence of plastic piece) or a single sided test (using a
migration cell or by incorporating the plastic piece into a bag) is
performed.
The total migration potential is determined as the difference
in weight be-fore and after extraction or as weight of the evaporation
residue of the ex-tractant.
The 3 commonly water based extractants are
distilled water, 3% acetic acid and 10 % ethanol. Since most plasticisers
are lipophilic it is most relevant to express the migration as migration
from plastic to fat containing food. As fat simulator olive oil is the
commonly used.
The amount of plasticiser extracted is extractant
dependent and usually the extraction time of olive oil and 95% ethanol is
10 days at 40 °C and for iso-octane 2 days at 20 °C.
The difference in extraction
time is due the extraction power of each ex-tractant and the ability of
the extractant to make the plastic swell. When the plastic swells the dept
of the layer in contact with the extractant increases and the amount of
platisicer extracted increases.
The extraction power of the
extractant types depends on the plastic type that is investigated, but
usually, when considering plastics that contains lipo-philic plasticisers
the order extraction power is: isooctane > olive oil > etha-nol..

5 Health and environmental assessment for compounds
Datasheets for the assessed substances appear in appendix and provide
detailed information. Here, the key data are presented and used for the
assess-ment. The results of the exposure and dose calculations performed
with EUSES are presented in tables. The selected scenarios cover consumer
exposure, exposure in the workplace and exposure from the environment. In
the tables presenting regional concentrations Surface_t and
Surface_d
denotes concentration of the substance in the total water and in the
dissolved phase, respectively.
The toxicity data selected for the
assessment of human toxicity are primarily observations in humans (where
available) and test results from standard animal tests used in
classification of chemical substances in accordance with the EU Substance
Directive (EEC 1967). In presenting human toxicity data the tables contain
what is considered the core data regarding the effects. These and
additional data can be found in the appendix. The information used for the
evaluation is discussed in the text.
Acute toxicity, irritation,
sensitivity, subchronic toxicity and long-term ef-fects are discussed
where possible. If a NOAEL or a LOAEL is established, this estimate is
included in the assessment and also discussed in relation to the selected
exposure scenarios. If an ADI-value is established for the substances,
the calculated exposure scenarios are discussed in the light of this value
taking all possible exposure routes and situations into consideration.
The
ecotoxicity data have been selected with preference to results based on
the standard ecotoxicity test methods for algae, crustaceans and fish, as
recommended in Pedersen et al. (1995) and used in the environmental
hazard classification process. Thus, in the case where the acute test is
the 72 hours algae test (IC₅₀), 48 hours crustacean test (EC₅₀), and 96
hours fish test (LC₅₀), the result in mg/l is presented without further
explanation. If the result comes from a test of other duration or
endpoint etc, the deviation will be stated. For biodegradation the
standard test is the 28 days of readily or in-herent degradability. Unless
it is stated otherwise, all BCF data are measured, and values above 100
are considered indicative of bioaccumulative properties.
5.1 Di(ethylhexyl) adipate; 103-23-1
Adipates are (as sebacates and azalates) diesters of aliphatic
dicarboxylic acids and are produced with varying alcohol groups.
The adipates are classified as low temperature plasticisers. The
compounds of this group are all relatively sensitive to water.
5.1.1 Use, emission and exposure
Physical-chemical properties

The measured solubility of di(ethylhexyl) adipate (DEHA) in water at
20-22 º C ranges from 0.8 mg/l to <100 mg/l,
which places this substance in the group of the moderately soluble
substances investigated in this assessment.
DEHA has a measured vapour pressure at 20-25 º C ranging from 8.5 10^-7 to 2.6 mm
Hg. A value of 8.5 1 10^-5 is used
for the assessment. The magnitude of this parameter places DEHA in the
group of investigated substances that possesses a moderate to low vapour
pressure.
The estimated LogP_ow values of 4.2 to 8.1 (BUA 1996a) and
one measured value of > 6.1 (HSDB 2000) indicates that this substance
is lipophilic. The default maximum value of 6 was used for the EUSES
estimation.
Migration

The measured reduced migration potential (household cling to olive oil) of
2.6-41.3 mg/dm² indicates that DEHA have the potential of
migrating from the PVC phase to a fatty phase in contact with the PVC
(Petersen, Breindahl, 1998). In the same study other plasticisers such as
dibutyl phthalate (DBP) were shown to possess lower migration potentials
(0.2-1.1 mg/dm²) relative to DEHP.
Use pattern for compound

DEHA is the dominant compound in the group of adipates, and is mostly used
in thin clear household cling intended for food wrapping.
As seen in Table 4.6 DEHA is expected to be widely used in the near
future to in various areas such as in products for the hospital sector and
in packaging. DEHA is also expected to be used in products such as
printing inks, adhesives, fillers and products now containing various
amounts of PVC-plastic.
Exposure in work place

The EASE calculation focuses on the production of floor and wall
coverings.
The following assumptions are made with regard to the process:

a press is used for production

the temperature is 200 º C

a required legal exhaust ventilation is in place.

Possible main exposure routes in the workplace:

inhalation of vapours and aerosols
skin contact from contact with aerosols is considered to be
insignificant.

Based on this scenario, the EASE calculation gives the following
estimates of exposures shown in Table 5.1.
Table 5.1 Estimated values of DEHA in the working environment
according to the EASE calculation.

Route of exposure

EASE value

Unit

Vapour concentration in air for workers

10-50

ppm

Vapour concentration in air for workers

154-771

mg/m³

Potential dermal uptake for workers

0

mg/kg/day

Consumer exposure

The direct exposure from floor and wall coverings is estimated by an EASE
calculation and the results are shown in Table 5.2.
Table 5.2 The estimated potential daily intake of DEHA by consumers
according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio to the ADI

(0.3 mg/kg bw/d)

Inhalatory intake

4.34 x 10^-10

1.45 x 10^-7

Dermal uptake

4.56 x 10^-4

1.52 x 10^-3

Oral intake

0

0

Total chronic uptake via different routes

4.56 x 10^-4

0.0015

Total acute uptake via different routes

0

0

The broad application of DEHA means that the total exposure of consumers
from all possible sources will be higher than the values indicated in Table
5.2.
The ability of DEHA to migrate from plasticised products e.g. packing
materials to more lipophilic environments leads to the conclusion that the
potential exposure of consumers may be even larger, if DEHA is going to
substitute phthalates as described in the substitution matrixes.
Haemodialysis

Haemodialysis is selected as a second scenario for consumer exposure to
DEHA. This is the application where high exposure is identified for
bis(2-ethyl-hexyl)phthalate (DEHP) in KemI (2000).
In this scenario focussing on the use of DEHA in plasticised tubing for
haemodialysis, the concentration of DEHA in blood is estimated at 6.0 - 8.4
mg/l. This figure is reached using the following data and assumptions:
Re-circulation of PVC-tubing with humane plasma for five hours resulted in
extraction of 4.2 mg DEHA into a volume of 500-700 ml and thereby a
concentration of 6.0 - 8.4 mg/l in blood. If this amount of DEHA is
distributed to the full blood volume (5 l), the resulting concentration would
be 0.84 mg/l. This figure is probably lower than what would be expected from a
real dialysis situation, where the full blood volume is re-circulated. A more
realistic value is expected to be in the range of 0.84 - 8.4 mg/l blood after
a single treatment. This corresponds to 16.8 - 168m g/kg bw for a 50 kg person
per treatment session. Assuming three treatments per week this will correspond
to an average daily exposure of 2.9 - 72m g/kg bw/day.
Milk tubes

A special scenario has been set up for the use of DEHA in tubes used when
stripping cows.
According to (Jensen, 2000) plasticised tubes are only used for
transporting the milk 1 meter from the cow to the milk carrier system in the
stable. This tube is estimated to have a internal diameter on 1.6 cm and an
external on 1.8 cm and a length equal to 1 meter (Jepsen, 2000). This leads to
a volume of the tube equal to = 0.214 dm³ = 0.214 l. The density of
the tube is estimated to 1 kg/l leading to a weight equal to 0.214 kg. The
lifetime is assumed to be one year.
The content of DEHA is 7-40% and this is estimated to migrate from the tube
100% within the lifetime. The amount of DEHPA migrating from 1 metre of tubing
is 85,000 mg pr year.
It is assumed that the tube is used to strip 25 cows pr. year. One cow
produces 6,836 kg milk pr. year with a density of 1 kg/l.
In this scenario the minimum concentration of DEHA in the milk will be
0.088 mg/l and the maximum will be 0.50 mg/l. If a child weighing 10 kg drinks
1 litre of milk per day, the average daily intake from this source would be a
maximum of 0.05 mg/kg bw/day.
Environmental exposure of human

The amount established in the ’Usage’ section is used to calculate
exposure for a number of environmental compartments by EU TGD/EUSES. The dose
is almost completely derived from consumption of root crops. This is due to
the extraordinary high LogP_ow of DEHA leading to accumulation in
agricultural soil when sludge is used for soil amendment. No measured data are
available for accumulation in plants.
Table 5.3 The estimated human doses of DEHA through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

DEHA

Estimation (~1,700t)
Worst case (10,700t)

mg/kg/d
mg/kg/d

Drinking water

6 10^-7
4 10^-6

Fish
BCF measured
5 10^-7
3 10^-6

Plants
Leaf crops
0.00005
0.00033

Root crops
0.007
0.047

Meat

0.00011
0.00072

Milk

0.00007
0.00042

Air

1 10^-7
6 10^-7

Total regional

0.0076
0.0481

Exposure in the environment

The estimated concentration levels of DEHA reflect the low solubility in
aqueous solutions combined with a high LogP_ow and a resulting
association with particles (sediment and soils).
Table 5.4 The estimated regional concentrations of DEHA in water,
soil and air.

Compartment
Aquatic
Terrestrial

Air

DEHA
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m³

Estimation (~1,700 t)
0.000022
0.00001
0.24
0.0023
0.24
0.00002
1.9
4.5 x 10^-5

Worst case
0.00014
0.00007
1.5
0.015
1.6
0.00013
12
2.9 x 10^-6

Secondary poisoning

The accumulated concentration in fish, roots of plants, meat and milk
reflects the estimated high lipophilicity of DEHA.
Table 5.5 The estimated regional concentrations of DEHA in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants
Meat
Milk

DEHA
Estimate
Measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~1,700 t)
0.48
2.8 x 10^-4
1.3
0.003
0.003
0.03
0.008

Worst case (10,700 t)
3.02
1.8 x 10^-3
8.5
0.019
0.019
0.17
0.053

5.1.2 Health assessment
The key toxicity data for the assessment of DEHA are presented in Table
5.6.
Table 5.6 Selected toxicity data on DEHA.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Rat
N.D.

LD₅₀=7,392 mg/kg bw
1a, 5, 9

Acute inhalation toxicity
Rat
N.D.
900 mg/m³ / 4h
No effects
11

Acute dermal toxicity
Rabbit
N.D.

LD₅₀=8,410 mg/kg bw
1a, 4, 5, 10

Acute toxicity, other routes
Rabbit
N.D.

LD₅₀, _i.v.=540 mg/kg bw
1a, 4, 5, 12

Rat
N.D.

LD₅₀, _i.v.=900 mg/kg bw
1a, 4, 5

Mouse
N.D.

LD₅₀, _i.p.=150 mg/kg bw
1a

Irritation

- skin
Rabbit

(albino)
Draize test
462 mg/6.5 cm²

24 hour
Slightly irritating (average of 0.83 points out of 8)
5

- eye
Rabbit
N.D.
462 mg (0.5 ml)

24 hours
Small foci with necrotic tissue
5

Rabbit
N.D.
0.1 ml (92.4 mg)
Not irritating
5

Sensitisation
Guinea pig (♂)
Draize
i.c.:1. day: 0.1% (0.5 ml) + 3 0.1% (0.1ml) for 3 weeks, Challenge:
0.1% (0.5ml)
No effect
5, 16

Repeated dose toxicity
Mouse (B6C3F1)
N.D
240-3750 mg/kg/day; 13 weeks
Reduced bodyweight gain at 465 mg/kg bw
1a, 5, 7

Mouse (B6C3F1)
Investigation of liver peroxisome proliferation (oral)
0, 32, 325, 3322, 6370 mg/kg/day;

21 days
Reduced bodyweight gain, increased liver weight and peroxisome numbers
in liver cells. NOAEL=325 mg/kg bw
1b

Rat (strain unknown)
N.D. (oral)
610-4760 mg/kg/day, 90 days
Reduced bodyweight gain, changes in liver and kidney weight. Adverse
effects on liver, kidney, spleen and testes. NOAEL=610 mg/kg bw
1a, 5, 6

Rat (strain unknown)
N.D. (oral)
700 and 1,500 mg/kg/day;

2 years
Reduced bodyweight gain, NOAEL=700 mg/kg/day, LOAEL= 1,500 mg/kg/day
3

Rat (Fisher 344)
Investigation of liver peroxisome proliferation (oral)
11, 122, 1177, 2275 mg/kg/day;

up to 21 days
Reduced bodyweight gain, increased liver weight and peroxisome numbers
in liver cells.

NOAEL=122 mg/kgbw
1b

Genetic toxicity
Salmonella typhimurium
Ames test, +/-

0.025-10 mg/plate
Not mutagenic
2, 3, 5, 13

Mouse
Dominant lethal mutation study
0, 0.45, 0.9, 4.6, 9.2 g/kg bw i.p.
LOAEL=450 mg/kg bw

3, 5, 8

Human lymphocytes
OECD 473

10, 50, 100m g/ml
Negative

1a, 5, 14

CHO cells
In vitro mammalian cell gene mutation test, +/-
<400m g/ml
Weak positive without S9
1a, 5, 15

Reproductive / developmental toxicity
Rat, Alpk:APfSD
Fertility study, OECD 415
28, 170 1,080 mg/kg/day; 10 weeks
NOAEL, parental = 170 mg/kg bw/day

NOAEL, F0 = 170 mg/kg bw/day
16

Rat, Alpk:APfSD
Developmental, OECD 414
28, 170 1,080 mg/kg/day; 22 days
NOAEL, foetotoxicity = 28 mg/kg bw/day

NOAEL, parental = 170 mg/kg bw/day, LOAEL = 1080 mg/kg bw/day.
3, 5

Carcinogencity
Mouse (B6C3F1)

N.D.

1,800 and 3,750 mg/kg bw/day, 103 weeks

Dose-dependent incidence of liver tumours (adenomas and carcinomas).
Significantly higher no. of ♀ with carcinomas.
1a, 2, 5, 7

Rat

(Fisher 344)
N.D.
600 and 1,250 mg/kg bw/day, 103 weeks
No substance related effect.
1a, 5, 7

Rat (F-344) and mouse (B6C3F1)
N.D.
2.5 g/kg bw/day

Duration unknown
Higher sensitivity for F-344 rats than B6C3F1 mice to peroxisome
proliferation.
2

Experience with human exposure
Human
Inhalation
11.7 - 14.6m g/m³
More pronounced reactions in humans with allergy case history
1a, 5

Human
Patch-test
Neat DEHA, booster after 14 days
No irritation or sensitisation
5

References: 1a) European Commission Joint Research Centre (1996), 1b)
European Commission Joint Research Centre (2000), 2) HSDB (2000), 3) IRIS
(2000) 4) NTP (2000), 5) BUA (1996a), 6) Smyth et al. (1951), 7) DHHS/NTP
(1981), 8) Singh et al. (1975), 9) Kolmar Res. Ctr. (1967), 10) Union Carbide
quoted in Sax, N.J. and Lewis, R.J. Jr. (eds); (1989), 11) Vandervort and
Brooks (1977), 12) Edgewood Arsenal (1954), 13) Zeiger et al. (1982), 14) ICI
PLC (1989b), 15) Galloway et al (1987), 16) SIDS dossier (1998).
Observations in humans

Most of the identified observations in humans are related to cosmetic
products with a certain content of DEHA, but without available information
regarding the other constituents. These observations are therefore not used in
the evaluation. Exposure to neat DEHA did not cause significant irritation or
sensitisation reactions (BUA, 1996a).
In the meatpacking industry, 685 workers were investigated. The average
DEHA concentration in the rooms was 11.7m g/m³to 14.6m g/m³.
Workers with asthma or allergy seemed to get more pronounced reactions. No
further details are available (BUA, 1996a).
Acute toxicity

DEHA shows very little acute toxicity in animal studies. Administered
orally, the lowest observed LD₅₀ in rat was 7,392 mg/kg bw. LD₅₀
values (oral) in rat have been reported up to 45,000 mg/kg. Dermal LD₅₀'s
have been found in the range of 8,410 to 15,100 mg/kg in the rabbit (European
Commission Joint Research Centre, 1996).
When administered intravenously, DEHA is slightly more toxic, with a LD₅₀to rat of 900 mg/kg bw and a LD₅₀ to rabbit of 540 mg/kg bw
(BUA, 1996a).
Based on the available limited data, DEHA does not show effects when
inhaled for a short period of time.
Irritation

DEHA has been reported to be non-irritating or slightly irritating to the skin
and eyes of rabbits in a number of different studies. Slight irritation was
observed in a study where 0.5 ml / 462 mg DEHA was applied to rabbit skin for
24 hours. 462 mg of test substance instilled in the in rabbit eye produced
small foci with necrotism. Detailed information about the test conditions and
results are not available (BUA, 1996a).
Sensitisation

DEHA did not produce signs of a sensitising potential in a Draize test in
guinea pigs (BUA, 1996a).
Repeated dose toxicity

A number of different repeated dose toxicity studies have shown that DEHA can
produce dose dependent changes in body and organ weights and in bio-chemical
parameters as well as changes indicative of peroxisome prolifera-tion. A
precise determination of a NOAEL for DEHA for repeated dose toxicity is not
available. A NOAEL in rats of 610 mg/kg bw/day was ob-served in a 13 week
feeding study (Smyth et al., 1951). In rats a NOAEL of 122 mg/kg bw/day for
peroxisomal proliferation was identified in 21 day feeding study, and in a
similar study in mice the NOAEL was identified at 325 mg/kg bw/day (European
Commission Joint Research centre, 2000). No details are available in the
reviewed literature. The Scientific Committee for Food has assigned a NOAEL
for DEHA in the rat, as measured by bio-chemical parameters and
electronmicroscopic analysis of peroxisome proliferation, at approximately 100
mg/kg bw/day (CSTEE, 1999).
Genetic toxicity

The mutagenicity of DEHA is weak in the available studies and only
ob-served in mice. Most significant was an observed dominant lethal effect in
male mice, here the LOAEL was 450 mg/kg bw (Singh et al., 1975).
Long term toxicity

According to IARC, DEHA is not classifiable as a human carcinogen. It is
grouped as a category 3 carcinogen: Limited evidence of carcinogenicity in
animals (IARC, 2000).
In the available literature DEHA has been shown to cause a significantly
increased incidence of liver tumours in female mice and a non-significantly
increased incidence in male mice (a 2-year study), and that changes in liver
biochemistry has been observed in rats (among other changes in cytochrome
P450) (European Commission Joint Research centre, 1996). Liver tumours are
proposed to be induced by peroxisome proliferation through a mecha-nism which
involves hormone receptors expressed at a much lower level in human liver than
in mice (CSTEE, 1999).
Reproductive and developmental toxicity is investigated in a number of
studies. In the available literature the lowest maternal toxicity was observed
at a level of 170 mg/kg bw/day in rats. A NOAEL of 28 mg/kg bw/day for foetal
toxicity resulting in skeletal variations, kinked or dilated ureters was
established in a rat study following the OECD 414 guideline (BUA, 1996a). The
Scientific Committee for Food has established a NOAEL for foetotoxicity at 30
mg/kg bw/day (CSTEE 1999).
NOAEL/LOAEL

The lowest reported NOAEL in the reviewed literature is this NOAEL of 28 mg/kg
bw/day for foetal toxicity in rats, which must be considered the most
sensitive effect. The most critical effect of the structural analogue DEHP,
namely testicular toxicity (KemI, 2000), has not been addressed for DEHA in
the reviewed literature.
Toxicokinetic

The main metabolite in human blood is 2-ethylhexanoic acid. Its
elimination half time was found to be 1.65 hrs. In urine the observed
metabolites were 2- ethylhexanoic acid (8.6%), 2-ethyl-5-hydrohexanoic acid
(2.6%) 2-ethyl-1,6-hexanedoic acid (0.7%), 2-ethyl-5-ketohexanoic acid (0.2%)
and 2-ethylhexanol (0.1%). The elimination half time was approx. 1.5 hours.
After 36 hrs no metabolites were detected in the urine (HSDB, 2000).
Summation/Conclusion

Based on the available literature DEHA has been shown be of low acute toxicity
and to cause slight irritation to rabbit skin and eyes in some studies. DEHA
has not shown a skin sensitisation potential in the reviewed literature.
In reproductive toxicity studies DEHA has shown to produce foetal toxicity
in rats. A NOAEL of 28 mg/kg bw /day was established (BUA, 1996).
DEHA is reported to cause liver tumours in mice. CSTEE (1999) proposes that
liver tumours are induced by peroxisome proliferation through a mechanism
which involves hormone receptors expressed at a much lower level in human
liver than in mice.
According to IARC, DEHA is not classifiable as a human carcinogen and it is
classified as a category 3 carcinogen: Limited evidence of carcinogenicity in
animals. This conclusion has been drawn by a working group re-evaluating the
evidence for carcinogenicity for 16 industrial chemicals, reported in the IARC
Monograph, Volume 77. DEHA causes peroxisome proliferation in the liver in
mice and rats, but evidence that this compound is carcinogenic in experimental
animals is less than sufficient. Considerations of mechanism or mode of action
of DEHA therefore played no role in the classification by the working group.
In relation to the structural analogue, DEHP, the working group has concluded
that the mechanism by which DEHP increases the incidence of hepatocellular
tumours in rats and mice is not relevant to humans. DEHP produces liver
tumours in rats and mice by a non-DNA-reactive mechanism involving peroxisome
proliferation, which has not been demonstrated in human hepatocyte cultures or
exposed non-human primates. (IARC, 2000).
The mutagenicity of DEHA is weak.
An ADI on 0.3 mg/kg bw/day for DEHA has been estimated by the EU´s
Scientific Committee for Food (SCF, 2000). This value is far above the results
from the EASE calculation. It is therefor estimated that the selected scenario
will not contribute to the daily human intake of DEHA in a significant amount.
Critical effect

The identified critical effect of DEHA in a developmental study is
foetotoxicity. The established NOAEL is 28 mg/kg bw/day.
Classification

Based on the available data, the only observed effect which could result
in classification according to the criteria in the EU Substance directive (EEC
1967) is foetal toxicity in rats. This would, however, require more detailed
information.
Exposure versus toxicity

A comparison between the calculated exposure of consumers and the
available toxicological information about DEHA indicates that the selected
exposure scenario regarding floor and wall coverings represents a minor risk
to human health. DEHA is however widely used, and when other possible sources
of exposure are taken into consideration, the total load of DEHA may reach the
same order of magnitude as the established ADI.
Comparing the estimated daily exposure to DEHA from haemodialysis to
estimated daily exposure in a similar scenario for DEHP shows that the average
daily exposure of 2.9 - 72m g/kg bw/day for DEHA is 50 - 1000 times lower than
for DEHP, which is considered more toxic than DEHA. For comparison the lowest
LD₅₀for DEHP administered intravenously to rats and reported in
the reviewed literature is 250 mg/kg bw. It should be mentioned that this
study is reported to be inappropriate for a risk assessment due to poor design
and/or reporting (KemI 2000). The LD₅₀for DEHA administered
intravenously to rats and reported in the reviewed literature is 900 mg/kg bw
and 540 mg/kg bw in rabbits. The NOAEL for the critical foetotoxic effect of
DEHA to rats is approximately 0.4 10³ - 10 10³ times
higher than the estimated average daily exposure from haemodialysis.
Possible adverse effects have been observed in humans following inhalation
of concentrations of 11.7m g/m³to 14.6m g/m³. As the
selected workplace scenario in EASE results in concentration levels 10⁴
times bigger, similar or more severe effects can be expected, even though the
EASE calculation must be considered rather conservative.
Based on the available data the milk tube scenario may indicate that if a
child with a weight of 10 kg drinks 1 l of milk pr. day the maximum dose will
be 0.05 mg/kg bw. As the ADI is 0.3 mg/kg/bw, the maximum dose is 17% of the
ADI.
5.1.3 Environmental assessment
Generally, data on the environmental effects from DEHA are available,
especially from the acute aquatic test systems. In the following the most
sensitive data is presented.
Table 5.7 Ecotoxicity and fate data on DEHA

Aquatic (mg/l)
Microorganisms
Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
mg/l

BCF
Aerobic
Anaerobic

Acute
> 100 x S_w (96 h)
0.66
> 100 x S_w
>10,000
N.D.
27
66 (ready)
N.D.

Chronic
N.D.
0.035-0.052

(MATC)*
N.D.
N.D.
N.D.
-
-
-

N.D.: No data found

-: Not relevant for the specific parameter.

*: Maximum acceptable toxicant concentration
Acute toxicity

DEHA is not toxic to algae at or below the water solubility level of DEHA
(0.78 mg/l). It should be noted that the test duration in this test was 96
hours, a day longer than standard acute tests for algae (Felder et al., 1986).
A number of acute studies in algae, crustaceans and fish observed toxicity
at concentrations above the solubility of DEHA in water (BUA, 1996a; European
Commission Joint Research Centre, 2000). However, the acute toxicity for D.
magna is shown to be 0.66 mg/l in one study performed with low
concentrations (Felder et al., 1986), and DEHA is therefore considered very
toxic to crustaceans.
Chronic toxicity

The chronic data for crustaceans shows that in a 21d flow through test
DEHA had adverse effects on the reproduction of Daphnia magna. The
maximum acceptable toxicant concentration (MATC) for reproduction (and body
length and mortality) ranged from 0.035 to 0.052 mg/l (Felder et al., 1986).
Microorganisms and terrestrial ecotoxicity

DEHA does not seem to have any apparent effects on microorganisms in
environmentally relevant concentrations. No data on terrestrial organisms was
found.
Bioaccumulation

DEHA has a measured bioaccumulation factor of 27 (Felder et al., 1986)
showing that DEHA is not a bioaccumulative substance. There is a discrepancy
between the measured and the estimated bioaccumulation, the estimated value
being 100 fold higher than the actual measured BCF, which indicate that DEHA
is not bioaccumulated as predicted by directly LogP_ow. This is
common for very lipophilic substances.
Aerobic and anaerobic biodegradation

According to the available data there is evidence of ready
biodegradability of DEHA (BUA 1996a), but no data are available on inherent or
anaerobic biodegradation. A simple mass balance of DEHA on three sewage
treatment plants in Denmark (Hoffmann 1996), shows that a 90% reduction is
achieved in the plants. However, also that between 15 and 25% of the DEHA
plasticiser in the inflow is later found in the sludge, which is comparable to
the fate of DEHP.
Environmental assessment

Most of the data on algae, crustacean and fish are reported as ‘>
water solubility’. For the purpose of the environmental assessment these
values are evaluated according to Pedersen et al. (1995) and the 50% effect
concentration set equal to the water solubility. The lowest observed acute LC₅₀was identified for Daphnia magna for the aquatic environment.
For this species a chronic test (reproduction test) result was also found. The
endpoint in the reproduction test was MATC, which may be a accepted as a NOEC,
and the assessment factor for derivation of PNEC is 100 according to the EU
TGD 1996 (three acute and one chronic results). The estimated PNEC is 0.00035
mg/l.
If the chronic test result is not considered as a NOEC, an assessment
factor of 1,000 based on the acute test results in a PNEC of 0.00066 mg/l. The
most conservative result is obtained using the MATC result, and this is used
in assessment presented below. The additional factor of 10 is applied for very
lipophilic substances to allow for additional intake via food in
benthic organisms (EU TGD 1996).
Table 5.8 Environmental Assessment for DEHA

Scenario
Aquatic

Surface_t
Sediment

Estimation

Aquatic
0.092
0.4^a

Worst case

Aquatic
0.583
2.2^a

^{a including additional factor 10 due to high lipophilicity (LogP_ow
> 5)
Conclusion

Under worst case assumptions the PEC/PNEC ratio exceeds 1 in the sediment
compartment, thus predicting potential effects to organisms living here. In
all other cases the aquatic PEC do not exceed the PNEC. A terrestrial risk
assessment cannot be performed due to lack of toxicity data.
5.2 O-acetyl tributyl citrate; 77-90-7
5.2.1 Use, emission and exposure
Physical-chemical properties

Citrates are esters of citric acid and these plasticisers are produced
with a variety of alcohol groups.
O-acetyl tributyl citrate (ATBC) is a relatively water-soluble plasticiser
with measured data ranging from insoluble to 0.005 g/l measured at an unknown
temperature. ATBC has an estimated vapour pressure of 4.6 10^-6 mm
Hg. The estimated LogP_ow value of 4.3 (HSDB 2000) indicates that
this substance is less lipophilic compared to phthalates and many other
plasticisers.
Migration

The measured reduced migration potential (household cling to olive oil
and acetic acid) of 2.8-4.7 mg/dm² indicates that ATBC possesses
the potential of migrating from the cling phase to a fatty or aqueous phase in
contact with the cling (Plastindustrien i Danmark 1996). The migration is
faster, when the receiving phase contains fat. The loss from film to food
(cheese) corresponds to 1-6% of the plasticiser in the film (Castle et al.,
1988b). ATBC migrates less than diisononyl phthalate (DINP) in a saliva
simulant test (Nikiforov, 1999).
Use pattern for compound

The main uses of acetyl tributyl citrate may be in products used in toys,
the hospital sector, packaging, printing inks, adhesives, fillers and products
containing various amounts of plastic material, cf. Table 4.6.
Exposure in the work place

The EASE calculation focuses on the production and use of printing inks
in printed magazines.
The following assumptions are made with regard to the workplace exposure:

production takes place at a temperature of max. 30 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.

Possible main exposure routes in the workplace is:

inhalation.

Based on this scenario, the EASE calculation gives the results shown in
Table 5.9.
Table 5.9 Estimated values of ATBC in the working environment
according to the EASE calculation

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
0.5-3
ppm

Vapour concentration in air for workers
8.37-50.2
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

Two scenarios have been selected for evaluation of consumer exposure to
ABTC: a limited exposure from plasticiser use in printing inks and an exposure
of a vulnerable group – infants chewing on a teething ring.
Printing ink

The selected scenario is the exposure of an adult half an hour a day
reading a printed magazine. Based on this scenario, the EASE calculation gives
the results shown in Table 5.10.
Table 5.10 Estimated potential daily intake of ATBC by consumers
according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
5.82 x 10^-6
*

Dermal uptake
8.04 x 10^-13
*

Oral intake
0
*

Total chronic uptake via different routes
4.36 x 10^-6
*

Total acute uptake via different routes
0
*

*: The ADI has not been established. An estimated ADI of 1 mg/kg bw/d is
calculated in Nikiforov (1999)
Teething ring

A special EASE-scenario has been set up for the use of ATBC in teething
rings used by small children. It is assumed that use occurs 3 hours pr day (10
events of 20 minutes each). In the scenario, uptake through the mucous
membranes in the gums is not considered as the absorption rate is unknown. The
result of the EASE-calculation is shown in Table 5.11.
Table 5.11 Estimated potential daily intake of ATBC by contact with
toys by consumers according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
3.85 x 10^-10
*

Dermal uptake
0.06
*

Oral intake
0
*

Total chronic uptake via different routes
0.06
*

Total acute uptake via different routes
0
*

*: The ADI has not been established. An estimated ADI of 1 mg/kg bw/d is
calculated in Nikiforov (1999).
The EASE calculation does not take exposure via mucous membranes into
consideration nor swallowing of saliva. An estimated total oral intake from
mouthing of plasticised toys must therefore be expected to be higher. However,
for ATBC a preliminary risk characterisation has been carried out on behalf of
the producer (Nikiforov, 1999) based on American and Dutch risk
characterisations for DINP. Considering that migration of ATBC was approx. one
third of DINP under identical conditions, an expected daily intake (EDI) after
mouthing 11 cm² of surrogate toy for four 15 minutes periods
amounts to an average of 0.006 mg/kg bw/day and 0.094 mg/kg bw/day for the 95^th
percentile. These results apply to infants 3-12 months old and assuming all
plasticiser in saliva is bioavailable.
In the EASE scenario the exposure time is considerably higher (200 minutes
compared to 60 minutes). Adjustment for this yields 0.31 mg/kg bw/day and
adding the 0.06 mg/kg bw/day results in a total EDI of 0.37 mg/kg bw/day. An
estimated ADI of 1 mg/kg bw/d is calculated in Nikiforov (1999).
Environmental exposure of humans

The amount established in ’Usage’ section is used to calculate
exposure for a number of environmental compartments by EU TGD/EUSES.
Table 5.12 The estimated human doses of ATBC through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

ATBC

Estimation (~ 550 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

2.9 10^-6
8.5 10^-6

Fish
BCF estimated*
0.00031
0.0009

Plants
Leaf crops
0.000006
0.000106

Root crops
2 10^-6
8 10^-6

Meat

7 10^-8
9.6 10^-7

Milk

4 10^-8
5.7 10^-7

Air

2 10^-8
3.6 10^-7

Total regional

0.00031
0.00102

* Measured BCF value not available
Exposure in the environment

The estimated concentration levels of ATBC indicate a high concentration
in the particulate phases (sediment and soils).
Table 5.13 The estimated regional concentrations of ATBC in water,
soil and air.

Compartment
Aquatic
Terrestrial
Air

ATBC
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m3

Estimation (~ 550 t)
0.0002
0.0002
0.027
0.00002
0.00018
2.3 10^-6
0.00096
1 10^-7

Worst case
0.0006
0.0006
0.078
0.00034
0.00060
7.7 10^-6
0.0186
1.7 10^-6

Secondary poisoning

Only estimated BCF values are available. These lead to relatively high
concentrations in fish.
Table 5.14 The estimated regional concentrations of ATBC in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants
Meat
Milk

ATBC
Estimate
Measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~ 550 t)
0.19
N/A.
0.0004
0.0004
0.0004
0.00002
4.9 10^-6

Worst case (10,700 t)
0.55
N/A.
0.0014
0.0062
0.0062
0.00022
7.08 10^-5

N/A.- not available. Data needed to perform estimation of BCF not
available.
5.2.2 Health assessment
The most significant toxicity data on ATBC are presented in Table 5.15.
Table 5.15 Selected toxicity data on ATBC

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Rat
N.D.

LD₅₀=31.4 g/kg bw
1

Acute inhalation toxicity
-

Acute dermal toxicity
-

Acute toxicity, other routes
Rabbit
N.D.
0.1 g/kg bw (i.v.)
Increased motor activity and respiration.
3

Rabbit
N.D.
Unspecified dose (i.v.)
Depressive effect on blood pressure and respiration.
3

Mouse and rat
N.D.
0.4 g/kg bw (i.p.)
Severe signs of CNS toxicity.
3

Irritation

- skin
Rabbit
N.D.
N.D.
Not irritating.
4

- eye
Rabbit

Rat
N.D.

N.D.
5%

N.D.
Temporarily abolished corneal reflex action

Moderate irritation.
3

4

Sensitisation
Guinea pig
Maximisation test
N.D.
Not sensitising
4

Repeated dose toxicity
Rat, Wistar
Repeated oral dose, OECD 408
100, 300, 1000 mg/kg bw/day

90 days
Haematological and biochemical changes. Increased liver weight at top
dose.

NOAEL = 100 mg/kg bw/day.
4

Genetic toxicity
Salmonella typhimurium
Ames test, +/-

N.D.
Not mutagenic
2

Rat lymphocytes
+/-
N.D.
No chromosomal aberrations
4

Rats
Unscheduled DNA synthesis
800, 2000 mg/kg, gavage
No UDS
4

Reproductive / developmental toxicity
Rat, Sprague Dawley
2-generation reproduction, OECD 416

0, 100, 300, 1000 mg/kg/day

Decreased bodyweights

NOAEL = 100 mg/kg bw/day
4

Carcinogeni-city
Rat, Sherman
N.D. Old guideline. Feeding study
0, 200, 2000, 20000 ppm.

2 years
No significant exposure related findings. Results cannot be evaluated
(old guideline).
4

Experience with human exposure
Human
Sensitisation test
N.D.
No sensitisation or irritation.
4

References: 1) HSDB (2000), 2) CCRIS (2000), 3) TNO BIBRA International Ltd
(1989), 4) CSTEE (1999)
Observations in humans

There was no evidence of irritation or sensitisation in a sensitisation
test in humans. No further information is available.
Acute and chronic toxicity

Acetyl tributyl citrate has exhibited low acute oral toxicity in
laboratory animals (LD₅₀=31.4 g/kg) (HSDB, 2000).
Studies where a single dose (0.1 - 0.4 g/kg bw) of ATCB has been
administered by the intraperitoneal or intravenous route have indicated that
the central nervous system and blood are the critical organs in various
species (rodents) of laboratory animals (TNO BIBRA, 1989).
Irritation

Available data indicate no irritation of skin and moderate eye irritation
(CSTEE, 1999; TNO BIBRA, 1989).
Sensitisation

O-acetyl tributyl citrate was not sensitising in a guinea pig maximisation test
(CSTEE, 1999).
Repeated dose toxicity

A NOAEL of 100 mg/kg bw/day was established in a 90 gavage study in rats where
haematological and biochemical changes and increased liver weights were observed
at higher doses (CSTEE, 1999).
Genetic toxicity

Acetyl tributyl citrate has not been shown to be mutagenic in the reported Ames
bacterial assay. ATCB did not cause chromosomal aberrations in rat lymphocytes
or unscheduled DNA synthesis in rats treated by gavage at 800 or 2,000 mg/kg bw.
The negative UDS study indicated that the in vivo genotoxic potential of ATCB is
low or absent (CSTEE 1999).
Long term toxicity

In a two-year carcinogenicity study, rats were fed doses of 200; 2,000 and
20,000 ppm ATBC in the diet. No significant dose related toxicological findings
were reported. The study is however not according to modern guidelines and the
carcinogenicity of ATBC cannot be evaluated properly based on these findings
(CSTEE, 1999).
In a two-generation reproduction study in rats according to OECD guideline
416, rats were fed doses of 100, 300 and 1,000 mg/kg bw/day. Decreased body
weights in F1 males from 300 mg/kg bw/day and F0 males at 1000 mg/kg bw/day were
observed. A NOAEL of 100 mg/kg bw/day was estab-lished (CSTEE, 1999).
NOAEL/LOAEL

Lowest reported NOAEL is 100 mg/kg bw/day (repeated dose 90 days oral
toxicity in rats and reproductive toxicity rats) (CSTEE, 1999).
Summation/Conclusion on health

Sufficient data were not found to make a profound health assessment.
ATCB has very low acute toxicity. LD₅₀ in rats was reported to
be 31.4 g/kg bw.
O-acetyl tributyl citrate was not found to be an irritant to skin or
sensitising. Moderate eye irritation has been observed. (CSTEE, 1999; TNO
BIBRA, 1989).
In the reviewed literature o-acetyl tributyl citrate has not been found
mutagenic. ATCB did not cause chromosomal aberrations in rat lymphocytes or
unscheduled DNA synthesis in rats treated by gavage. The negative UDS study
indicated that the in vivo genotoxic potential of ATCB is low or absent
(CCRIS, 2000; CSTEE, 1999)
Repeated dose toxicity in rats included haematological and biochemical
changes and increased liver weights. A NOAEL of 100 mg/kg bw/day was
established (CSTEE, 1999).
The carcinogenic potential cannot be evaluated based on the available
literature.
Decreased body weights were observed in F1 male rats (300 mg/kg bw/day) and
F0 male rats (1,000 mg/kg bw/day) in a 2-generation study. A NOAEL of 100
mg/kg bw/day was established.
Critical effect

Based on the available limited data, the identified critical
effect in rats appears to be reproductive toxicity resulting in decreased body
weights and repeated dose toxicity resulting in haematological and biochemical
changes and increased liver weights.
Classification

Sufficient data are not available to evaluate the classification of the
substance for all effects.
Exposure versus toxicity

A comparison between the calculated exposure of consumers and the very
limited available toxicological information about ATBC indicates that the
selected exposure scenario represents a minor risk to human health.
General exposure of the population may occur through dermal contact with
consumer products containing O-acetyl tributyl citrate and ingestion of
contaminated food. O-acetyl tributyl citrate has been found in the aquatic
environment.
The selected scenario for EASE-calculation of the consumer exposure of
o-acetyl tributyl citrate results in low exposures. It is therefore estimated
that only a limited contribution of the overall exposure of humans comes from
products.
No ADI has been established for ATBC. A preliminary ADI has been estimated
to 1 mg/kg bw/day (Nikiforov 1999). An ADI of 0.05 mg/kg bw/day may be
assigned on a conservative basis from DEHP proliferation peroxisome data, but
it should be mentioned that there is no information in the available
literature indicating that ATBC causes peroxisome proliferation.
The selected EASE-scenario for teething rings modelling the exposure of
o-acetyl tributyl citrate in children from dermal contact is 6% of a
preliminary ADI and similar to the assigned ADI. It should, however, be
mentioned that the EASE scenario of exposure to ATCB from toys does not
adequately model the oral exposure from plasticisers in teething rings since
swallowing of saliva and uptake via the mucous membranes is not included. A
different approach including these sources yields seven times the assigned ADI
and 37% of the preliminary ADI for infants.
By the oral route, ATBC exhibits low acute toxicity in laboratory animals,
but no data have been found describing toxicity by inhalation or dermal
toxicity.
With regard to exposure in the working environment, relevant data have not
been identified. Exposure may occur through inhalation of dust particles and
dermal contact when working in places where O-acetyl tributyl citrate is
handled.
The EASE-calculation indicates that the concentration of o-acetyl tributyl
citrate in the working environment of the selected scenario can be in
quantities of up to 50 mg/m³. Due to the lack of toxicity data, it
is not possible to assess whether this value gives rise to concern.
5.2.3 Environmental assessment
Very few ecotoxicity data was found for ATBC. Biodegradation data has been
identified.
Table 5.16 Ecotoxicity and fate data on ATBC.

ATBC
Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
N.D.
N.D.
38-60
N.D.
N.D.
1,100 (estimated)
80% at 30 mg/l

(inherent)
N.D.

Chronic
N.D.
N.D.
N.D.
N.D.
N.D.
-
-
-

Aquatic and terrestrial ecotoxicity

The only ecotoxicological data identified for ATCB originates in
volunteered proprietary information. Two species of typical freshwater test
species showed LC₅₀’s ranging from 38-60 and 59 mg/l,
respectively (Ecosystems Laboratory 1974). No chronic ecotoxicological data
was found.
Bioaccumulation

The estimated BCF indicate that ATBC can be bioaccumulated (Syracuse
Research Corporation, 2000). An estimated LogP_ow value on 4.3
supports this assumption.
Aerobic and anaerobic biodegradation

Aerobic biodegradation in non-standard test showed a rather slow
degradation 26% after 21 days (Ecosystems Laboratory 1974). No data on
anaerobic biodegradation was found.
ATBC was degraded 80% in an inherent biodegradation test. The compound is
therefore assessed as inherently biodegradable.
Risk assessment

The data available is insufficient for calculating a PNEC according to
the EU TGD. If however, a PNEC is based on the single study available a PNEC
of approx. 0.04 mg/l is estimated for the aqueous phase, the predicted
concentrations (PECs) for surface water and for sediment are 50-500 times
lower than PNEC.
Table 5.17 Risk Assessment on ATBC (based on incomplete data set).

Risk assessment
Aquatic

Surface_t
Sediment

Best guess

Aquatic
0.005
0.002

Worst case

Aquatic
0.015
0.005

Based on the relatively slow degradation and lipophilicity of ATBC it is
assumed that effects in the environment may be associated with the potential
for bioaccumulation in fauna in the receiving environment.
5.3 Di(2-ethylhexyl) phosphate; 298-07-7
Physical-chemical

The water solubility of di(2-ethylhexyl) phosphate (DEHPA) has been
measured to 100 mg/l at an unknown temperature. Under the assumption
that the solubility was measured at standard temperature, DEHPA is a
relatively soluble compound when compared to the other substances
investigated.
This substance is an acid with a pK_a in the range of 1.72-2.17,
which indicates that this compound is fully dissociated at neutral pH.
DEHPA has an estimated vapour pressure of 4.65 10^-8 mm Hg. Under
the assumption that the estimated vapour pressure is valid at standard
temperature, the magnitude of the vapour pressure places DEHPA among the
substances investigated that possess a very low vapour pressure.
The measured LogP_ow value of 2.67 indicates that this substance
is moderately lipophilic agrees with low BCF values (BUA 1996b). The estimated
LogP_ow value of 6.07 presumably overestimates lipophilicity due to
the presence of the dissociable phosphate group. Under the assumption that the
measured P_ow is valid in natural pH range, DEHPA possess low
lipophilicity when compared to the other substances investigated. This
substance is also an acid with a pK_a in the range of 1.72-2.12,
which indicates that this compound is almost completely dissociated at pH 5-9
(BUA, 1996b).
Migration

No information on the migration potential of DEHPA has been located.
Migration of diphenyl 2-ethylhexyl phosphate from food films ranged from
0.1-0.5 mg/dm² when measured in a range of fat containing food
products (Castle et al, 1988b).
5.3.1 Use, emission and exposure
The group of phosphate plasticisers are triesters of phosphoric acid and
includes triaryl and trialkylesters. This group of plasticisers is more
resistant to ignition and burning than all the other groups of ester
plasticisers and is most often used as flame-retardants in products with
specific fire resistant demands.
Use pattern for compound

The main uses of DEHPA may be in PVC-products used in e.g. the hospital
sector, packing, cables, profiles and floor and wall coverings, cf Table 4.6.
Exposure in the work place

The EASE-calculation focuses on the production of cables.
The following assumptions are made with regard to the workplace exposure:

production takes place at a temperature of 180 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.

Possible main exposure routes in the workplace:

inhalation.

Based on this scenario, the EASE calculation provides the results shown in
Table 5.18.
Table 5.18 Estimated values of DEHPA in the working environment
according to the EASE calculation.

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
0-0.1
ppm

Vapour concentration in air for workers
0-1.34
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

The EASE-calculation focuses on use of cables in a normal private house.
Possible main routes of consumer exposure:

inhalation
dermal contact with consumer goods
ingestion of contaminated food.

Based on this scenario, the EASE calculation gives the results shown in
Table 5.19.
Table 5.19 The estimated potential daily intake of DEHPA by
consumer according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
5.82 x 10^-6
*

Dermal uptake
8.04 x 10^-13
*

Oral intake
0
*

Total chronic uptake via different routes
4.36 x 10^-6
*

Total acute uptake via different routes
0
*

*: The ADI has not been established. Other phosphorous acid dialkyl esters
have been allocated a group restriction value of 0.05 mg/kg bw/d based on DEHP
peroxisome proliferation data (SCF, 2000).
Environmental exposure of humans

The EUSES-calculation indicates that humans may by exposed for the
substance as illustrated in Table 5.20.
Table 5.20 The estimated human doses of DEHPA through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

DEHPA

Estimation (~ 2,000 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

1.1 x 10^-5
5.7 x 10^-5

Fish
BCF measured
3.7 x 10^-6
2.0 x 10^-5

Plants
Leaf crops
1.3 x 10^-5
6.9 x 10^-5

Root crops
2.1 x 10^-6
1.1 x 10^-5

Meat

3.7 x 10^-9
1.9 x 10^-8

Milk

4.6 x 10^-9
2.4 x 10^-8

Air

4.4 x 10^-9
2.3 x 10^-8

Total regional

0.00003
0.00016

Exposure in the environment

The estimated concentration levels of DEHPA show that concentrations in
the aqueous compartment are relatively high compared to other plasticisers due
to the high solubility of DEHPA.
Table 5.21 The estimated regional concentrations of DEHPA in water,
soil and air.

Compartment
Aquatic

Terrestrial

Air

DEHPA
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m3

Estimation (~ 2,000 t)
0.0004
0.0004
0.0017
0.0005
0.0003
6.6 x 10^-5
0.0049
2.1 x 10^-8

Worst case (10,700 t)
0.0020
0.0020
0.0090
0.0026
0.0013
3.5 x 10^-4
0.0256
1.1 x 10^-7

Secondary poisoning

DEHPA is not expected to bioaccumulate and there is no anticipation of
secondary poisoning.
Table 5.22 The estimated regional concentrations of DEHPA in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants

Meat
Milk

DEHPA
estimate
measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~ 2,000 t)
0.014
0.002
0.0004
0.0008
0.0008
9 10^-7
6 10^-7

Worst case (10,700 t)
0.073
0.011
0.0020
0.0040
0.0040
4.8 10^-6
3.0 10^-6

5.3.2 Health assessment
The most significant toxicity data on DEHPA are presented in Table 5.23.
Table 5.23 Selected toxicity data on DEHPA.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Rat
N.D.

LD₅₀=4,742 mg/kg bw
2

Acute inhalation toxicity
Dogs
N.D.
380 ppm, 8 hours
Death occurred (no further info)
2

Acute dermal toxicity
Rabbit
N.D.
1.25 ml/kg, 24 hours
LD₅₀=1,200 mg/kg bw
2

Acute toxicity, other routes
Rat
N.D.
i.p.
LD₅₀=50-100 mg/kg bw
2

Irritation

- skin
Rabbit
Occlusive test, intact skin
10m l (24 hours)
Necrosis after 24 hours
2

- eye
Rabbit
N.D.
5m l (1%)
Corrosive to cornea
2

Sensitisation
-

Repeated dose toxicity
Rat (Sprague Dawley)

25, 100, 200 mg/kg bw (5 days)
Significant increased in relative liver weights at 100 and 200 mg/kg
bw/day. Potent induction of P450b+e system.
2

Genetic toxicity
Salmonella typhimurium
Ames test, +/-

4-2,500m g/plate (cytotoxic from 100 g/plate)
Not mutagenic
2

Reproductive / developmental toxicity
-

Carcinogencity
-

Experience with human exposure
Human
Irritation test
N.D.
Smarting of skin and 1^st degree burn
1

Human
Inhalation
2 ppm
Weakness, irritability and headache
1

References: 1) HSDB (2000), 2) BUA (1996b)
Observations in humans

Inhalation of 2 ppm showed weakness, irritability and headache.
DEHPA caused irritation of eyes and first and second degree skin burns.
Acute and chronic toxicity

An oral LD₅₀ in rats of 4,742 mg/kg is reported representing
low acute toxicity. The observed dermal LD50 leads to classification with R21 (Harmful
in contact with skin).

Irritation/corrosion

The substance is reported to corrosive to skin and eyes in rabbits.
Sensitisation

No information is available on skin sensitisation.
A repeated dose toxicity study in rats dosed for five days showed a
signifi-cant increase in relative liver weights at 100 and 200 mg/kg bw and
induction of the P450b+e system.
Genetic toxicity

DEHPA has not been shown to be mutagenic (BUA 1996b).
Long term toxicity

Concerning reproductive and teratogenic effects of DEHPA, relevant data have not
been identified.
NOAEL/LOAEL

Relevant data have not been identified in the investigation.
Summation/Conclusion on health

Sufficient data were not found to make a profound health assessment.
However, inhalation of 2 ppm caused weakness, irritability and headache in
humans.
Acute oral toxicity of di(2-ethylhexyl) phosphate to rats seems to be low,
whereas dermal toxicity to rabbits is pronounced.
Di(2-ethylhexyl) phosphate exhibits strong corrosive effect in cornea at 5m
l doses (1% solution) as well as corrosive effects on rabbit skin. Mutagenic
activity has not been observed.
Data establishing reproductive toxicity or teratogenicity were not found.
Critical effect

All endpoints have not been sufficiently investigated. Dermal toxicity
and local corrosive effects on skin and eyes observed in rabbits seem to be
the most severe effects.
Classification

Sufficient data are not available for classification. DEHPA has been
classified by Bayer AG in 1993 as C (Corrosive); R34 (Causes
burns) and Xn (Harmful); R21 (Harmful in contact with skin).

Exposure versus toxicity

A comparison between the calculated exposure of consumers and the
available toxicological information about DEHPA indicates that the selected
exposure scenario represents a minor risk to human health. This is based on
calculated exposure values several orders of magnitude lower than the observed
effect levels in animal studies.
General exposure of the population may occur through dermal contact with
consumer products containing di(2-ethylhexyl) phosphate and ingestion of
contaminated food.
Based on the selected scenario, the EASE-calculation indicates that the
exposure of di(2-ethylhexyl) phosphate in consumers represents very small
values and constitutes a limited contribution to the overall exposure of
consumers.
The values are at the same level or below the values arising from the
indirect exposure by contaminated food.
Concerning exposure in the working environment, inhalation of 2 ppm has
been observed to cause weakness, irritability and headache. Exposure may occur
through inhalation of dust particles and dermal contact when working in places
where di(2-ethylhexyl) phosphate is handled.
The EASE-calculation indicates that the concentration of di(2-ethylhexyl)
phosphate in the working environment related to the selected scenario can be
in quantities up to 0.1 ppm. This value is only a factor 20 from the
concentration that may cause adverse effects from inhalation.
5.3.3 Environmental assessment
Aquatic and terrestrial ecotoxicity

The ecotoxicological data from acute standard tests indicate, that
di(2-ethylhexyl) phosphate is harmful to algae (BUA 1996b), crustaceans (US
EPA 2000) and fish (BUA 1996b), i.e. the L(E)C₅₀’s are in the
10-100 mg/l range. Slightly increased acute toxicity is, not surprisingly,
seen in the tests of longer duration. Data from true chronic tests are not
available, but growth inhibition is reported down to 0.3 mg/l in fish and
microorganisms (HSDB 2000). The nature of the tests has not been identified.
The respiration of the micro-organism Thiobacillus ferrooxidans
was inhibited 68% in a three hours test (BUA 1996b). No data on terrestrial
ecotoxicity was identified.
Table 5.24 Ecotoxicity and fate data on DEHPA.

DEHPA
Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
50-100
42-84
20-56
443

(IC₆₈, 3h)
N.D.
1.1-6
0-17%, 75%
N.D.

Chronic
N.D.
N.D.
0.3-100

Growth inhibition
0.3-100

Growth inhibition
N.D.
-
-
-

Bioaccumulation

The bioaccumulation of DEHPA is low. A BCF of only up to 6 has been
measured in fish (BUA 1996b). The bioaccumulation potential expressed by LogP_ow
is also less than three (2.67), and significant bioaccumulation is not
expected.
Aerobic and anaerobic biodegradation

Inconsistent data on the biodegradability of di(2-ethylhexyl) phosphate
are quoted in BUA (1996b). At lower substrate concentration (30 mg/l) the
substance does not biodegrade, but a three times higher concentration the
substance is readily biodegradable. The compound is assessed as inherently
biodegradable
No data on anaerobic degradation is available. There is no data for DEHPA
from sludge, but three phosphate triesters has been found in 11 of 20 sewage
sludge samples at an average of 0.2 to 1.8 mg/kg dryweight (Kristensen et al.,
1996).
Risk assessment

The PNEC is calculated with a safety factor of 1000 since no chronic data
is available. The lowest standard test value is a fish test value of 20 mg/l,
corresponding to a PNEC of 0.02 mg/l.
Table 5.25 Risk Assessment on DEHPA.

Risk assessment
Aquatic

Surface_t
Sediment

Estimation

Aquatic
0.019
0.01

Worst case

Aquatic
0.1
0.05

Conclusion

The PEC/PNEC ratio does not exceed 1 in any aquatic compartment and
hereby predict no potential effect on organisms in the aquatic water and
sediment compartments.
A terrestrial risk assessment cannot be performed due to lack of toxicity
data.
5.4 Tri(2-ethylhexyl) phosphate; 78-42-2
5.4.1 Use, emission and exposure
Physical-chemical properties

Tri(2-ethylhexyl) phosphate (TEHPA) is in general produced and used
similarly to DEHPA.
The solubility data on TEHPA ranges from insoluble in water to <0.5 -
<100 mg/l at 18-24 C with one exact solubility of 0.6 mg/l at 24 C. The
exact water solubility on TEHPA indicates that this substance possess a low
water solubility.
TEHPA has an estimated vapour pressure of 8.3 10^-7 mm Hg at 25
C. The magnitude of the vapour ranges in the lower end of the 11 substances
investigated.
The available LogP_ow values on TEHPA ranges from 0.8-5.0.
Indications of the origin and pH at measurement of the high-end values are
however not available (BUA 1996b). The measured BCF value on TEHPA of 2.4-22
does suggest the LogP_ow values in the high end of the LogP_ow
range are overestimates. Similarly to DEHPA, this substance may also be
dissociated at neutral pH. TEHPA is therefore among the substances
investigated that possesses a low lipophilicity. However, as a worst case
assumption a LogP_ow of 5 has been used in calculating TEHPA in the
sediment compartment.
Migration

No data has been located on the migration potential of TEHPA.
Exposure in the work place

The EASE-calculation focuses on the production of cables.
The following assumptions are made with regard to the workplace exposure:

production takes place at a temperature of 180 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.

Possible main exposure routes in the workplace:

inhalation of vapours.

Based on this scenario the EASE calculation gives the results shown in
Table 5.26.
Table 5.26 Theoretical values of TEHPA in the working environment
according to the EASE calculation

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
0.5-3
ppm

Vapour concentration in air for workers
9.04-54.2
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

In the EASE calculation focus is on use of cables in a private household.
Possible main routes of consumer exposure:

inhalation
dermal contact with consumer goods
ingestion (children).

Based on this scenario, the EASE calculation gives the results shown in
Table 5.27.
Table 5.27 The theoretical potential daily intake of TEHPA by
consumers according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
5.82 x 10^-6
*

Dermal uptake
8.04 x 10^-13
*

Oral intake
0.0286
*

Total chronic uptake via different routes
0.0286
*

Total acute uptake via different routes
0
*

*: The ADI has not been established. Other phosphorous acid dialkyl esters
have been allocated a group restriction value of 0.05 mg/kg bw/d based on DEHP
peroxisome proliferation data (SCF, 2000).
Environmental exposure of humans

The amount established in ’Usage’ section is used to calculate
exposure for a number of environmental compartments by EU TGD/EUSES. The dose
is mainly derived from consumption of root crops and meat. This is due to the
LogP_ow of TEHPA leading to a slight accumulation in agricultural
soil. No measured data are available for accumulation in plants.
Table 5.28 The estimated human doses of TEHPA through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

TEHPA

Estimation (~ 2,200 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

0.00001
0.00535

Fish
BCF measured
0.00002
0.00008

Plants
Leaf crops
0.00002
0.00008

Root crops
0.0007
0.0032

Meat

0.00046
0.000002

Milk

3 10^-7
1 10^-6

Air

8 10^-8
4 10^-7

Total regional

0.0012
0.0087

Exposure in the environment

The estimated concentration levels of TEPHA reflect the relatively high
aqueous concentration due to the high solubility with a limited estimated
association with particles (sediment and soils).
Table 5.29 The estimated regional concentrations of TEHPA in water,
soil and air.

Compartment
Aquatic

Terrestrial

Air

TEHPA
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m³

Estimation (~ 2,200 t)
0.0005
0.0005
0.10
0.008
0.05
0.0004
0.2
4 10^-7

Worst case (10,700 t)
0.0022
0.0022
0.50
0.037
0.24
0.0019
1.2
1.7 10^-3

Secondary poisoning

TEHPA may dissociate in the aqueous environment and the measured and
estimated accumulation potential may therefore not imply risk of secondary
poisoning in the environment.
Table 5.30 The estimated regional concentrations of TEHPA in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants

Meat
Milk

TEHPA
estimate
measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~ 2,200 t)
0.7
0.01
0.1
0.001
0.001
0.0001
0.00003

Worst case (10,700 t)
3.4
0.05
0.6
0.005
0.005
0.0005
0.00016

5.4.2 Health assessment
The most significant toxicity data on TEHPA are presented in Table 5.31.
Table 5.31 Selected toxicity data on TEHPA.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Mouse

N.D.

LD₅₀>12,800 mg/kg bw

1

Rat
N.D.

LD₅₀>2000 mg/kg bw
4

Rat
N.D.

LD₅₀=37,080 mg/kg bw
4

Rat
N.D.

LD₅₀=39,800 mg/kg bw
4

Rabbit
N.D.

LD₅₀=46,000 mg/kg bw
4

Acute inhalation toxicity
Rat
N.D.
450 mg/m³, duration unknown.
No mortality
4

Guinea pig
N.D.
450 mg/m³, 0.5 hours
LC₅₀=450 mg/m³/30 min
3, 4

Acute dermal toxicity
Rabbit
N.D.
N.D.
LD₅₀=18,400 mg/kg bw
4

Acute toxicity, other routes
-

Irritation

- skin
Rabbit

Applied to shaved skin.
(24 hours)

Moderate erythema within 24 hours.
4

Rabbit

10-20 ml
Mortality after single application.
4

- eye
Rabbit

N.D.

0.1-0.5 ml (24 hours).
Moderate conjunctivitis which cleared up after 24 hour.
4

Rabbit
N.D.
0.01-0.05 ml
Light irritation.
4

Sensitisation
Guinea pig

Not sensitising
4

Repeated dose toxicity
Mouse (B6C3F1)
Oral
0, 500, 1000, 2000, 4000, 8000 mg/kg bw (13 weeks, 5 days
/week).
Dose dependent gastritis, lowest dose 500 mg/kg bw.
Decrease in bw gain. NOEL<500 mg/kg bw.
4

Rat (Crj:CD(SD))
Oral
30, 100, 1000 mg/kg bw, (28 days).
Reduced protrombin time (♀) and increased partial
tromboplastin time (♂). Reduced serumcholineesterase activity.

NOEL= 100 mg/kg bw
4

Rat (Sherman)

Oral
110-1550 mg/kg bw/day (30 days)
Reduced bodyweight gain.

NOEL=430 mg/kg bw/day
4

Monkey (Rhesus)
Inhalation, average particle size=4.4m m.
10.8, 26.4, 85 mg/m3 (12 weeks, 5 days/weeks, 6
hours/day).
No effects
4

Rabbit

(New Zealand)
Dermal
92 mg/animal/day (5 days/week, 3-17 days) 10-20 appl.
Hyperkeratose, mild parakeratose, acute dermatitis,
thickening of epidermis. Effects disappeared.
4

Genetic toxicity
Salmonella typhimurium
Ames test, +/-
N.D.
Not mutagenic.
4

CHO cells

In vitro mammalian cell gene mutation test, +/-
Up to 1670m g/ml.

No chromosome aberration.

4

Rat
Micronucleus test
0, 0.25, 0.50 mg/l air (2 weeks, 5 days / week, 6hrs/day
No micronuclei
4

Reproductive / developmental toxicity
-

Carcinogeni-city
Mouse (B6C3F1)
N.D. (gavage)
0, 500, 1000 mg/kg 5 days/week (102-104 weeks)
Increased incidence of hepatocellular carcinoma in female
mice at 1000 mg/kg bw. No evidence of carcinogenicity in male mice..
1, 2

Rat
N.D. (gavage)
♀: 1000 or 2000 mg/kg bw

♂: 2000 or 4000 mg/kg bw
♀: No evidence of carcinogenicity

♂: Equivocal evidence of carcinogenicity (increased incidence of
pheochromocytomas in adrenal glands.
1

Experience with human exposure
Human

Irritation test, underarm
24 hours
No irritation
4

References: 1) HSDB (2000) 2) CCRIS (2000) 3) NTP (2000) 4) BUA (1996b)
Observations in humans

A 24 hours exposure of the underarm on six test persons did not result in
any irritation of the skin.
Acute toxicity

Tri(2-ethylhexyl) phosphate appears to have very low acute oral toxicity. LD50
in rats was more than 37.08 g/kg and LD50 was approx. 46.0 g/kg in rabbits.
Irritation

Tri(2-ethylhexyl) phosphate may produce moderate erythema in skin irritation
test and slight irritation to eyes.
Sensitisation

Sufficient data on skin sensitisation was not found.
Repeated dose toxicity

Repeated dose toxicity observed in rats involved haematological changes and
reduced body weight gain. Slight behavioural changes and minor chronic infection
in lungs were observed in dogs administered 10.8, 26.4, 85 mg/m3 (12 weeks, 5
days/week, 6 hrs/day). No effects were observed in monkeys receiving the same
treatment.
Genetic toxicity

Based on the available data, TEHPA cannot be regarded as mutagenic and has not
been found genotoxic in chromosome aberration test and micronuclei assays.
Neither tri-n-ethyl phosphate nor tri-n-octyl phosphate were found mutagenic in
Salmonella test (Zieger et al., 1987).
Long term toxicity

A slight evidence of carcinogenicity was observed in female mice and equivocal
evidence in male rats (HSDB 2000). Based on the evaluation as slightly
carcinogenic in mice and not mutagenic and genotoxic, it has been concluded by
an ECETOC working group that TEPHA is unlikely to be car-cinogenic to humans
(BUA 1996b). Data on reprotoxicity, embryotoxicity and teratogenicity were not
found.
NOAEL/LOAEL

In repeated dose toxicity tests, the lowest NOEL of 100 mg/kg for TEHPA
was observed in male rats was following 28 days exposure.
Critical effect

Based on the available data the critical effect appears to be
heamatological changes from repeated dose toxicity after oral administration
in rats and local effects on skin and eyes.
Classification

TEHPA has been classified according to the substance directive by Bayer
AG in 1993 as follows: Xi (Irritant); R36/38 (Irritating to skin
and eyes).

Summary of known toxicity

Tri(2-ethylhexyl) phosphate appears to have slight acute oral toxicity.
Slight neurotoxic effects were observed in dogs administered 10.8, 26.4, 85
mg/m³ (12 weeks, 5 days/week, 6 hrs/day). Based on tests in
animals, tri(2-ethylhexyl) phosphate may produce moderate irritation of skin
and eyes, but a 24 hours exposure of the underarm on six test persons did not
result in any irritation of the skin although moderate erythema is observed in
exposed rabbits. Repeated dose toxicity studies in rats have shown
haematological changes at concentrations above the NOEL of 10 mg/kg bw.
Available studies indicate that there slight evidence of carcinogenicity in
female mice and equivocal evidence in male rats. An ECETOC working group ha
concluded that TEHPA is unlikely to be carcinogenic in humans.
Exposure versus toxicity

A comparison between the calculated exposure of consumers and the
available toxicological information about TEHPA indicates that the selected
exposure scenario represents a minor risk to human health, although moderate
erythema is observed in exposed rabbits.
General exposure of the population may occur through dermal contact with
consumer products containing tri(2-ethylhexyl) phosphate and ingestion of
contaminated food. Based on the selected scenario, the EASE-calculation
indicates that the consumer exposure to tri(2-ethylhexyl) phosphate is
relatively small and constitutes a limited contribution to the overall
exposure of humans. Concerning exposure in the working environment exposure
may occur through inhalation of dust particles and dermal contact when working
in places where tri(2-ethylhexyl) phosphate is handled.
The EASE-calculation indicates that the concentration of tri(2-ethylhexyl)
phosphate in the working environment of the selected scenario can reach levels
of up to 55 mg/m³ and 3 ppm. Inhalation of concentrations of this
magnitude has produced high mortality in rats.
5.4.3 Environmental assessment
Generally, data on environmental effects from TEHP from the acute aquatic
test systems are available. In the following the most sensitive data are
presented.
Table 5.32 Ecotoxicity and fate data on TEHPA.

TEHPA
Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation

(%)

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
50-100 (48 hrs)
>1.0
100 (LC₀)
>100 (3 hrs)
N.D.
2-22
0
25

(1.4 mg/l, 70 days)

Chronic
N.D.
N.D.
N.D.
N.D.
N.D.
-
-
-

Aquatic and terrestrial ecotoxicity

Based on the available data TEHPA is not toxic to aquatic organisms at
TEHPA water solubility level (up to 0.7 mg/l).
The available acute data on ecotoxicity show that TEHPA is harmful to algae
but the test duration is only 48 hours and not 72 hours as prescribed in the
recommended method, it is not possible to classify the toxicity more
precisely. A test on the ciliate Tetrahymena pyriformis is also
available where the LC50was 10 mg/l (Yoshioka et al., 1985).
No acute effects were seen on crustaceans in a low range study (Bayer 1999)
or up to the solubility limit of 1.0 mg/l (BUA 1996b).
TEHPA is not toxic to fish. In an acute 96 hours fish test with Brachydanio
rerio LC₀ was more than 100 mg TEHPA/l (Bayer 1999).
No chronic data was available.
Bioaccumulation

The available measured BCF values indicate that TEHPA is not
bioaccumulative Chemicals Inspection and Testing Institute, 1992). Log P_ow
values range from 0.8 to 5.04 predicting that TEHPA range from not
bioaccumulative to bioaccumulative.
Aerobic and anaerobic biodegradation
TEHPA is not readily biodegradable according to the available aerobic ready
biodegradation data (Chemicals Inspection and Testing Institute, 1992). The
compound is slowly biodegraded under anaerobic conditions when present in weak
solutions.
There is no data for TEHPA itself in Denmark, but three other phosphate
triesters were found in 11 of 20 sewage sludge samples at an average of 0.2 to
1.8 mg/kg dryweight (Kristensen et al., 1996) suggesting incomplete
degradation in sewage treatment plants.
Risk assessment

The PNEC is calculated with a safety factor of 1000 since data is
available for algae, crustacean and fish, and no chronic data is available
(Pedersen et al., 1995).
The lowest aquatic EC/LC₅₀ is 50, corresponding to an aquatic
PNEC of 0.05. In the following Table 5.33 the result of the risk assessment is
presented.
Table 5.33 Risk Assessment on TEHPA

Risk assessment
Aquatic

Surface_t
Sediment

Best guess

Aquatic
0.01
0.001

Worst case

Aquatic
0.05
0.005

According to the risk assessment the PEC will not exceed the PNEC in the
aquatic compartment.
No ecotoxocity data were available on organisms living in the neither in
the sediment or in soil.
5.5 Tri-2-ethylhexyl trimellitate; 3319-31-1
The family of trimellitates, pyromellitates and other polycarboxylic acid
esters are used for heat resistant plasticised PVC articles due to their
excep-tional thermal properties. Trimellitates are similar to phthalates in
compati-bility and plasticising effect.
5.5.1 Use, emission and exposure
Physical-chemical properties

This group is esters of trimellitic acid (1,2,4-benzene tricarboxylic
acid) and generally have a higher molecular weight and corresponding lower
vapour pressure resulting in a lower migration potential to aqueous solutions
compared to phthalates and other plasticisers.
The available solubility data of Tri-2-ethylhexyl trimellitate (TETM)
ranges from <100-100 mg/l at 20-25 C. The upper end of the water solubility
range places TETM among the relatively soluble substances investigated.

TETM has an estimated vapour pressure of 3.94 10^-11 mm Hg at 25 C,
which is a very low vapour pressure when compared to the other nine
substances.
The only measured LogP_ow value of 4.35 (European Commission
Joint Research Centre, 1996), indicates that TETM is lipophilic. The structure
of this substance also supports high (above 3) LogP_ow values. TETM
is among the more lipophilic substances in this assessment.
Migration

In a study of plasticisers in polypropylene packaging for foods TETM was
accidentally found almost half the samples (in the printing ink), but
migration was not studied (Nerín et al., 1993).
Migration from PVC to sunflower oil, isooctane or ethanol was 1,280; 1,220
and 450 mg/dm² respectively in studies over 1-3 days at the same
temperature (Hamdani, Feigenbaum 1996), corresponding to 30-80% of the total
TETM amount in the PVC piece. This was approx. twice the migration observed of
DEHP. The two PVC samples contained 23.5% DEHP and 27.5% TETM, respectively.
Blood platelet bags, which contained tri-(2-ethylhexyl) trimellitate as a
plasticiser, showed that a negligible amount of it leached into calf serum
(Chawla et al., 1991).
Use pattern for compound

The main uses of TETM may be in PVC-products used e.g. in the hospital
sector, packing, cables, profiles and floor and wall coverings, cf. Table 4.6.
Exposure in work the place

Focus in the EASE-calculation is on the production of cables.
The following assumptions are made with regard to the workplace exposure:

production takes place at a temperature of 180 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.
Possible main exposure routes in the workplace:
inhalation of vapours.

Based on this scenario, the EASE calculation provides the results shown in
Table 5.34.
Table 5.34 Estimated values of TETM in the working environment
according to the EASE calculation

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
3-10
ppm

Vapour concentration in air for workers
68.2-227
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

The EASE calculation focus has on use of cables in a normal private
house.
Based on this scenario the EASE calculation gives the results shown in
Table 5.35.
Table 5.35 The estimated potential daily intake of TETM by consumer
according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
2.16 x 10^-16
*

Dermal uptake
8.04 x 10^-21
*

Oral intake
0
*

Total chronic uptake via different routes
1.62 x 10^-16
*

Total acute uptake via different routes
0
*

*: The ADI has not been established. A Group restriction value of 0.05
mg/kg bw/d based on DEHP peroxisome proliferation data has conservatively been
assigned to other dialkyl esters.
Environmental exposure of humans

The amount established in the ’Usage’ section is used to calculate
exposure for a number of environmental compartments by EU TGD/EUSES. A
restriction value of 0.05 mg/kg bw/d (Group R) for food contact materials have
been allocated (SCF, 2000) for TETM, and this value is not exceeded according
to the EUSES estimates. Furthermore, as an ester TETM may potentially
hydrolyse in the gastro-intestinal fluid. Whether this also may occur to some
extent in the environment is not clear, and no data is available for TETM on
this property.
Table 5.36 The estimated human doses of TETM through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

TETM

Estimation (~ 1,800 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

4.6 10^-8
2.6 10^-7

Fish
BCF estimated*
1.0 10^-5
6.0 10^-5

Plants

Leaf crops
1. 10^-11
8 10^-11

Root crops
4 10^-10
2 10^-9

Meat

6 10^-10
4 10^-9

Milk

4 10^-10
2 10^-9

Air

3 10^-7
2 10^-6

Total regional

1.0 10^-5
6.2 10^-5

* Measured BCF value not available
Exposure in the environment

The estimated concentration levels of TETM reflects the low solubility in
aqueous solutions combined with the extraordinary high estimated LogP_ow
and a resulting association with particles (sediment and soils).
Table 5.37 The estimated regional concentrations of TETM in water,
soil and air.

Compartment
Aquatic

Terrestrial

Air

TETM
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. Soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m3

Estimation (~ 1,800 t)
6 10^-6
6 10^-6
0.00092
2 10^-10
9 10^-8
4 10^-10
8 10^-7
1 10^-6

Worst case (10,700 t)
4 10^-5
4 10^-5
0.0054
1 10^-9
5 10^-7
2 10^-9
5 10^-6
8 10^-6

Secondary poisoning

ETM has an extraordinary high estimated LogP_ow, which may give
rise to high bioaccumulation provided BCF also increases, and consequently a
risk of secondary poisoning.
TETM has a potential for secondary poisoning if the evaluation is based on
the estimated BCF alone and the estimated LogP_ow. However, if TETM
occurs under acidic or basic conditions a hydrolysis may take place thus
cleaving the ester bond producing the trimellitic acid and 2-ethylhexanols.
Whether this also may occur to some extent in the environment is not clear,
and no data is available for TETM. Trimellitic anhydride formed from the acid
at elevated temperature has a range of respiratory effects.
Table 5.38 The estimated regional concentrations of TETM in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants

Meat
Milk

TETM
Estimate
measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~ 1,800 t)
0.0063
n/a
8 10^-8
8 10^-10
0.0001
1 10^-7
5 10^-8

Worst case (10,700 t)
0.037
n/a
4 10^-7
5 10^-9
0.0008
9 10^-7
3 10^-7

5.5.2 Health assessment
Key toxicity data on TETM are presented Table 5.39.
Table 5.39 Selected toxicity data on TETM.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref. (datasheet)

Acute oral toxicity
Mouse

Rat

Rat
N.D.

N.D.

N.D.

LD₅₀>3.2 g/kg bw

LD₅₀>3.2 g/kg bw

LD₅₀=9.85 g/kg bw
2, 3

1, 3

2

Acute inhalation toxicity
Rat
N.D.
4 hrs
LC₅₀=2.6 mg/l
2, 3

Acute dermal toxicity
Rabbit
OECD 402/1981
24 hrs, covered
LD₅₀=1.97 g/kg bw. No overt clinical signs
2

Acute toxicity, other routes
Rat
i.p.

LD₅₀=3,200 mg/l
2

Irritation

- skin
Rabbit
OECD 404/1984
0.5 ml, occlusive, 24 hrs
Slightly irritating
2

- eye
Rabbit
OECD 405/1984
0.1 ml
Slightly irritating
2

- inhalation
Rat
N.D.
230 mg/m³, 6 hrs
Minimal irritation, no deaths
2

Rat
N.D.
16 ppm, 6 hrs
Moderate irritation
2

Rat
N.D.
2640 mg/m³, 6 hrs
Severe irritation
3

Sensitisation
Guinea pig
OECD 406/1981
0.5 ml, occlusive, 24 hrs, 10 applications
Not sensitising
2, 3

Repeated dose toxicity
Rat (Fisher 344)

Oral

0, 184, 650, 1826 mg/kg bw in diet (28 days).
LOAEL=184 mg/kg bw/day, slightly increased liver weights, slight
peroxisome proliferation
2

Dog
N.D.
14 and 42 mg/kg bw/day injections for 14 days
Increased relative liver and spleen weight in top dose group. LOAEL=42
mg/kg bw/day
2

Genetic toxicity
Salmonella typhimurium
Ames test, +/-

N.D.

Not mutagenic

2

CHO cells
In vitro mammalian cell gene mutation test, +/-
5-200 nl/ml
No chromosome aberration
2

Rat hepatocytes
HGPRT assay +/-
250-5000 nl/ml
No indication of UDS
2

Reproductive / developmental toxicity
-

Carcinogeni-city
Mouse (A)
N.D.
1,400 mg/kg bw/day
Negative
2

Experience with human exposure
Human

Inhalation
Mist and fumes from hot processing
May irritate eyes, nose, throat and upper respiratory tract
1

References: 1) European Commission Joint Research Centre (1996), 2)
European Commission Joint Research Centre (2000), 3) TNO BIBRA International
Ltd (1993)
Observations in human

Mist and fumes from hot processing may cause irritation, nausea and
vomiting.
Acute toxicity

TETM has been found to be of low acute oral and dermal toxicity in
laboratory animals. By inhalation the substance is more toxic and should be
classified as Xn (Harmful); R20 (Harmful by inhalation)
according to the classification criteria.
Irritation

TETM has been shown to irritate the skin of guinea pigs, rabbits and mice and
the eyes of rabbits (European Commission Joint Research Centre, 2000). TETM has
been shown to cause irritation when it is inhaled in rat studies (TNO BIBRA,
1993).
Sensitisation

An attempt to induce sensitisation in 10 guinea-pigs did not show any sign of
effect (TNO BIBRA, 1993).
Repeated dose toxicity

Increased weight of liver and spleen were reported in dogs following i.p.
exposure for 14 days. LOAEL was 42 mg/kg bw/day (European Commission Joint
Research Centre, 2000), In rats 28 days administration of TETM in the diet
resulted in slightly increased liver weights and peroxisome proliferation. LOAEL
was 184 mg/kg bw/day (European Commission Joint Re-search Centre, 2000).
Genetic toxicity

TETM is not found to produce any genotoxic effects, and the available data do
not indicate that TETM is mutagenic (European Commission Joint Research Centre,
2000).
Long term toxicity

Signs of reproductive toxicity or carcinogenicity were not reported in the
available data from laboratory studies. TETM was found to be negative in a
cancer study with mouse (European Commission Joint Research Centre, 2000).
NOAEL/LOAEL

The lowest identified LOAEL was 42 mg/kg bw/day following injections in
dogs for 14 days and 184 mg/kg bw/day following oral exposure in rats
(European Commission Joint Research Centre, 2000).
Summary of known toxicity

TETM has been found to be of low acute oral and dermal toxicity in
laboratory animals.
The skin of guinea pigs, rabbits and mice can be irritated by TETM, which
is also seen to irritate eyes of rabbits. TETM can cause irritation when
inhaled by rats.
Repeated oral administration of TETM in rats produced slightly increased
liver weights and peroxisome proliferation. Repeated injections in dogs
resulted in increased liver and spleen weights.
Critical effect

The identified critical effects related to lung changes observed in rats
from inhalation of the substance.
Classification

Based on one available inhalation study TETM should be classified Xn (Harmful);
R20 (Dangerous by inhalation). Other effects cannot be evaluated
properly.
Exposure versus toxicity

A comparison between the calculated exposure of consumers and the
available toxicological information about TETM indicates that the selected
exposure scenario represents a limited risk to human health. Slight irritation
may be expected.
General exposure of the population may occur through dermal contact with
consumer products containing TETM and ingestion of contaminated food. Based on
the selected scenario, the EASE-calculation indicates that the exposure of
TETM in consumers represents very small values and therefore probably
constitutes a limited contribution to the overall exposure of consumers.
Concerning exposure in the working environment, exposure may occur through
inhalation of dust particles and dermal contact when working at places where
TETM is handled. The EASE-calculation indicates that the concentration of TETM
in the working environment in relation to the selected scenario can reach
levels of up to 227 mg/m³ and 10 ppm. Rats exposed to 10 times this
concentration level have shown minimal irritation, but precautionary measures
may be necessary.
5.5.3 Environmental assessment
Generally, data on environmental effects from TETM are not available. Only
data on biodegradation are available. In the following the most sensitive data
are presented.
Table 5.40 Ecotoxicity and fate data on TETM.

TETM
Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
N.D.
>1

>1

N.D.
N.D.
N.D.
14, OECD 301C
N.D.

Chronic
N.D.
0.082

NOEC 21d
N.D.
N.D.
N.D.
-
-
-

N.D.: No data available.
Aquatic and terrestrial ecotoxicity

Very limited data on aquatic ecotoxicity of TETM are available (European
Commission Joint Research Centre, 2000), but in these experiments TETM is not
acutely toxic at solubility limit. A NOEC from a 21 days chronic experiment is
available. No data on terrestrial ecotoxicity were identified.
Bioaccumulation

No BCF data were available, but LogP_ow is above three (4.35),
and bioaccumulative properties may therefore be expected. The molecular weight
is close to 600, which may be assumed to limit the membrane transport and
general uptake of the compound.
Aerobic and anaerobic biodegradation

The available data indicates that TETM does not biodegrade readily
(European Commission Joint Research Centre, 2000). It should be noted that the
conditions of the biodegradation test were not listed in the reference, and it
cannot be determined whether the degradation is in reality ready or inherent.
Risk assessment

The data availability is insufficient for calculating PNECs according to
the EU TGD, since only two acute tests are available. If, however, it is
assumed that a PNEC for water based on e.g. the NOEC/100 is acceptable, the
assessment gives the following results (PNEC for water 0.0008 mg/l):
Table 5.41 Risk Assessment on TETM (based on incomplete data set)

Risk assessment
Aquatic

Surface_t
Sediment

Best guess

Aquatic
0.0075
0.005

Worst case

Aquatic
0.05
0.026

Based on the experience with phthalates and the relatively high
octanol-water partition coefficient of TETM, it may be assumed that the potential
for environmental effects is associated with the accumulation of the compound
in biota, in aquatic sediments and in soils amended with sewage sludge.
5.6 O-toluene sulfonamide; 88-19-7
5.6.1 Use, emission and exposure
Physical chemical properties

Alkyl sulfone esters are based on phenol, sulphate, and an alkyl chain.
The sulfone esters are more resistant toward hydrolysis than other ester based
plasticisers.
The available solubility data of o-toluene sulfonamide (OTSA) ranges from
slightly soluble in water to 1.62 g/l at 25 C. OTSA is relatively soluble
compared to the other investigated compounds.
OTSA has an estimated vapour pressure 6 10^-5 at 25 C, which is
one of the highest vapour pressure among the compounds investigated.
Only one measured value LogP_ow of 0.84 is available on OTSA
(HSDB 2000). The P_ow value places OTSA among the least lipophilic
compounds investigated here.
Migration

Less than 0.2 mg/kg (detection limit) migrated from package material
containing 0.96-3.3 mg/dm² to food (Nerín et al., 1993). The OTSA
concentration in the packaging material was, however, 100 times lower than for
other plasticisers.
Use pattern for compound

OTSA is not used much presently for plasticising purposes, and
information has proven difficult to obtain. In the substitution process it is
assumed that the main uses of OTSA may be in PVC-cables, cf. Table 4.6.
Exposure in the work place

The EASE-calculation focuses on the production of cables.
The following assumptions are made with regard to the workplace exposure:

production takes place at a temperature of 180 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.

Based on this scenario the EASE calculation provides the results shown in
Table 5.42.
Table 5.42 Estimated values of OTSA in the working environment
according to the EASE calculation.

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
0.5-3
ppm

Vapour concentration in air for workers
3.56-21.4
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

In the EASE, focus is on the use of cables in a private household.
Based on this scenario the EASE calculation provides the results shown in
Table 5.43.
Table 5.43 The estimated potential daily intake of OTSA by
consumers according to the EASE calculation.

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
5.82 x 10^-6
*

Dermal uptake
8.04 x 10^-13
*

Oral intake
0
*

Total chronic uptake via different routes
4.36 x 10^-6
*

Total acute uptake via different routes
0
*

*: The ADI has not been established
Environmental exposure of humans

The EUSES-calculation indicates that humans may by exposed for the
substance as illustrated in the following table.
Table 5.44 The estimated human doses of OTSA through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

OTSA

Estimation (30 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

0.000002
0.000253

Fish
BCF estimated*
2 10^-7
2.1 10^-5

Plants
Leaf crops
1 10^-7
5.2 10^-5

Root crops
2 10^-8
5.2 10^-6

Meat

2 10^-11
2.4 10^-9

Milk

3 10^-10
4 10^-8

Air

1 10^-10
5 10^-8

Total regional

0.000002
0.000331

* Measured BCF value not available
Exposure in the environment

The estimated concentration levels of OTSA show that concentrations in
the aqueous compartment are relatively high compared to other plasticisers due
to the high solubility of OTSA.
Table 5.45 The estimated regional concentrations of OTSA in water,
soil and air.

Compartment
Aquatic

Terrestrial

Air

OTSA
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m³

Estimation (30 t)
0.0001
0.0001
0.00005
9 10^-7
9 10^-7
3 10^-6
1 10^-5
7 10^-10

Worst case (10,700 t)
0.0089
0.0089
0.00634
3.1 10^-4
3.1 10^-4
9.4 10^-4
3.4 10^-3
2.4 10^-7

Secondary poisoning

Due to the high aqueous solubility and low LogP_ow the is no
indication of risk of secondary poisoning from OTSA.
Table 5.46 The estimated regional concentrations of OTSA in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants

Meat
Milk

OTSA
estimate
measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (30 t)
0.0001
N/A
3 10^-6
9 10^-6
9 10^-6
4 10^-9
4 10^-8

Worst case (10,700 t)
0.0125
N/A
9.6 10^-4
3.0 10^-3
3.0 10^-3
6 10^-7
6 10^-6

5.6.2 Health assessment
The key toxicity data on OTSA are presented in Table 5.47.
Table 5.47 Selected toxicity data on OTSA. No data on acute
toxicity, irritation, sensitivity or subchronic toxicity were identified.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
-

Acute inhalation toxicity
-

Acute dermal toxicity
-

Acute toxicity, other routes
-

Irritation

- skin

-

- eye
-

Sensitisation
-

Repeated dose toxicity
-

Genetic toxicity
Salmonella typhimurium
Ames test
N.D
Not mutagenic
2

Salmonella sp.
Modified Salmonella/microsome test
N.D.
Weak mutagenic effect.
1

Reproductive / developmental toxicity
Rat
N.D. (gavage)
0-250 mg/kg throughout gestation and lactation
Dose-response for bladder calculi in 21-day-old pubs and 105-day old
rats. Found to be teratogenic.
1

Carcinogenicity
Rat

N.D. (oral)

N.D.

Limited evidence.

1

Rat
N.D. (oral)
0, 20 and 200 mg/kg bw.

(lifetime)
No increased incidence of malignant tumours.
1

Experience with human exposure^*
A 2-month old infant

Oral dose

1,500 mg dose of sulfasalazine (same group as o-toluene-sulphonamide)
No symptoms of toxicity following inadvertent uptake.
1

* Only information on chemically related products; References: 1) HSDB
(2000), 2) Genetox (2000)
Observations in humans

No information regarding OTSA is available. A 2-month old infant did not
develop symptoms of toxicity following inadvertent uptake of a 1,500 mg dose
of sulfasalazine (same group as o-toluene sulphonamide).
One patient developed seizures, coma, hypoxia, hyperglycemia, metabolic
acidosis and methemoglobinemia after an oral dose of 50 mg sulfasalazine and
50 mg paracetamol.
Overdose of sulfasalazine resulted in coma in one patient and tremor in
another.
Acute toxicity

Relevant data not found.
Irritation

Relevant data not found.
Sensitisation

Relevant data not found.
Repeated dose toxity

Relevant data not found.
Generic toxicity toxicity

OTSA is reported to exhibit only weak mutagenic activity (Genetox
2000).
Long term toxicity

OTSA has been reported to be teratogenic in rats (HSDB 2000). This,
however, is based on studies without detailed descriptions of the study
design.
In connection with assessment of saccharine and its impurities, among
others OTSA, it has been found that these impurities are responsible for
the reproductive effects of impure saccharine.
There is limited evidence that OTSA is carcinogenic when administered
orally to rats. This has been suggested as the cause of carcinogenicity of
saccharin. The available data suggest that OTSA impurities at the levels
normally found in commercial saccharin do not contribute to the
carcinogenicity of saccharin
NOAEL/LOAEL

No NOAEL or LOAEL has been established.
Summary of known toxicity

O-toluene sulphonamide has been reported to be teratogenic in rats, but
only exhibiting a weak mutagenic activity.
There is limited evidence that o-toluene sulphonamide is carcinogenic when
administered orally to rats.
Critical effect

Based on very limited data the critical effect has been identified as
possible teratogenicity observed in rats.
Classification

It is not possible to evaluate the data against the classification
criteria for teratogenicity, as information is too sparse. Other described
effects are not classifiable.

Exposure versus toxicity

A comparison between the calculated exposure of consumers and the
available toxicological information about OTSA indicates that the selected
exposure scenario represents a minor risk to human health.
General exposure of the population may occur through dermal contact with
consumer products containing OTSA and ingestion of contaminated food. Based on
the selected scenario, the EASE-calculation indicates that the exposure of
OTSA in consumers represents very small values and therefore probably
constitutes a limited contribution to the overall exposure of consumers.
Concerning exposure in the working environment, exposure may occur through
inhalation of dust particles and dermal contact when working in places where
OTSA is handled. The EASE-calculation indicates that the concentration of OTSA
in the working environment of the selected scenario can reach levels of up to
21.4 mg/m³ and 3 ppm. Data are not available for comparison.
5.6.3 Environmental assessment
Generally, data on environmental effects from OTSA are not available. Only
data on bioaccumulation and biodegradation are available. In the following the
most sensitive data are presented.
Table 5.48 Ecotoxicity and fate data on OTSA

OTSA
Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
N.D.
N.D.
N.D.
N.D.
N.D.
0.4-2.6
0 (14 days)
N.D.

Chronic
N.D.
N.D.
N.D.
N.D.
N.D.
-
-
-

N.D.: No data available.
Aquatic and terrestrial ecotoxicity

No data on aquatic organisms or on terrestrial ecotoxicity of OTSA were
available.
Bioaccumulation

The available measured BCF indicate that OTSA do not bioaccumulate (Chemicals
Inspection and Testing Institute, 1992). The compound has no potential for
bioaccumulation based on the measured LogP_ow (0.84).
Aerobic and anaerobic biodegradation

According to the available data OTSA do not biodegradable readily or
inherently (Chemicals Inspection and Testing Institute, 1992).
Risk assessment

The data available are insufficient for calculating PNECs or providing other
indications of ecotoxicity for the assessment of risk of OTSA.
Based on the physical-chemical properties of OTSA, it must be assumed that
the potential for environmental effects is associated with the relatively high
aqueous solubility and consequent distribution to the aquatic environment.
5.7 2,2,4-trimethyl 1,3-pentandiol diisobutyrate;
6846-50-0
5.7.1 Use, emission and exposure
Physical chemical properties

Very little or no data is available on production and properties of
2,2,4-trimethyl 1,3-pentandiol diisobutyrate (TXIB).
The solubility data of 1,3-pentandiol diisobutyrate measured at an unknown
temperature is 0.001-0.002 g/l. TXIB is relatively insoluble compared to the
other investigated compounds.
In the latest edition of IUCLID (2000) an estimated vapour pressure of TXIB
is given (0.009), but no unit is reported. An EUSES assessment can not be
performed due to an incomplete data set.
Only an estimated value LogP_ow of 4.1 based on
extrapolation after liquid chromatography is available for TXIB (European
Commission Joint Research Center, 2000). The P_ow value places TXIB
among the more lipophilic compounds investigated here.
Use pattern for compound

The main uses of TXIB may be in the PVC-products used e.g. in the hospital
sector, packing, cables, profiles, floor and wall coverings, printing ink and
paint/lacquer, cf. Table 4.6.
Exposure in the work place

Sufficient physical-chemical data have not been available to perform an EASE
calculation.
It is estimated that part of the production is a calendar/press. This
process has been assumed to take place at a temperature of 200 º C and with
the legally required exhaust ventilation. It is further assumed that contact
with the substance may be extensive due to formation of aerosols during the
production.
Based on this scenario, and in recognition of the lack of data concerning
health, it may be concluded that TXIB may occur in the working environment in
concentrations, which can be of concern. However, there is a need for more
information to substantiate this conclusion.
Consumer exposure

The lack of available physical-chemical and toxicological data points at a
need for further investigation of the exposure of the substance to consumers.
Exposure in the environment

Insufficient data is available for estimation of environmental concentrations
with the EUSES model.
5.7.2 Health assessment
Summary of known toxicity

The key available toxicity data for TXIB are presented in Table 5.49.
Table 5.49 Selected toxicity data on TXIB.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Rat
N.D.

LD50 > 3,200 mg/kg bw
1

Acute inhalation toxicity
Rat
N.D.
0.53 or 0.12 mg/l for 6h
LC50 > 5.3 mg/l
1

Acute dermal toxicity
Guinea pig
N.D.

LD50 > 20 ml/kg
1

Acute toxicity, other routes
Rat
N.D. (i.p.)

LD50 approx. 3,200 mg/kg bw
1

Irritation

- skin
Guinea pig
N.D.
Covered and uncovered. Dose not mentioned.
Slight skin irritation when uncovered. More irritating when covered.
1

- eye
Rabbit
OECD 405
0.1 ml
Not irritating
1

Sensitisation
Guinea pig
OECD 406
Injection via foot pad. No detailed information
Not sensitising
1

Repeated dose toxicity
Sprague Dawley rats
N.D. (oral)
0.1 and 1 % w/w for 52 or 99 days
NOAEL = 0.1%

LOAEL=1%

Reversible liver weight change in high dose group
1

Dog (Beagle)
N.D. (oral)
0.1%, 0.35%, 1%

13 weeks
No significant findings
1

Genetic toxicity
-

Reproductive / developmental toxicity
-

Carcinogenicity
-

Experience with human exposure
-

References 1) European Commission Joint Research Centre (2000)
Acute toxicity

Acute toxicity has been tested at doses where no effects were observed.
Precise LD₅₀-values are therefore not identified ((European
Commission Joint Research Centre, 2000).
Irritation

TXIB was observed to be slightly irritating in guinea pigs, especially when
covered, but has not been observed to be irritating to rabbit eyes (European
Commission Joint Research Centre, 2000).
Sensitisation

Sensitisation has not been observed in the reviewed data (European Commission
Joint Research Centre, 2000).
Repeated dose toxicity

In a repeated dose toxicity study in rats reversible liver weight changes
were observed in the high dose group (1%) (European Commission Joint Research
Centre, 2000).
Genetic toxicity

No data available.
Long term toxicity

No data available.
NOAEL/LOAEL

In a repeated dose toxicity study in rats a NOAEL of 0.1% TXIB in the diet.
has been identified. Reversible liver weight changes were observed in the high
dose group (1%) (European Commission Joint Research Centre, 2000).
Critical effect

The critical effect based on the available data appears to be the repeated
dose toxicity following oral administration in rats.
Classification

It id not possible to conclude about the classification of TXIB based on the
available literature.
Summary of known toxicity

The few available data indicate that TXIB is a substance of low toxicity.
Results from animal tests do not fulfil the classification criteria with
regard to acute toxicity, skin and eye irritation and skin sensitisation.
Reversible liver changes were found rats in a chronic study whereas chronic
toxicity testing in beagles did not reveal any significant findings.
5.7.3 Environmental assessment
The only available data on TXIB is the estimated LogP_ow of 4.1,
which indicates that this compound is lipophilic with some potential for
bioaccumulation (LogP_ow >3).
Only a very limited data set is available on aquatic ecotoxicity for TXIB.
No effects were apparently observed in the reported test ranges, and a NOEC

(96h) for these acute tests are given as 1.55 mg/l. No information on
terrestrial ecotoxicity of TXIB was available.
Aerobic and anaerobic biodegradation cannot be evaluated since no data or
incomplete data on TXIB were available.
Table 5.50 Ecotoxicity and fate data on TXIB.

TXIB
Aquatic (mg/l)

Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
N.D.
>1.46

LC₅₀(96h)
>1.55

N.D.
N.D.
N.D.
99.9 % at

650 mg/l (incomplete)
N.D.

Chronic
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.

N.D.: No data available.
Risk assessment

The data availability is insufficient for calculating PNECs or providing other
indications of ecotoxicity for the assessment of risk of TXIB.
5.8 Epoxidised soybean oil; 8013-07-8
5.8.1 Use, emission and exposure
Physical-chemical properties

Epoxidised soybean oil (ESBO) the dominant plasticiser among the epoxidised
oils and is produced by epoxidation of soybean oil. ESBO has a high molecular
weight and a spacious molecular structure. These two properties in combination
make ESBO more resistant to migration. The high molecular weight and the
linear structure of ESBO cause these plasticisers to work less effective at
lower temperatures.
The only available data on ESBO is the estimated LogP_ow of >6
which indicates that this compound is lipophilic (Syracuse Research
Corporation, 2000). When compared to the other investigated substances, the
magnitude of the LogP_ow value is in the higher end.
Migration

ESBO (used as a stabiliser) showed limited migration from PVC to three
lipophilic solvents in the study by Hamdani and Feigenbaum (1996). Typically,
approx. half the migration observed for DEHP and less than half compared to
TETM. However, in the more polar ethanol ESBO migrate equal to or more than
the other plasticisers.
Gilbert et al. (1986) demonstrated that ESBO migrated from PVC bottles to
diethyl ether in a 10 days test at 306 mg/dm² or 3,492 mg/kg. The
ESBO was characterised as ranging from C₁₂ to C₂₀ with
mainly epoxy-oleate (25%) and epoxy-linoleate (52%). Migration of ESBO into
three aqueous simulants (water, 50% ethanol and 3% acetic acid) ranged from
0.23 to 0.3 mg/kg.
Levels of ESBO in fresh retail meat samples wrapped in film ranged from
less than 1 to 4 mg/kg, but were higher in cooked food and in foods heated in
microwave oven (Castle et al., 1990).
The available data on physical-chemical properties does not suffice to
establish an EUSES scenario. This is a general problem for mixtures.
Use pattern for compound

The main uses of ESBO may be in PVC-products such as those used in packing,
cables, printing ink, paint/lacquer, adhesives and fillers, cf. Table 4.6.
Exposure in the work place

Since ESBO is a mixture of different substances, it is not possible to make an
EASE-calculation. As seen in the next section, ESBO may be regarded as only
slightly acute toxic by ingestion.
As a worst-case situation involving ESBO in the working environment,
professional painting in a room with out ventilation (e.g. a private
household) has been selected.
It is concluded that the exposure in the work place is of minor importance,
since the substance is mainly toxic by ingestion. Normal hygiene in the
working environment, such as washing hands before eating, is sufficient to
reduce the exposure.
Consumer exposure

It is not possible to conduct an EASE-calculation on a mixture such as ESBO.
Living in a painted house, which is painted once a year has been assumed to
be a worst-case situation.
As the most important toxic feature of ESBO is oral toxicity, living in a
painted house is not expected to result in severe effects.
It cannot be excluded that consumers may ingest minor amounts of ESBO
during the yearly work with painting in the house. The most sensitive persons
may develop effects as described in the following section.
Environmental exposure of humans

Environmental exposure of humans and exposure of the environment cannot be
assessed by EUSES or EASE due to lack of data. However, the prominent
physical-chemical feature of ESBO is the LogP_ow, which is
relatively high. Exposures from the environment will therefore be expected
from particulate phases (soil and sediment) and possibly from biological
material.
5.8.2 Health assessment
The most significant toxicity data on ESBO are presented in Table 5.51.
Table 5.51 Selected toxicity data on ESBO.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Rat
N.D.
5,000, 21,000 - 40,000 mg/kg bw.
5,000 mg/kg caused dyspnoe and diarrhoea.

LD50>5,000 mg/kg bw.
1

N.D.

N.D.
LD50>5,000 mg/kg bw

Acute inhalation toxicity
-

Acute dermal toxicity
Rabbit
N.D.
Occlusion (24 hours)
LD50>20,000 mg/kg bw
1

Acute toxicity, other routes
-

Irritation

- skin
Rabbit
EPA, Federal reg., Vol 43, No.163
Occlusion (24 hours)
Not irritating
1

- eye
Rabbit
EPA, Federal reg., Vol 43, No.163
0.5 ml instillation
Not irritating
1

Sensitisation
Guinea pig
N.D.
Induction, i.c. injections, rechallenge with patch tests
Not sensitising
1

Repeated dose toxicity
Rat
N.D. (oral)
0.25% and 2.5%

2 years
NOAEL=1.3 mg/kg bw. Slight injury in uterus at 2.5%.

1

Rat
N.D.
10 g/kg bw. Epoxide no. 14.6 - 111.5

Up to 10 weeks
Slow growth, death in group receiving ESBO with epoxide no.>49.7.
E.No. 105-111.5 – severe degeneration of testes.
1

Rat
N.D. (oral)
1.4 g/kg/ appl.,

2 appl. / week

16 months
NOAEL=1.400 mg/kg

(effects not mentioned)
1

Genetic toxicity
Salmonella typhimurium

Mouse lymphoma cell, L5178Y
Ames test

+/-
N.D
Not mutagenic

Not mutagenic
1

1

Reproductive / developmental toxicity
Rat
OECD 415

(gavage)
100, 300 and 1000 mg/kg bw.0-250 mg/kg
NOAEL, parental=1,000 mg/kg bw; NOAEL, offspring=1,000 mg/kg bw.
Severe degeneration of testes in animals treated with compound with
epoxide no. 105-111.5.
1

Carcinogeni-city
Rat
N.D. (Oral)

<2.5% (1.4 g/kg bw).
No evidence of carcinogenicity.
1

Experience with human exposure
Human
Inhalation

Asthma developed in a worker exposed to vapour from heated polyvinyl
chloride film containing ESBO. Challenge with ESBO vapour of unspecified
concentration produced asthmatic symptoms within 5 min.
1

References: 1) European Commission Joint Research Centre (1996)
Observations in humans

A worker exposed to vapours from heated polyvinyl chloride film containing
ESBO developed asthma. Challenge with ESBO vapour of unspecified concentration
produced asthmatic symptoms within 5 min (European Commission Joint Research
Centre, 1996).
Acute toxicity

In the acute oral tests LD₅₀in rats ranged between
21,000-40,000 mg/kg bw. indicating low acute oral toxicity. Acute dermal
toxicity was low as well; LD50<20,000 mg/kg bw (European Commission
Joint Research Centre, 1996).
Irritation

ESBO was shown to be not irritating to skin (European Commission Joint
Research Centre, 1996).
Sensitisation

Sensitisation has not been observed in the reviewed data (European
Commission Joint Research Centre, 1996).
Repeated dose toxicity

ESBO was found to produce slight injuries in uterus of rats in a repeated
dose toxicity study (European Commission Joint Research Centre, 1996).
Genetic toxicity

In the reviewed data ESBO has not been seen to be mutagenic (European
Commission Joint Research Centre, 1996).
Mutagenicity testing was conducted on two plasticisers commonly used in
plastic clingfilm manufacturing, acetyl-tributylcitrate and epoxidized
soy-bean oil. There are no records of mutagenic testing using a bacterial
screening method for these two compounds. The two plasticisers were
screened using mutant strains of Salmonella typhimurium. The tests
indi-cated that they were not mutagenic (Heath & Reilly 1982).
Long term toxicity

Based on the limited available data, ESBO was not found to be a potential
carcinogen or to exhibit reproductive toxicity. Severe degradation of
testes has been observed with test material characterised by a high
epoxide no. (105-111.5) (European Commission Joint Research Centre, 1996).
NOAEL/LOAEL

In a repeated dose toxicity study in rats a NOAEL of 1.3 mg/kg bw. has been
identified. At the higher concentration, slight injury in uterus appeared. In
reproductive toxicity tests in mouse and rat, the NOAEL for the parental group
was 1,000 mg/kg bw and the NOAEL for the F1 offspring were 1,000 mg/kg bw
(European Commission Joint Research Centre, 1996).
Critical effect

The critical effect based on the available data appears to be repeated dose
toxicity following oral administration and reproductive toxicity.
Classification

The substance is not classifiable based on available data.
Summary of known toxicity

Based on the available data ESBO can only be regarded as slightly acute toxic
by oral exposure. A TDI of 1 mg/kg has been allocated from the EU Scientific
Committee for Food (SCF, 2000).
5.8.3 Environmental assessment
Generally, some data on environmental effects from ESBO are available,
especially from acute aquatic test systems. In the following the most
sensitive data are presented.
Table 5.52 Ecotoxicity and fate data on ESBO.

ESBO
Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
N.D.
8 (24 hrs)
900 (48 hrs)
>100 (3 hrs)
N.D.
N.D.
78-79

(at 2 or 10 mg/l)
N.D.

Chronic
N.D.
N.D.
N.D.
N.D.
N.D.
-
-
-

N.D.: No data available.
Aquatic and terrestrial ecotoxicity

No data from test following standard methodology were available. All test
results are from test with a shorter duration. Despite the shorter test
duration ESBO was shown to be toxic (LC₅₀=8 mg/l) to the crustacean
Daphnia magna in a 24 hours test (European Commission Joint
Research Centre, 1996). ESBO could be classified as toxic to crustaceans but a
more precise classification is not possible on the basis of the present data.
ESBO was not toxic to the freshwater fish Leuciscus idus in a 48
hours acute toxicity test (European Commission Joint Research Centre, 1996).
Bioaccumulation

No BCF data were available. The estimated Log P_ow>6 indicate
that ESBO is bioaccumulative.
Aerobic and anaerobic biodegradation

ESBO is ready biodegradable according to the results of two standard OECD
tests.
Risk assessment

The PNEC for ESBO is 0.008 mg/l based on the available data and an assessment
factor on 1,000 (only test results from two trophic levels).
The data availability is insufficient for calculating PEC and therefore no
risk assessment of ESBO is possible.
5.9 Dipropylene glycol dibenzoate; 27138-31-4
5.9.1 Use, emission and exposure
Physical-chemical properties

The water solubility of dipropylene glycol dibenzoate (DGD) is 1.5 mg/l at 25
C. The magnitude of the water solubility of DGD, places this substance in the
group of less water soluble among the substances investigated.
DGD has a vapour pressure of 4.7 10^-7 mmHg at 25 C, which when
compared to the nine other substances is of smaller magnitude.
Only an estimated LogP_ow of 3.88 value is available on
DGD. The magnitude of this parameter indicates that DGD has lipophilic
properties.
Migration

Migration data on DGD has not been identified.
Use pattern for compound

Information on the production and uses of DGD has not been located. The main
uses of DGD may be in adhesives and fillers, cf. Table 4.6.
Exposure in the work place

The EASE calculation focuses on the production of adhesives and fillers.
The following assumptions are made with regard to the workplace exposure:

production takes place at a temperature of 20 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.

Based on this scenario the EASE calculation provides the results shown in
Table 5.53.
Table 5.53 Estimated values of DGD in the working environment
according to the EASE calculation

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
0.5-3
ppm

Vapour concentration in air for workers
7.12-42.7
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

In the calculation in EASE, focus is on normal use of the bathroom in a
private household.
Based on this scenario the EASE calculation gives the results shown in
Table 5.54.
Table 5.54 The estimated potential daily intake of DGD by consumer
according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ADI

Inhalatory intake
5.82 x 10^-6
*

Dermal uptake
8.04 x 10^-13
*

Oral intake
0
*

Total chronic uptake via different routes
4.36 x 10^-6
*

Total acute uptake via different routes
0
*

*: The ADI is not established
Environmental exposure of humans

The slight lipophilic properties of DGD cause the compound to accumulate in a
minor degree in fish. A measured BCF is not available.
Table 5.55 The estimated regional concentrations of DGD in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants

Meat
Milk

DGD
estimate
measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~ 200 t)
0.1
N/A
0.007
0.0028
0.0028
8 10^-6
2 10^-6

Worst case (10,700 t)
1.3
N/A
0.093
0.0051
0.0051
1.03 10^-4
3.3 10^-5

Exposure in the environment

DGD has lipophilic properties based on an estimated LogP_ow and this
will tend to distribute the compound to the particulate phases.
Table 5.56 The estimated regional concentrations of DGD in water,
soil and air.

Compartment
Aquatic

(mg/l)

Terrestrial

Air

DGD
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m3

Estimation (~ 200 t)
0.0004
0.0004
0.02
0.0004
0.003
0.0001
0.007
1 10^-8

Worst case (10,700 t)
0.0032
0.0032
0.17
0.0220
0.046
0.0013
0.346
5.8 10^-7

Secondary poisoning

No BCF value is available. The LogP_ow is relatively high (3.88) and
secondary poisoning cannot be excluded. However, if DGD occurs under acidic or
basic conditions hydrolysis of the ester bond may take place producing the
benzoic acid and diethylene glycol. Whether this also may occur to some extent
in the environment is not clear, and no data on hydrolysis is available for
DGD.
Benzoic acid occurs in nature in free and combined forms. It has been used
over many years as a preservative in foodstuffs in concentrations up to 0.1%.
The human intake from natural sources is low compared to the contribution from
foodstuffs (Thorup 1999). An ADI has been assigned by FAO/WHO (cf. Thorup,
1999) of 5 mg/kg bw for benzoic acid.
Table 5.57 The estimated human doses of DGD through intake of
water, fish, leaf of crops, roots of crops, meat, milk and air.

DGD

Estimation (~ 200 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

0.00001
0.00009

Fish
BCF estimated*
0.0002
0.0021

Plants

Leaf crops
4.80 10^-6
8.67 10^-5

Root crops
0.00004
0.00051

Meat

3 10^-8
4.4 10^-7

Milk

2 10^-8
2.6 10^-7

Air

3 10^-9
1.3 10^-7

Total regional

0.0003
0.0028

* Measured BCF value not available
5.9.2 Health assessment
Summary of known toxicity
There is not sufficient data to describe the toxicity of the substance.
Some benzoic acid derivatives will hydrolyse in aqueous solutions,
especially in the acidic gastro-intestinal environment. Information regarding
this property is not available for DGD. If the ester bonds of DGD are
hydrolysed before exposure of humans this would significantly change the
toxicological properties. The resulting benzoic acid is a compound well known
to man and it is permitted for conservation purposes in food (Thorup, 1999).
5.9.3 Environmental assessment
No data on the environmental effects from DGD are available.
Aquatic and terrestrial ecotoxicity

No data on aquatic and terrestrial ecotoxicity of DGD were available, and
there is no information regarding toxicity to microorganisms. Preliminary QSAR
estimates by Danish EPA lead to the classification N; R50/53 (May cause long
term effects in the aquatic environment).
Bioaccumulation

No BCF data on DGD were available. The estimated Log P_ow of 3.88
(Syracuse Research Corporation, 2000) indicate that DGD is potentially
bioaccumulative.
Biodegradation

No data were available on aerobic or anaerobic biodegradation of DGD.
Risk assessment

The data availability is insufficient for calculating PNECs or providing other
indications of ecotoxicity for the assessment of risk of DGD.
In parallel with case for humans some benzoic acid derivatives will
hydrolyse in aqueous solutions, especially in an acidic environment. This
would significantly alter the ecotoxicological and fate properties relative to
the parent substance. Benzoic acid occurs naturally, e.g. in berries (Thorup,
1999). Information regarding this property is not available for DGD.
5.10 Dioctyl sebacate; 122-62-3
Sebacates are used to impart good low temperature flexibility similarly to
adipates and azelates, and generally have the same plasticising properties (Gächter
and Müller, 1993).
5.10.1 Use, emission and exposure
Physical-chemical properties

Dioctyl sebacate (DOS) is in fact the ethylhexyl rather than the octyl
compound, but is usually referred to as DOS, and this denotion is kept here.
DOS has very low water solubility. The data range from ‘insoluble’ to an
estimated 0.35^mg/l. The upper end of the water solubility range
places DOS among the most water insoluble substances assessed here.
The estimated log octanol-water partition coefficient of 10 indicates that
DOS is a very lipophilic compound when compared to the other substances in
this assessment.
DOS has an estimated vapour pressure of 1.0´10^-7 mm Hg at 25 C,
which is moderate among the investigated substances.
In the same chemical family, dibutyl sebacate exhibits the characteristics
of a slightly smaller compound with higher water solubility, a higher vapour
pressure, and it will presumably be less lipophilic. For the EUSES calculation
DOS has been set at the maximum octanol-water partition coefficient allowed
(LogP_ow = 6) and the lowest possible water solubility.
Migration

A British study of retail food wrapped in plasticised PVC showed considerably
higher concentrations of dibutyl sebacate in several food products (76-137
mg/kg) than various phthalate esters, acetyl tributyl citrate and diphenyl
2-ethylhexyl phosphate, which were typically less than 10 mg/kg (Castle et
al., 1988b).
Use pattern for compound

The main uses of DOS is anticipated to be in printing ink and adhesives, cf.
Table 4.6.
Exposure in work place

The EASE calculation focuses on the production of printing inks.
The following assumptions are made with regard to the workplace exposure:
production takes place at a temperature of 30 °C
required legal exhaust ventilation is in place
contact with the substance will only take place incidentally, e.g. in
relation to cleaning and maintenance of production equipment.
Based on this scenario, the EASE calculation provides the results shown in
Table 5.58.
Table 5.58 Estimated values of DOS in the working environment
according to the EASE calculation

Route of exposure
EASE value
Unit

Vapour concentration in air for workers
0.5-3
ppm

Vapour concentration in air for workers
8.87-53.2
mg/m³

Potential dermal uptake for workers
0
mg/kg/day

Consumer exposure

In the calculation in EASE focus is on half an hour daily reading of magazine
containing printing ink.
Based on this scenario the EASE calculation gives the results shown in
Table 5.59.
Table 5.59 The estimated potential daily intake of DOS by consumer
according to the EASE calculation

Route of exposure
Daily intake in mg/kg bw/day
Ratio of the ‘ADI’ (0.05 mg/kg bw/day)^a%

Inhalatory intake
5.82 x 10^-6
5.01 x 10^-2

Dermal uptake
8.04 x 10^-13
1.61 x 10^-9

Oral intake
0
0

Total chronic uptake via different routes
4.36 x 10^-6
8.72 x 10^-3

Total acute uptake via different routes
0
0

^{a The Group restriction value of 0.05 mg/kg bw/d is based on DEHP
peroxisome proliferation data (which is considered conservative).
Environmental exposure of humans

The amount established in ’Usage’ section is used calculate exposure for a
number of environmental compartments by EU TGD/EUSES. The dose is almost
completely derived from consumption of root crops. This is due to the
extraordinary high LogP_ow of DOS leading to accumulation in
agricultural soil. No measured data are available for accumulation in plants.
In consideration of the large differences between measured and estimated
BCFs, care must be exerted in the interpretation of the actual
bioconcentration in the environment and estimates based on high LogP_ow.
This is also even clearer reflected in the roots crop dose. If the group
restriction value of 0.05 mg/kg bw/d is applied as an ‘ADI’, the ratio to
‘ADI’ is higher than acceptable (almost 1 in ‘Estimation’, almost 6 in
‘Worst case’), and further elucidation is necessary. A TDI of 3 mg/kg bw/d
is available for sebacic acid (SCF, 2000). Data are not available to determine
whether DOS will hydrolyse when ingested with root crops.
Table 5.50 The distribution of DOS seen in relation to the accepted
daily intake.

DOS

Estimation (1,500 t)
Worst case (10,700 t)

mg/kg/d
mg/kg/d

Drinking water

3.0 x 10^-6
2.2 x 10^-5

Fish
BCF estimate
0.0015
0.011

Plants
Leaf crops
8.1 x 10^-6
0.000058

Root crops
0.037
0.27

Meat

0.00023
0.0017

Milk

0.00014
0.00098

Air

8.7 x 10^-8
6.2 x 10^-7

Total regional

0.039
0.28

Exposure in the environment

The estimated concentration levels of DOS indicate the expected very low
aqueous concentration due to the low solubility, and a high concentration in
the particulate phases (sediment and soils).
Table 5.61 The estimated regional concentrations of DOS in water,
soil and air.

Compartment
Aquatic

(mg/l)

Terrestrial

Air

DOS
Surface_t
Surface_d
Sediment
Natural
Agricultural
Porewater of agri. soil.
Industrial

mg/l
mg/l
mg/kg
mg/kg
mg/kg
mg/l
mg/kg
mg/m3

Estimation (~ 1,500 t)
0.00004
0.00002
0.5
0.3
1.2
0.00011
4.0
4 10^-7

Worst case (10,700 t)
0.00030
0.00014
3.3
2.2
8.8
0.00076
28.5
2.9 10^-6

Secondary poisoning

DOS has a potential for secondary poisoning if the evaluation is based on the
estimated BCF alone and the estimated LogP_ow. The ADI is exceeded
in the worst case scenario, and nearly so in the estimation scenario. The dose
is almost completely derived from consumption of root crops. This is due to
the extraordinary high LogP_ow of DOS leading to accumulation in
agricultural soil. No measured data are available for accumulation in plants.
In consideration of the large differences between measured and estimated
BCFs, care must be exerted in the interpretation of the actual
bioconcentration in the environment and estimates based on high LogP_ow.
However, a dibutyl derivative of sebacic acid has been shown to hydrolyse in
the gastro-intestinal fluid. Whether this also may occur to some extent in the
environment is not clear, and no data is available for DOS. The TDI of sebacic
acid (3 mg/kg bw) is 60 times higher than the value for DOS.
Table 5.62 The estimated regional concentrations of DOS in fish,
plants, meat and milk.

Articles of food
Wet fish
Plants

Meat
Milk

DOS
estimate
measured
Roots
Leaves
Grass

mg/kg
mg/kg
mg/kg
mg/kg
mg/kgww
mg/kgww
mg/kgww

Estimation (~ 1.500 t)
0.92
n/a
6.8
0.0005
0.0005
0.54
0.017

Worst case (10,700 t)
6.58
n/a
48.5
0.0034
0.0034
0.39
0.122

5.10.2 Health assessment
The most significant toxicity data on DOS are presented in Table 5.63.
Table 5.63 Selected toxicity data for DOS.

Toxicology
Species
Protocol
Dose levels / duration
Results
Ref.

Acute oral toxicity
Rat
N.D.

LD₅₀=1,280 mg/kg bw.
4

Acute inhalation toxicity
Rat
N.D.
250 mg/m³ for 4 hours
No adverse effects observed
1

Acute dermal toxicity
-

Acute toxicity, other routes
Rat

Rabbit
N.D. (i.v.)

N.D. (i.v.)

LD₅₀=900 mg/kg bw.

LD₅₀=540 mg/kg bw
4

Irritation

- skin
N.D.
N.D.
N.D.
Not irritating, not absorbed through skin.
2

- eye
-

Sensitisation
-

Repeated dose toxicity
Rat
N.D. (inhalation study)
250 mg/m³ for 4 hrs/d, 5 d/week, 13 weeks
No adverse effects observed
1

Rat (♂)
N.D. (oral)
1 g/kg bw/day

3 weeks
Increased liver weight, peroxisome proliferation, increased levels of
peroxisome enzymes
1

Genetic toxicity
Salmonella typhimurium
Ames test
N.D
Not mutagenic
3

Reproductive / developmental toxicity
Rat
N.D. (oral)
10 mg/kg bw/day (19 months)
No effects observed
2

Carcinogeni-city
Rat
N.D. (oral)
10 mg/kg bw/day (19 months)
No effects observed
2

Experience with human exposure
Human
-
60 mg/m³; 1 min

Inhalation
Reported threshold of irritant action on mucous membranes of upper
resp. tract and eyes.
1

Humans
-
48 h covering and patch test
No effects observed
1

References: 1) BIBRA (1996), 2) HSDB (2000), 3) CCRIS (2000), 4) NTP (2000)
Observations in humans

Volunteers did not produce signs of irritation or sensitisation during a
48 hours covering and patch test (BIBRA, 1996).
DOS aerosols have been used to demonstrate particle deposition in lungs and
respiratory tract, apparently without producing overt toxic effects.
Exposure to 60 mg/m³ for 1 minute is reported to be the
threshold of irritant action on the mucous membranes of the upper respiratory
tract and eyes. No further details are available (BIBRA, 1996).
Acute toxicity

The oral LD₅₀ for rats is found to be relatively low equal to 1,280
mg/kg bw (NTP, 2000).
No adverse effects were observed when rats were exposed to a concentration
of 250 mg/m³ for 4 hours.
Irritation/Sensitisation

Exposure to DOS
did not cause irritation or sensitisation on skin in human volunteers during 48
hours covering and patch tests (HSDB 2000).
Repeated dose toxicity

Adverse effects were also not seen in a 13 weeks study where 12 rats were
exposed to 250 mg/m³ for 4 hours per day, 5 days a week (BIBRA,
1996).
Genetic toxicity

DOS was not found to be mutagenic in Ames test.
Long term toxicity

Rats fed a diet containing 10 mg/kg bw for up to 19 months did not show any
carcinogenic effects and the reproduction was normal in a 4 generation study of
rats fed about 10 mg/kg bw (HSDB 2000).
NOAEL/LOAEL

A NOAEL or LOAEL has not been established, but a dose of 10 mg/kg bw did not
produce any carcinogenic effects or reprotoxic effects in 19 month feeding
studies in rats (HSDB 2000).
Critical effect

The critical effect based on the available data is the acute toxic effect
following oral administration.
Classification

The critical effect based on the available data is the acute toxic effect
observed in rats following oral administration. Effects include reduced
co-ordination, laboured breathing and diarrhoea, with tissue damage in the
liver, spleen, brain and heart (Bibra 1996).
Summary of known toxicity

DOC exhibits moderate acute toxicity when administered orally to rats and
fulfils the criteria for classification as harmful if swallowed.
The substance does not seem to be an irritant or a sensitiser.
Repeated oral administration to rats showed effects on the liver but no
signs of carcinogenicity or reproductive toxicity were seen in rat studies.
Daily intake

The EU's Scientific Committee for Food has defined a group restriction for DOS
and other dialkyl esters equal to 0.05 mg/kg bw/day (SFC 2000).
Exposure versus toxicity

A comparison between the calculated exposure of consumers and the available
toxicological information about DOS indicates that the selected exposure
scenario represents a minor risk to human health.
General exposure of the population may occur through dermal contact with
consumer products containing DOS and ingestion of contaminated food. Based on
the selected scenario, the EASE-calculation indicates that the exposure of DOS
in consumers represents for some routes very small values and therefore
probably constitutes a limited contribution to the overall exposure of
consumers. However the inhalation of the product represents a relatively high
ratio of the daily intake at a level (0.05%). As seen in Table 5.64 this means
that the intake of fish and root crops might be of concern.
Concerning exposure in the working environment, exposure may occur through
inhalation of dust particles and dermal contact when working in places where
DOS is handled. The EASE-calculation indicates that the concentration of DOS
in the working environment of the selected scenario can reach levels of up to
53.2 mg/m³ and 3 ppm.
5.10.3 Environmental assessment
Table 5.64 Ecotoxicity and fate data on DOS.

Aquatic

(mg/l)

Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
Microorganisms

Aerobic
Anaerobic

BCF
28 days

Acute
N.D.
N.D.
N.D.
N.D.
N.D.
45,000
N.D.
N.D.

Chronic
N.D.
N.D.
N.D.
N.D.
N.D.
(estimate)
N.D.
N.D.

Aquatic and terrestrial ecotoxicity

No data on ecotoxicity has been identified for DOS or dibutyl sebacate.
Sebacic acid is generally considered relatively safe (see ‘secondary
poisoning’), but no data on hydrolysability is available. Aquatic or
terrestrial PNECs cannot be calculated with basis in data on DOS.
Bioaccumulation

Only an estimated BCF is given indicating high bioaccumulation potential
(Syracuse Research Corporation, 2000).
Aerobic and anaerobic biodegradation

The high lipophilicity of DOS and other sebacate plasticisers will generally
lead to low bioavailability to microorganisms in STP. The biodegradation of
phthalate esters is relatively slow due to a lag phase, but complete
mineralisation is possible under anaerobic conditions (Kleerebezem et al.,
1999).
Risk assessment

The data availability is insufficient for calculating PNECs or providing other
indications of ecotoxicity for the assessment of risk of DOS or dibutyl
sebacate.
Based on the experience with phthalates and the physical-chemical
properties of DOS, it must be assumed that the potential for environmental
effects is associated with the accumulation of the compound in biota, in
aquatic sediments and in soils amended with sewage sludge.
5.11 Polyester (polyadipates)
Physical-chemical properties

Polyester plasticisers are polymers based on divalent acids, such as adipic,
sebacic or azelaic acid (some times also on phthalic acid) condensed with
diols. The polycondesation reaction yields a more or less broad molecular
weight distribution of the polyester plasticiser, and the end product will
display an average molecular weight, which is specific for the individual
polymer. Typically, the polyester is a polymer with a molecular weight between
850 and 3500 (Gächter, Müller 1993).
Migration

The polyesters of high viscosity have a good resistance to hydrocarbons, and
primarily due to their high molecular weight they show little tendency to
migration (Castle et al., 1988a).
Exposure

Due to the chemical nature of polyester plasticisers, the substance data (e.g.
a specific molecular weight) required for a quantitative estimate of
distribution and concentration by models are not available.
Human health assessment

A polyester based on adipic acid and 1,2-propanediol is frequently used in
plasticising PVC, and has been suggested for the assessment. The EU Scientific
Committee for Food has a range of polyesters of adipic acid, azelaic acid and
various diols in their Synoptic list regarding substances in food contact
materials (European Commission, 2000). Limited studies based on a polyester
(end capped with fatty acids) are quoted, and a group TDI of 0.5 mg/kg bw/d
has been allocated.
The parent compounds adipic acid and 1,2-propanediol have been considered
by the same committee in food contact materials. Human health ADI of 5 mg/kg
bw/d has been allocated to adipic acid and an ADI of 25 mg/kg bw/d allocated
to 1,2-propanediol.
Environmental assessment

No data on the polymer has been identified for the environmental assessment.
Comparing polyester plasticisers with the lower molecular weight parent
substances will lead to the following generalised pattern. The polyester will
have

little bioavailability (MW >> 600)
low volatility
high tendency to bind to particles
low or insignificant biodegradability

Risk assessment

All in all, the above characterises an inert substance in the environment,
which will not enter the biosphere until the polymeric structure begins to
break. Thus, if these substances do not release large quantities of mono- or
oligomers, the possible effects should be associated with very long-term
exposure or accumulation. Information on this issue has not been identified.
The high molecular weight of the substances places polyester plasticisers
are in a borderline area approaching the polymer materials with respect to the
evaluation of risk to man and environment.
6. Health and environmental assessment for materials
Polymers may be divided into two categories defined by their chemical
structure (OECD 1998):
Thermoplastic polymers are melted or softened in order to be
formed under pressure into the required shape, which is established on cooling
the product. The process is reversible and the plastics materials can be
reshaped and reused. Polyethylene (PE) is a thermoplastic polymer.
Thermosetting resins are converted into finished products with the
application of heat and pressure. Chemical cross-linking takes place and the
process is not reversible. The materials cannot readily be recovered and
reused. Polyurethane (PU) is a thermosetting polymer.
Such properties may have implications in a recycling process e.g. allowing
only downcycling. However, the problems associated with these aspects, and the
risks associated with production processes for the polymers, the energy
consumption or the use of specific (perhaps undesired) chemicals in the
production process are not part of the evaluation.
The evaluation of materials is directed toward a comparison with the
properties found for the chemicals proposed as substitutes for phthalates in
PVC. Being polymers PU and PE and cannot be assessed by the ordinary tools for
health and environmental assessment of chemicals. A different approach is
used, where migration of mono- or oligomers is considered and their potential
for effects are evaluated. The polymer itself is considered in a general
assessment. Polymers most often contain various additives, such as pigments,
extenders, slip agents, antioxidants etc.
Both PU and PE are already used extensively in the society and the use
considered here is therefore an addition to the existing exposure to the
polymers. The choice of exposure scenarios is directed toward maximum human
contact at the consumer level. There will be given no assessment of the
combined load of PU respectively PE to humans or to the environment from the
total use of the polymers.
6.1 Polyurethane
PU is assessed through the monomer methylene diphenylene diisocyanate
(MDI). In the applications where PU may be a substitute for flexible PVC (e.g.
water proof clothing), PU will most likely be based on MDI. This PU is a
thermoset plastic formed in a step growth process.
6.1.1 Use, emission and exposure
Physical-chemical properties

MDI in commercial form typically exists as a mixture of the 4,4’-MDI
(monomer) and various oligomers of MDI. The commercial mix has CAS no.
9016-87-9 and the 4,4’-monomer has no. 101-68-8. The content of monomeric
MDI generally is between 45% and 65 % on a w/w basis. The monomer is rarely
separated from the mixture, which typically contains 50% monomer and 50%
trimers and higher oligomers (US EPA 1998). This composition, which is very
similar to that used in the workplace, renders the material semisolid and
suitable for aerosol generation. Monomeric MDI is formed as a by-product of
PMDI synthesis and is rarely separated from the mixture except in special-use
applications. The exact composition of monomeric MDI in a mixture likely
varies with the manufacturer. Any change in the monomeric composition is
expected to be compensated by an increase or decrease in oligomer content.
Monomeric MDI is a solid at room temperature whereas the PMDI mixture is a
viscous liquid at room temperature and the vapour pressure is extremely low,
about 2 x 10^-6 kPa at 20 ° C of both
mixture and MDI (US EPA 1998). Vapour pressure of MDI according to Swedish
Chemicals Inspectorate (1994) is 0.003 kPa at room temperature.
Theoretically, isocyanates hydrolyse readily to amine and carbonate
moieties. This hydrolysation may, however, also lead to methylene dianiline
according to Gilbert (1988), but no data is presented. Monomeric MDI
solidifies to a hard crust upon contact with soil or water, if spilled in the
pure form. The polymeric mixture has a density larger than water’s and will
sink without being finely dispersed (Gilbert 1988).
The fate of MDI under test conditions in Salmonella test has been studied.
A rapid disappearance was observed in test media, 28% and 0.3% remaining in
solution after 45 seconds depending on the co-solvent. A slight increase in
the concentration of the aniline degradation product diaminodiphenyl methane
occurred (up to ~3%). In distilled water 95% remained (Seel et al 1999).
Migration

No data on migration of monomer MDI from PU has been identified.
Isocyanates belong to a chemical family of high reactivity with biological
functional groups, such as hydroxyl, amine, and sulfhydryl groups (US EPA
1998).
After loss of MDI from products to air, soil or water exposure of humans or
the general flora and fauna in the environment is not expected. The reactivity
of the monomer will presumably lead to binding of MDI to abiotic dissolved or
particulate organic material before interaction with biota. The complexes are
typically not bioavailable and no exposure takes place. After spraying with
commercial mix and consequent loss to the atmosphere in a working environment
no unreacted MDI was found on filters, only urethane and MDI-urethane (US EPA
1998).
Use pattern for compound

The main use of PU as substitute for PVC-products is anticipated in the
waterproof clothes, shoes, boots and waders (see section 4.3.2).
Exposure in the work place

The vapour pressure of MDI at room temperature is less than 10^-5
mmHg. Due to the low vapour pressure at room temperature, only negligible
amounts of MDI vapours are expected to be released into the environment during
normal application, e.g. by roller coating, brushing or curtain coating of
products containing MDI and when using such products in the form of fillers or
joint sealants. Experience gained in monitoring the air during application of
MDI-based coatings shows that the concentrations, which from under these
conditions are below the occupational exposure limit (0.05 mg/m³)
provided that there is a minimum of air circulation.
Monitoring of MDI concentrations must however be accorded particular
attention. Especially when spraying MDI-based formulations or when working at
high temperatures, e.g. exposure to sunlight or coating of heated surfaces.
Under such conditions, concentrations of MDI aerosols for exceeding the
occupational exposure limit can be formed, either by mechanical means or by
recondensation of MDI vapours which are supersaturated at room temperature. At
high application temperatures, the vapour pressure and the saturation
concentration of MDI increase considerable (Bayer, 1996). Based on information
in OECD (1998) for the UK, PU is processed in closed systems.
Consumer exposure

It is not possible to conduct an EASE-calculation on a polymer such as
PU. The exposure of consumers may be associated with the release of MDI and
oligomers from the polymer. However, no data on migration has been identified.
Environmental exposure of humans

It is not possible to conduct an EUSES-calculation on a polymer such as
PU. The exposure of humans from environmental sources may be associated with
the release of MDI and oligomers from the polymer. However, no data on
migration has been identified.
6.1.2 Health assessment
Observations in humans

Exposure to isocyanates is a leading cause of occupational asthma
worldwide. High exposure concentrations, such as might occur during a spill,
are a likely risk factor in human sensitisation.
In a cross-sectional study, MDI-induced sensitisation was evaluated in 243
PMDI/MDI foam workers in a 3-year-old facility in which air levels were
monitored continuously be area monitors for 24 h per day, during which time
the air levels never exceeded 5 ppm. The average duration of employment was
18.2 months. Three cases of occupational asthma were identified, one of which
was attributable to a spill.
The available human data concerning occupational exposure to PMDI/MDI,
coupled with lack of knowledge about mechanism of action and the possible role
of genetic predisposition are insufficient to identify exposure conditions and
scenarios responsible for the isocyanate-induced sensitisation.
In a retrospective cohort, mortality and cancer incident study involving
4,154 workers employed at any of nine Swedish polyurethane manufacturing
plants, the association between excess cancer deaths or excess deaths from
destructive lung diseases was investigated. Workers were exposed to both TDI
and MDI. Exposure levels to MDI were normally below the detection limit of the
analytical method (<0.01 mg/cm³) and nearly all were below 0.1
mg/m³. At the 10% level of significance, no statistically
significant association was formed between all-cause cancer and diisocyanate
exposure using any of five exposure measures, or for non-Hodkin's lymphoma and
rectal cancer (five cases).
Acute toxicity

The LC₅₀ in rats has been estimated at 178 mg/m³ in
rats. An LD₅₀ in rats of 9,200 mg/kg is reported corresponding to
low acute toxicity by ingestion.
Subacute and chronic toxicity

In a subchronic toxicity study (range finding) rats were exposed to PMDI
aerosol in concentrations of 4, 8 or 12 mg/m³ for 6h/day, 5 d/week
for 13 weeks. Severe aspiratory distress, degenerative lesions in the
olfactory epithelium of the nasal cavity and mortality was observed at the
highest close level. Histo-pathological lesions of the lungs were also
observed in the 8 mg/m³ dose group suggesting impaired lung
clearance. This study demonstrated adverse effects in the lungs and nasal
cavity at levels of 4 mg/m³ and above. However, because of lack of
data on aerosol sizes, a quantitative LOAEL could not be derived.
Long term effects

According to IARC, MDI is classified as Group 3: The agent is not
classifiable as to its carcinogenicity to humans.
The results of a two-year inhalation study in rats using aerosols of PMDI
revealed a carcinogenic potential. These observations have however been
discussed as a result of the irritant effect of the high concentrations of
aerosols to which the rats were exposed.
In the cancer bioassay, rats were whole-body exposed to aerosols of PMDI
for 6h/d, 5d/w for 24 months in concentrations of 0, 0.2, 1.0 and 6.0 mg/m³.
A NOAEL of 0.2 mg/m³ and a LOAEL of 1.0 mg/m³ for
respiratory tract effects in both the pulmonary and extrathoracic regions were
identified. Although there were no compound-related nasal tumours solitary
pulmonary adenomas, described as rare in Wistar rats, were observed. Only one
pulmonary adenocarcinoma was observed in one male exposed to 6 mg/m3. Although
the study provides evidence of a tumourigenic response to treatment, the
significance of only one pulmonary adenocarcinoma is insufficient to
distinguish PMDI as an animal carcinogen.
Prenatal toxicity was evaluated in a study with pregnant Wistar rats
exposed to respirable PMDI in concentrations of 1, 4, and 12 mg/m³
for 6h/d from day 6 to day 15. Statistically, significant effects were
observed at the high dose level, effects, which may be a result of maternal
toxicity. The study identified a maternal NOAEL at 4 mg/m³ and a
developmental LOAEL of 12 mg/m³. The study suggests that the
potential of PMDI to cause prenatal toxicity and teratogenic effects in this
strain is low.
In another developmental study where Wistar rats were whole-body exposed to
aerosols of MDI in concentrations of 1, 3 and 9 mg/m3 for 6h/d from day 6 to
15, the NOAEL for developmental effects was identified at 3 mg/m³.
MDI yielded mixed results in genotoxicity tests. Technical grade MDI was
positive in the salmonella reverse-mutation plate-incorporation assay in
strains TA 98, TA100 in the presence of metabolic actuation and negative in
TA1537 at concentrations of up to 100 m g/plate.
Conflicting findings are however observed with strains TA98 of TA100. This may
partly be attributed to the instability of MDI in DMSO.
Genotoxic metabolic reaction products of MDI have been identified. Free MDA
(methylene dianiline) and AMD (N-acetylmethylene dianiline) have been detected
in e.g. urine. The level of AMD was about three times higher than that of MDA.
MDA is a known animal carcinogen.
Irritability

MDI causes irritation of skin and development of rashes by contact.
Exposure to vapours and aerosols irritates eyes, nose, throat and lungs
causing coughing, wheering, chest tightness and/or shortness of breath.
Sensitisation

MDI may produce skin sensitisation and allergic symptoms like redness,
swelling and inflammation.
An impairment of pulmonary function and induction of sensitisation of the
respiratory tract are generally observed when a MDI concentration of 0.2 mg/m³
(vapours, aerosols) is exceeded. These effects are believed to be no more
frequent in exposed persons than in non-exposed control persons, if a maximum
air concentration of 0.1 mg/m³ is maintained.
Allergic sensitisation usually develops after months of exposure.
Asthma characterised by bronchial hyperreactivity, cough, wheeze, tightness
in the chest and dysnea, was observed in 12 of 78 foundry workers exposed to
MAI concentrations greater than 0.02 ppm (0.2 mg/m³). Inhalation
provocation tests in 6 out of 9 of the asthmatics resulted in specific
asthmatic reaction to MDI.
NOAEL/LOAEL

Lowest reported LOAEL in the available literature was 1.0 mg/m³
for respiratory tract effects in a chronic study. A NOAEL of 0.2 mg/m³
in the same study was identified.
Summary of known toxicity

Exposure to MDI has been shown to cause irritation and occupational
asthma in humans. Skin sensitisation has been observed as well. Impairment of
pulmonary function is also observed.
Sensitisation from low-level exposure is not described.
MDI is classified in Group 3 by IARC: The agent is not classifiable as to
it’s carcinogenicity to humans. Positive tumourgenic response to treatment
has however been shown in a two-year rat study. Findings were not significant.
Conflicting results in Ames mutagenicity tests have been reported.
Exposure of pregnant rodents to MDI has not been shown to cause prenatal
effects.
6.1.3 Environmental assessment
Aquatic and terrestrial ecotoxicity

Data quoted from other studies in Gilbert (1988) reportedly show that MDI
is virtually non-toxic to crustaceans and fish as tested with a series of
standard OECD tests. A result from a 24 hours test on reproduction in
crustaceans is reported as no effect at the highest concentration (10 mg/l).
The original data are not available. In an experiment with a simulated spill
of MDI in marine water the concentration after one day had fallen to 5% of the
initial value (Brockhagen, Grieveson 1984), however, zooplankton organisms
were reduced in numbers. The same authors report a study showing that
mortality in 0.001% MDI over 35 days was 7 of 8 animals.
In comparison acute toxicity of toluen-2,4-diisocyanate to freshwater fish
ranged from 165-195 mg/l on exposures from 24 to 96 hours (Curtis et al.
1979). No significant mortality was observed in exposure of saltwater fish up
to 500 mg/l.
Biodegradation

Aerobic biodegradation is reported as ‘None’ in the OECD test for
inherent biodegradability (Gilbert 1988). No data was reported for anaerobic
biodegradation.
Table 6.1 Ecotoxicity and fate data on MDI

MDI
Aquatic(mg/l)

Microorganisms
Terrestrial
Bioaccumulation
Biodegradation (%)

Algae
Crustaceans
Fish
EC₅₀ 24h

Aerobic
Anaerobic

LC₀

BCF
28 days

Acute
N.D.
> 1,000
> 1,000
> 50
N.D.
N.D.
None (Inherent test)
N.D.

Chronic
N.D.
>10

(LC₀ – 24h)
N.D.
N.D.
N.D.
-
-
-

N.D.: No data available.
Bioaccumulation

Bioaccumulation data have not been identified for MDI or for the PU. The
reactivity (and polarity) of MDI makes the use of equilibrium distribution
models unsuitable for prediction of bioaccumulation. For the PU polymer as
such the average molecular weight is above the value of 600-1000 considered a
maximum for uptake in living organisms.
Risk assessment

The risks of significant release of MDI from PU polymer leading to acute
effects in the environment seem highly unlikely. Although the data on chronic
effects is incomplete, the risks to the environment based on these limited
data set seem limited.
6.2 Polyethylene (PE)
PE is a thermoplastic produced from ethylene as an addition or chain growth
polymer. It is commercially available in two main forms: high and low density
polyethylene (H and LDPE). The former is an almost linear polymer both rigid
and hard.
LDPE is branched leading to a more spacious compound and lower density
polymer. LDPE substitutes flexible PVC as such, and not only the phthalate
plasticiser of the PVC. The assessment evaluates the LDPE material and
although PE may be added various substances, e.g. antioxidants (Wessling et al
1998,), the additives are not included in the assessment.
Polyethylene and LDPE has the same CAS no. 9002-88-4.
6.2.1 Use, emission and exposure
Physical-chemical properties

The polymer has a melting point of 130-145 C and a density of 0.92. No
information on vapour pressure or LogP_ow are available. The average
molecular weight ranges from 100.000 to 500.000 depending on the application.
Migration

There is no data available on migration of base monomers or oligomers.
The monomer ethylene is a highly volatile chemical and if present in the crude
formulation it will evaporate quickly from the polyethylene matrix. Typically,
the production process (a chain growth reaction) is also ended with capping of
the ends of the chains. There is very limited reaction with the polymer, which
is also treated with additives such as antioxidants to avoid the introduction
of reactive groups in the polymer skeleton leading to a less stabile material.
Thus, no migration is anticipated.
Use pattern for compound

LDPE has to some extent already substituted PVC used in flexible toys. It
is expected that a major part of PVC application can be substituted with LDPE
products. In the substitution matrix all flexible PVC in toys is converted to
LDPE.
Exposure in the work place

PE is produced from ethylene and for (Linear) LDPE also variable amounts
of higher alkenes depending on the branching. LDPE is produced in closed
systems, but processed in both opened (88%) and closed systems (12%), based on
data for the UK (OECD 1998).
Typically, PE granules are heated to 160-260 C before processing into
shape. If excessive heat is applied thermooxidation may take place above 360 C
and aldehydes of short chain alkanes can be formed. These may irritate the
respiratory tract.
Consumer exposure

It is not possible to conduct an EASE-calculation on a polymer such as
LDPE. It is anticipated that mouthing of LDPE toys by children will be a
primary exposure route. A considerable recovery of the volatile alkenes takes
place in production (Danish EPA 1995) and it is not expected that consumer
products will contain monomers.
Environmental exposure of humans

No environmental exposure to LDPE or it’s monomer is anticipated from
the polymer due to the apparent lack of migration potential. Ethylene occurs
naturally, and is also used in small amounts to ripen fruit and vegetables.
6.2.2 Health assessment
No toxicity data on LDPE are available.
Observations in humans

The massive production of ethylene and polyethylene and the general use
of the polymer over the past several decades indicate that exposure of workers
and the general population is common. In addition, medical use (e.g., for
intrauterine contraceptive devices) has been extensive.
Acute toxicity

No data on LDPE has been identified.
Subacute toxicity

Relevant data were not found.
Chronic toxicity

There is no information on LDPE, except for carcinogenicity of implants,
which the IARC classification is ’Organic polymeric materials as a group are
not classifiable as to their carcinogenicity to humans (Group 3)’.
The base chemical ethylene is ’not classifiable as to its carcinogenicity to
humans (Group 3)’ (IARC 1998).
Long term effects

Relevant data were not found.
Irritability

Relevant data were not found.
Sensitisation

Relevant data were not found.
NOAEL/LOAEL

Relevant data were not found.
Summary of known toxicity

Incomplete information is available for an assessment. As a reflection of
the general recognition of low toxicity no limit value exist for working
environment for the base chemical ethylene although considerable amounts is
used (Danish EPA 1995).
6.2.3 Environmental assessment
Aquatic and terrestrial ecotoxicity

No toxicity data for aquatic or terrestrial organisms have been
identified. The lack of biological availability due to the high molecular
weight of LDPE indicates that the unbroken polymer itself will not have direct
toxic effects in the environment.
Aerobic and anaerobic biodegradation

There is no data identified for biodegradation. However, LDPE is often
referred to as a non-degradable polymer, and the primary environmental concern
(visible pollution) is associated with lack of degradability.
Bioaccumulation

Bioaccumulation data have not been identified for LDPE. The large
molecular weight (100,000-500,000) of the polymer is above the value of
600-1000 considered a maximum for uptake in living organisms.
Risk assessment

The lack of information precludes an assessment of the risk to the
environment based on test data or calculation of predicted environmental
concentrations. The characteristics of LDPE are those of an inert substance in
the environment, which will not enter the biosphere until the polymeric
structure begin to break. Thus, as LDPE do not release large quantities of
mono- or oligomers, the possible effects would be associated with unknown
long-term exposure or accumulation. Possible effects associated with the
existence of fibres and polymers under slow degradation in the environment
have not received the same intense investigation as the effects associated
with the chemical substances.
PE is generally considered one of the least problematic plastics, and no
indications of toxicity associated with the polymer have been identified from
authorities, industry or NGOs. Environmental or health problems are only
described in relation to synthesis of the polymer (energy consumption, base
chemicals etc.), which is beyond the scope this evaluation.
7. Combined Assessment of Use, Exposure and
Effects
7.1 Chemical Hazard Evaluation
7.1.1 Data availability
Data pattern

The data availability is very variable among the suggested alternatives for
phthalate plasticisers and materials. A majority of information is collected
based on the CAS number of the suggested compound. For DEHA, ATBC, TEHPA and
TETM information is available covering a range of results from tests on
toxicological and ecotoxicological properties. However, only DEHA can be
considered adequately covered, although some areas need further investigation.
DEHPA, OTSA, TXIB, ESBO, DGB and DOS are covered in less detail, either
because of lack of information or because of inferiour quality of the tests. For
the substance polyadipate no CAS number is available and infor-mation has been
searched in bibliographic databases. For this substance no information has been
located. A similar lack of data is seen for LDPE. How-ever, the MDI base for PU
is well described.
The type of data that are missing varies between compounds. Typically missing
data on the environment side are biodegradation data and measured
bioaccumulation data. On the health side a less clear pattern is observed,
although adequate studies on long-term effects, e.g. reproductive toxicity
studies are often lacking.
Data sources

The sources of the data are given primarily in the data sheets in the
report appendix and for core information also in the main report. The
information includes peer reviewed original papers, databases, previous reviews
and reports, books, and proprietary information from suppliers.
It has been attempted to prioritise studies performed after standard test
methods and guidelines for inclusion. In a number of cases the database IUCLID
(European Commission Joint Research Center, 1996 and 2000), which contains
information submitted by the industry, is almost the sole data source (e.g.
TXIB). Again standardised tests have been selected when-ever possible.
Attention is drawn to the fact that the majority of data are evaluated on the
basis of databases on physical-chemical, toxicity and ecotoxicity studies.
Although the studies as a rule are reviewed before inclusion in the databases
the quality cannot be guaranteed a priori, nor is it possible to scrutinise the
testing conditions of the original studies. Especially, for older studies the
relation to modern guideline based experiments can be difficult to assess and
consequently compliance with e.g. classification criteria may not be obvious.
7.1.2 Physical-chemical data
The available data show that none of the substances display hazardous
physical-chemical properties, such as flammability etc. The typical sub-stance
has low water solubility and a moderate to high lipophilicity (LogPow 4 and
higher). Vapour pressures are generally low (a tentative grouping is shown in
Table 7.1).
Table 7.1 Relative volatility of substances suggested as alternative
to phthalates in PVC.

Tentative estimates for substances for which data is not available are
given in parenthesis. DEHP is included for comparison.

Low

Medium

High

Name
CAS no.

Diethylhexyl adipate
103-23-1

DEHA

O-acetyl tributyl citrate
77-90-7

ATBC

Di(2-ethylhexyl) phosphate
298-07-7

DEHPA

Tri(2-ethylhexyl) phosphate
78-42-2

TEHPA

Tri-2-ethylhexyl trimellitate
3319-31-1

TETM

O-toluene sulfonamide
88-19-7

OTSA

2,2,4-trimethyl 1,3-pentandiol diisobutyrate
6846-50-0

(TXIB)

Soybean oil epoxide
8013-07-8

(ESBO)

Dipropylene glycol dibenzoate
27138-31-4

DGD

Dioctyl sebacate
122-62-3

DOS

Polyadipate
-

(Polyadipate)

DEHP

DEHP

Hydrolysis

Many of the alternative plasticisers are, similarly to DEHP, esters of
car-boxylic acid compounds. Information on hydrolysis, which potentially may be
an important environmental fate property for this type of substances, is rarely
available and only very limited information has been found.
In general, hydrolysis of the carboxylic acid esters is rather slow except
when the sidechain contains halogens or unsubstituted carbons. The process is
also slower with the length of the alkyl chain. The dicarboxylic acid esters
proposed as alternatives belong to groups of substances with relatively long
alkyl chains. In Schwarzenbach et al. (1993) the estimated half time for
hy-drolysis of the relevant bond types range from 38 days to 140 years. In the
same reference dimethyl phthalates are estimated to have hydrolysis half lives
of 12 years at 10 °C and pH 7. A similar slow hydrolysis of the dialkyl acid
ester bonds may be the case for DEHA, TETM, TXIB, DGD and DOS. For DEHA the
BUA-review (BUA 1997) concludes on the prolonged reaction in a study performed
at elevated pH and temperature, that hydrolysis under environmental conditions
will proceed extremely slow.
Also for the tri-phosphate (BUA 1996) no significant hydrolysis is to be
expected at typical environmental pH and temperature, which may also apply to
DEHPA. An evaluation of the possible hydrolysis is not made for the remaining
substances.
Migration

The substances display a range of migration potentials. The lipophilic
substances such as DEHA, TETM, TXIB and DOS migrate to organic solvents and oil,
whereas those with relatively high aqueous solubility migrate to water and weak
acids (see Table 7.2).
Table 7.2 Comparison of migration potential for assessed substances
into fatty food simulant (bold) or water/acid. Tentative estimates for
substances for which data is not available are given in parenthesis. DEHP is
included for comparison

Low

Medium

High

Name
CAS no.

Diethylhexyl adipate
103-23-1

DEHA

DEHA

O-acetyl tributyl citrate
77-90-7

ATBC
ATBC

Di(2-ethylhexyl) phosphate
298-07-7

DEHPA

Tri(2-ethylhexyl) phosphate
78-42-2
(TEHPA)

(TEHPA)

Tri-2-ethylhexyl trimellitate
3319-31-1
TETM

TETM

O-toluene sulfonamide
88-19-7

OTSA

(OTSA)

2,2,4-trimethyl 1,3-pentandioldiisobutyrate
6846-50-0

(TXIB)

(TXIB)

Soybean oil epoxide
8013-07-8
ESBO

ESBO

Dipropylene glycol dibenzoate
27138-31-4

(DGD)

(DGD)

Dioctyl sebacate
122-62-3
DOS

DOS

Polyadipate
-
Polyester)
(Polyester)

DEHP

DEHP

DEHP

7.1.3 Humans
Four of the possible phthalate substitutes fulfil the criteria for
classification with regard to acute toxicity or local effects. Based on the
available litera-ture DEHPA should be classified as Corrosive (C) and Harmful
(Xn) with the risk phrases R34 (Causes burns) and R21 (Harmful in contact with
skin). This classification was suggested by Bayer AG (Bayer, 1993) and is
sup-ported by the toxicological findings in the literature. TEHPA should be
clas-sified as Irritant (Xi) with the risk phrase R36/38 (Irritating to eyes and
skin) also according to Bayer (1993). TETM fulfils the classification criteria
with respect to acute toxicity as Harmful (Xn) with the risk phrase R20 (Harmful
by inhalation) and DOS as Harmful (Xn) with the risk phrase R22 (Harmful if
swallowed) based on LC50 and LD50 values. There are apparently no sub-stances
with severe organ effects, but the data set is very limited. It has not been
possible to evaluate all effects according to their possible classifica-tion.
The data are presented in Table 7.3.
The citrate, mellitate, epoxidised soybean oil, sebacate, and di-phosphate
have been tested and found without CMR effects. One study showed foeto-toxicity
(reduced ossification) for DEHA in mice, but results were not sta-tistically
significant. The toluene sulfonamide may be the only of the sub-stances having
effects of the CMR type. However, the suspicion for OTSA is based on tests done
in connection with assessments of saccharine and its impurities, among others
OTSA. Here it was found that the impurities are responsible for the reproductive
effects of impure saccharine. No results are available on the pure substance.
Only weak mutagenic activity was described and there is limited evidence that
OTSA is carcinogenic when administered orally to rats. Based on the available
data it cannot be assessed whether OTSA is responsible for these effects,
although it is suggested in the studies.
The sensitisation effects have been tested for many of the substances and the
adipate, citrate, di-phosphate, trimellitate, epoxidised soybean oil, and
seba-cate have been found not to have this effect. Only the PU precursor MDI is
a recognised sensitiser.
It must be stressed that for the majority of the compounds an insufficient
data set is available for a complete human health risk assessment.
7.1.4 Environment
The combination of high persistence and high bioaccumulation potential does
warrant attention to uses that leads to emission to the environment. Such
substances are possibly the mellitate, the citrate, the dibenzoate and the
sebacate.
The compounds for which ecotoxicity data are available (only data for
the aquatic environment available) show relativly high acute ecotoxicity,
that in all cases would lead to an environmental hazard classification.
For the trimellitate and the sebacate, the low aqueous solubility in
combination with persistence and bioaccumulation potential would lead to a
classification as 'May cause long term effects in the aquatic environment'
(R53).
The polymer materials and the polyadipate are estimated as unlikely to give
rise to effects in the aquatic environment. No data was identified for the
terrestrial environment.
7.2 Risk evaluation
It is beyond the scope of the present report to evaluate the risks associated
with the use of the chemicals or materials in specific production, formula-tion
or processing activities, since such evaluation must be coupled to a de-tailed
knowledge of the particular technical and occupational environment. However,
core properties such as volatility and migration are included. The data on risk
is presented in Table 7.4.
7.2.1 Working environment
The exposure in the working has not been estimated at values above toxic
values in the various scenarios, except for the adipate, where the selected
scenario results in concentrations in workplace air 104 times the concentra-tion
resulting in more pronounced reactions in workers with an allergy or asthma case
history. In general, the loss of plasticiser will depend on the volatility of
the com-pound. OECD has made an allocation of plasticisers into low, medium and
high classes of volatility (OECD 1998). Based in this the 11 plasticisers have
been grouped relative to each other at standard 20-25 C.
7.2.2 Consumer exposure
Migration from PVC products has been measured for several of the alternative.
In Table 7.2 it is attempted to show the migratory properties for the substances
in a fatty food simulant (typically olive oil) and in an aqueous solvent (water
or weak acids).
In the special teething ring scenario the citrate does reach 37% of a
preliminary ADI of 1 mg/kg bw/day. The preliminary ADI is not officially
recog-nised and a closer investigation of the citrate exposure conditions and
human toxicity may be warranted.
7.2.3 Human exposure in environment/secondary poisoning
Several of the assessed substances have lipophilic properties based
esti-mated LogPow values, and they may consequently have a high tendency for
accumulation in biota. This is particularly clear in the estimation of
concen-trations of the adipate and sebacate in root crops, and the ADI is
exceeded for sebacate in the regional worst case scenario. Virtually all the
daily dose of these substances to humans from the environment arises in the root
crops. The EUSES model is not well calibrated at high LogPow values and may
overestimate the accumulation. However, some plants do accumulate an-thropogenic
substances and EUSES does not model this very precisely (Trapp, Schwartz, 2000).
No data on terrestrial toxicity were identified to determine whether this
accumulation may take place for these substances.
7.2.4 Aquatic ecosystems
The combination of high persistence and high bioaccumulation potential does
warrant attention to uses that leads to emission to the environment. Such
substances are possibly the mellitate, the citrate, the dibenzoate and the
sebacate. Toxicity in the environment (only data for aquatic organisms
available) is also of concern. The adipate, the tri-phosphate and the epoxidised
soybean oil display acute aquatic toxicities below 10 mg/l.
7.2.5 Sediment
The DEHA exceeds the risk quotient of one for the sediment compartment due to
its sorptive properties, but only in the scenario with complete substitution to
this substance. ATBC (limited data set), DEHPA, TEHPA, and TETM (limited data
set) had risk quotients less than one. Several other substances could not be
quantitatively assessed for risk in the sediment (or the aquatic) environment:
TXIB, ESBO, OTSA, DGD, DOS. This applies to the materials as well.
7.2.6 Groundwater, soil and microorganisms
Only the toluene sulfonamide has a water solubility suggesting transport to
groundwater. However, not only dissolved species are found in groundwater.
Substances bound to dissolved organic matter are also found in the groundwater.
It must be stressed that a number of the assessed substances are lipophilic
and may have a high affinity for sludge particles similar to that of DEHP. No
data on terrestrial toxicity has been identified and very limited informa-tion
on effects on microorganisms in the sewage treatment plant is found.
7.3 Overview
Assessment of chemicals is challenging when few and not necessarily the same
parameters are available for all substances. A profound and compre-hensive or
quantitative ranking is by far a possibility with the data set pre-sented for
the substances and materials included in the present project. However, to allow
for comparison among the substances and materials a compressed overview of the
data and the (occasionally tentative) assess-ments is provided. It must be
emphasised that the data sets rarely allow haz-ard and risk assessment strictly
according to the various applicable guidelines, and that the assessment to some
extent relies on data obtained in databases published by European and American
authorities.
In the following two tables the properties of the alternatives to phthalates
and to flexible PVC are considered. The choice of properties shown in Table 7.3
has been based on the hazard indicators for humans as mentioned in CSTEE (2000),
i.e. carcinogenicity, reproductive and developmental effects, mutagenicity,
sensitisation and severe organ toxicity supplemented here with assessment of
acute and/or local effects. For the substances and materials evaluated none of
three with sufficient data exhibited 'Severe organ toxicity' and this column has
therefore been omitted (data was available for DEHA, ATBC and TETM). It should,
however, be mentioned that one study from 1964 showed signs of CNS toxicity in
rats and mice after intraperito-neal injection of 400 mg ATBC/kg bw. No
supporting evidence for this effect has been found.
In addition to evaluating hazards, the risk is also assessed (Table 7.4). For
humans this is achieved by comparing the estimated dose of the substance in
consumer and environmental exposure with existing or estimated ADI. For the
environment the environmental risk quotient is calculated from PNEC and
estimated environmental concentrations.
Table 7.3 The inherent properties for the investigated subtances are
summarised using key parameters: acute and local effects, carcinogenicity(C),
genetic toxicity (M), reproductive toxicity (R), sensitisation, persistance,
bioaccumulation and aquatic toxicity. If data are not available for all
parameters or only from non standard test results a tentative assessment is
given (shown in parentheses). For the materials an evaluation is given based on
general polymer properties. The symbols: ● identified potential hazard,
○ no identified potential hazard, and – no data available.

Humans

Environment

Name of substance
CAS No.
Acute and local effect (A/L)
CMR^e
Sensitisation
Persistence
Bioaccumulation
Aquatic Toxicity

Diethylhexyl adipate
103-23-1
○/○
(○)^a
○
○
○
●

very toxic

O-acetyl tributyl citrate
77-90-7
○/○
○

M, R
○
●

(inherent)
(●)
●

(harmful)

Di(2-ethylhexyl) phosphate
298-07-7
●/●
○
○
●

(conflicting)
○
●

harmful

Tri(2-ethylhexyl) phosphate
78-42-2
(○)/●
○

M, C
-
●
○
●

toxic

Tri-2-ethylhexyl trimellitate
3319-31-1
●/○
○
○
●
(●)
-

O-toluene

sulfonamide
88-19-7
-/-
(○)^c
-
(●)
#9675;
-

2,2,4-trimethyl

1,3-pentandiol

diisobutyrate
6846-50-0
-/-
-
-
-
-
-

Epoxidised soybean oil
8013-07-8
-/○
○
○
○
-
●

toxic

Dipropylene glycol dibenzoate
27138-31-4
-/-
-
-
-^b
(●)^b
-^b

Dioctyl sebacate
122-62-3
●/(○)
○
○
-
(●)
-

Polyadipates
-
-/-
-
-
-

(persistent)
-

(unlikely)
-

(unlikely)

PU (MDI)
101-68-8
●/●
(○)
●
-

(persistent)
-

(unlikely)
-

(unlikely)

LDPE
9002-88-4
-/-
-
-
-

(persistent)
-

(unlikely)
-

(unlikely)

^aFoetotoxicity (reduced ossification) has been identified as the
most sensitive effect in a developmental toxicity study.

^b QSAR estimates by Danish EPA leads to the classification N; R50/53
(May cause long term effects in the aquatic environment).

^c A test on reproductive effects performed on a product containing
OTSA as impurity attributes effect to OTSA. No substance specific data
available.

^d C,M,R indicated that the effect is investigated but no effects are
seen.
Table 7.4 The evaluated risks to humans or the environment are
summarised for the investigated substances (the polymer materials are not
included). The estimated exposure of humans is compared to the
Acceptable Daily Intake (ADI). Predicted environmental concentrations in the
aquatic environment (PEC) are compared to predicted no-effect concentrations
(PNEC). "Worst case" scenarios are used. The reader is referred to the
main text and the data sheets for further explanations to the table. Parentheses
show an assigned ADI. The symbols: ● ratio >1 (identified potential
risk), ○ ratio <1 (no identified potential risk), and –no data
available

Ratio of dose to ADI

Ratio of PEC to PNEC

Substance or material
CAS no.
Consumer
Humans from environment
Water
Sediment
Remarks (ADI in

mg/kgbw/d)

Diethylhexyl adipate
103-23-1
○
○
○
●
ADI 0.3

O-acetyl tributyl citrate
77-90-7
(○)^a
(○)
○^b
○^b
Preliminary ADI 1.0^c

Di(2-ethylhexyl)

phosphate
298-07-7
○
○
○
○
Group ADI 0.05

Tri(2-ethylhexyl)

phosphate
78-42-2
○
○
○
○
Group ADI 0.05

Tri-2-ethylhexyl

trimellitate
3319-31-1
(○)
○
○^d
○^d
Assigned ADI 0.05

O-toluene sulfonic acid amide
88-19-7
(○)
(○)
-
-
Assigned ADI 0.05

2,2,4-trimethyl 1,3-pentandiol diisobutyrate
6846-50-0
-
-
-
-
No exposure data

Epoxidised soybean oil
8013-07-8
-
-
-
-
No exposure data

Dipropylene glycol

dibenzoate
27138-31-4
(○)
(○)
-
-
Assigned ADI 0.05

Dioctyl sebacate
122-62-3
○
●
-
-
Group ADI 0.05

Polyadipates
-
-
-
-
-
No exposure data

PU (MDI)
101-68-8
-
-
-
-
No exposure data

LDPE
9002-88-4
-
-
-
-
No exposure data

^a Dose reaches 37% of preliminary ADI in teething ring scenario.

^b Tentative estimate based on only one ecotoxicity study.

^c Preliminary ADI from Nikiforov (1999)

^d Data set comprise only two acute values and one chronic NOEC value.

8. Conclusion
Physical chemical parameters

Key parameters with respect to release of plasticisers under polymer production
and consumer use are their potential for evaporation and migration out of the
PVC polymer. Some data exists for volatility, but only few data has been
identified on migration potential for the substitutes.
Hazardous properties

Available toxicity data for acute and local effect suggests classification for
some of the substances. This is the case for di(2-ethylhexyl) phosphat which
should be 'Corrosive' (R34) and 'Harmful' (R21), tri(2-ethylhexyl)phosphate
which should be 'Irritant' (R36/38), tri-2-ethylhexyl trimellitate which should
be 'Harmful' (R20) and dioctyl sebacate which should be 'Harmful' (R22). The
classification for the phosphates is suggested by Bayer AG and supported by the
literature. For other effects it is either not possible to suggest a
classification based on the reviewed literature or the substances do not display
these effects.
The substances for which data are available for some of the critical
properties toward humans, such as CMR, sensitisation etc., do not display such
effects based on the available data. This concerns diethylhexyl adipate,
o-acetyl tributyl citrate, tri-2-ethylhexyl trimellitate, epoxidised soybean oil
and the dioctyl sebacate. For some substances the available data suggest that
reproductive and developmental toxicitity is investigated further in order to
conlude about a possible effect. This is the situation for diethylhexyl adipate,
o-acetyl tributyl citrate, tri(2-ethylhexyl)phosphate, o-toluene sul-fonamide
and epoxidised soybean oil.
The compounds for which ecotoxicity data are available (only data for the
aquatic environment available) show relatively high acute ecotoxicity that in
all cases would lead to an environmental hazard classification. The adipate
would be 'Very toxic' (R50/53) and epoxidised soybean oil is classifiable as
'Toxic' (R51/53). O-acetyl tributyl citrate, di(2-ethylhexyl) phosphate and
tri(2-ethylhexyl) phosphate would be classified as 'Harmful' (R52/53). For the
trimellitate and the sebacate, the low aqueous solubility in combination with
persistence and bioaccumulation potential would lead to a classification as 'May
cause long term effects in the aquatic environment' (R53).
It is emphasised that for o-toluene sulfonamide, diisobutyrate (TXIB),
epoxidised soybean oil, dipropylene glycol dibenzoate and dioctyl sebacate the
lack of data regarding ecotoxicity is limiting the assessment. The tentative
classification of the citrate and trimellitate is based on only one and two
studies, respectively (the citrate study is almost 30 years old).
Degradability

Several substances show limited degradability in the environment (the
trimellitate and possibly both phosphates). Some have a high estimated
bio-accumulation potential (citrate, trimellitate, dibenzoate and sebacate). The
trimellitate possibly combines both of the environmentally undesired properties.
It must be emphasised that this is based on estimated values for
bio-accumulation based on estimated octanol-water partition coefficients. It is
possible that these compounds to some extent degrades through hydrolysis in the
environment and the bioaccumulation is then expected to be considerably less.
Although no data on the dibenzoate and sebacate are available similar processes
may apply to these structurally related compounds. Measured bioaccumulation for
the adipate and the two phosphates are below the criteria for bioaccumulation.
Risk for humans from environment

A possible risk to humans has only been suggested by the selected scenarios for
a few of the substances and primarily in relation to the workplace sce-narios.
The workplace scenario considers aerosol generation in connection with
production of floor and wall coverings using a process temperature of 200°C and
eight exposure events per day, which is most likely a very con-servative
scenario. For the adipate the selected scenario results in concen-trations in
workplace air 104 times the concentration resulting in more pro-nounced
reactions in workers with an allergy or asthma case history. For the two
phosphates the estimated concentrations were lower than observed ef-fect levels
in animal studies, but within commonly used safety margins.
The estimated exposure of consumers and the public to the phthalate
alternatives were generally much lower than the established ADI value even in
the worst case scenarios. Only the worst case scenario for dioctyl sebacate
displayed doses exceeding the ADI (conservatively) based on peroxisome
proliferation data for di-ethylhexyl phthalate. The human exposure comes almost
exclusively from the contribution by root crops due to high estimated
octanol-water partitioning values and the low biodegradation potential. Only
limited toxicological and ecotoxicological data are available and conservative
default values are used. More data may very well change the risk perception.
The citrate does reach 37% of a preliminary ADI of 1 mg/kg bw/day in a
teething ring scenario. The preliminary ADI is not officially recognised and a
closer investigation of the citrate exposure conditions and human toxicity may
be warranted.
Risk for the environment

The risk quotient does not exceed one (the critical value) in the water phase
for any of the five compounds for which it could be calculated (diethylhexyl
adipate, o-acetyl tributyl citrate, di(2-ethylhexyl) phosphate,
tri(2-ethylhexyl) phosphate, and tri-2-ethylhexyl trimellitate). The adipate
exceeded the risk quotient of one for the sediment compartment due to the
lipophilicity. PEC/PNECs could not be calculated for o-toluene sulfona-mide, the
diisobutyrate (TXIB), epoxidised soybean oil, dipropylene glycol dibenzoate and
dioctyl sebacate.
Terrestrial and microbial toxicity

It must be stressed that a number of the assessed substances are lipophilic and
may have a high affinity for sludge particles similar to that of DEHP. No data
on terrestrial toxicity has been identified and virtually no information on
effects on microorganisms in the sewage treatment plant was found.
Assessment of polymer materials

Due to the assessment principles of the EU TGD the materials and the
poly-adipate plasticiser are assessed by expert judgement. The polymer materials
and the polyadipate are estimated as unlikely to give rise to effects in the
aquatic environment. In general, no effects are expected in the consumer use
situation of these.
Data availability

The data availability varies among the suggested alternatives for phthalate
plasticisers and materials. For di(2-ethylhexyl) adipate, o-acetyl tributyl
cit-rate, tri(2-ethylhexyl) phosphate and tri-2-ethylhexyl trimellitate
information is available covering a range of results from tests on toxicological
proper-ties. However, only di(2-ethylhexyl) adipate can be considered adequately
covered, although some areas need further investigation. Di(2-ethylhexyl)
phosphate, o-toluene sulfonamide, 2,2,4-trimethyl 1,3-pentandiol diisobuty-rate,
epoxidised soybean oil, dipropylene glycol dibenzoate and dioctyl se-bacate are
covered in less detail, either because of lack of information or because of
inferiour quality of the tests.
For di(2-ethylhexyl)adipate a large number of studies are covering acute
toxicity, local effects, sensitisation, repeated dose/chronic toxicity, genetic
toxicity, reproductive toxicity and carcinogenicity. Reviews discussing the
toxicological profile of the substance are also available. In a substitution
context it is however important to consider all areas which may give rise to
concern, to make sure that only less hazardous substituents are introduced.
Based on comparisons with the structural analogue, di(2-ethylhexyl) phthalate,
for which the most critical effect is considered to be testicular toxicity, a
need to address this issue for the adipate as well has been identified.
For o-acetyl tributyl citrate the available data are not sufficient for a
profound assessment. Data on acute toxicity are sparse and other effects like
carcinogenicity are not sufficiently covered for a qualified assessment.
For the two phosphates, di(2-ethylhexyl)phosphate and
tri(2-ethylhexyl)phosphat, a number of studies are available, sufficient to
suggest a classification of the substances for acute and local effects. Studies
on re-peated dose and chronic toxicity like reproductive toxicity and
carcinoge-nicity are either not available or not sufficient for an assessment.
For tri-2-ethylhexyl trimellitate a number of studies are available covering
acute and local effects. More details are however needed in order to classify
the substance with regard to irritant effects. More data are also needed on
repeated dose and chronic toxicity studies. Reproductive toxicity is not covered
at all in the reviewed literature.
O-toluene sulfonamide is sparsely covered in the literature and no data are
found available on acute toxicity. Few studies are available on other effects,
but not sufficient for a qualified assessment or classification. Human data are
only available for related substances or combined products.
Few data are available for 2,2,4-trimethyl 1,3-pentandiol diisobutyrate. In
order to make a proper evaluation of acute toxicity more detailed information is
necessary. Repeated dose and chronic toxicity are not covered in the reviewed
information.
A limited number of studies are available for epoxidised soybean oil. Studies
on acute toxicity suggest low toxicity, but more detailed information is needed
for a proper evaluation. Data on repeated dose toxicity and chronic effects are
also insufficient for a qualified assessment.
No toxicological data have been found for dipropylene glycol benzoate.
Also dioctyl sebacate is sparsely covered in the available literature. Few
data are available describing acute toxicity and only oral toxicity has been
evaulated. Data on other effects are not sufficient for an evaluation.
No toxicological data have been found for polyester (polyadipate).
Regarding environmental properties only di(2-ethylhexyl) adipate, o-acetyl
tributyl citrate, and tri(2-ethylhexyl) phosphate have a data set comprising
algae, crustaceans and fish, and data on biodegradation. The remaining
substances have very few or no ecotoxicological data. There are very few data on
chronic endpoints, very limited data on effects on microorganisms and no data on
terrestrial ecotoxicity.
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Appendix 1 Abbreviations used

Abbreviation

Explanation

ADI

Acceptable daily intake

ATBC

O-acetyl tributyl citrate

BCF

Bioconcentration factor

BOD

Biological Oxygen Demand

bw

Body weight

d

day

DEHA

Di(ethylhexyl) adipate

DEHP

Di(2-ethylhexyl) phthalate

DEHPA

Di(2-ethylhexyl) phosphate

DGD

Dipropylene glycol dibenzoate

DIN

Deutsche Industrielle Norm

DINP

Diisononyl phthalate

DOS

Dioctyl sebacate

Dw

Drinking water

EASE

Estimation and Assessment of Substance Exposure

EC₅₀

Effect concentration for half population

ECB

European Chemicals Bureau

EPA

(US) Environmental Protection Agency

ESBO

Epoxidised soy bean oil

EU

European Union

EUSES

European Uniform System for the Evaluation of Substances

fw

Fresh water

h or hrs

hour or hours

HPVC

High Production Volume Chemical

i.p.

intra peritoneal (in blood stream)

i.v.

intra venous (in a vein)

IARC

International Agency for Research on Cancer

IUCLID

International Uniform Chemical Information Database

LC₅₀

Lethal concentration for half population

LD₅₀

Lethal dose for half population

LDPE

Low Density Polyethylene

LOAEL

Lowest observed adverse effect level

LogP_ow

Octanol water partitioning coefficient

Lw

Lake water

MDI

Methylene phenylene diisocyante

NOAEL

No observed adverse effect level

NOEC

No observed effect concentration

OECD

Organisation for Economic Coorperation and Development

OTSA

O-toluene sulfonamide

PEC

Predicted Environmental Concentration

PNEC

Predicted No-Effect Concentration

ppm

Parts per million (e.g. mg/l)

PU

Polyurethane

PVC

Polyvinyl chloride

Rw

River water

SCAS

sw

Salt water

S_w

water solubility

TDI

Tolerable Daily Intake

TEHPA

Tri(2-ethylhexyl) phosphate

TETM

Tri-2-ethylhexyl trimellitate

TGD

Technical Guidance Document

TXIB

2,2,4-trimethyl 1,3-pentanediol diisobutyrate

UDS

Unscheduled DNA synthesis

w/w

Weight/weight

ww

Wet weight

SI units are not included in list of abbreviations.
Appendix 2 Standard conditions for exposure scenario
Table 1 EUSES scenario overview

Substance

Substitution type

Amount substituted

(tons)

Di(ethylhexyl) adipate

Complete

10735

Partial

1703

O-acetyl tributyl citrate

Complete

10735

Partial

554

Di(2-ethylhexyl) phosphate

Complete

10735

Partial

2040

Tri(2-ethylhexyl) phosphate

Complete

10735

Partial

2244.5

Tri-2-ethylhexyltrimellitate

Complete

10735

Partial

1853.4

Alkylsulfonic acid ester

Complete

10735

Partial

30

Dipropylene glycol dibenzoate

Complete

10735

Partial

204

Dioctyl sebacate

Complete

10735

Partial

110

Table 2 EUSES scenario overview

Substance

Scenario type

Scenario description

Di(ethylhexyl) adipate

Worker

Production of floor and wall covering

Consumer

Daily use of a bathroom with floor and wall coverings

O-acetyl tributyl citrate

Worker

Production of printing inks

Consumer

Daily reading of printed advertisement

and

Daily use of PVC-toys

Di(2-ethylhexyl) phosphate

Worker

Production of cables – open tube after the extruders

Consumer

Exposure from cables in private houses

Tri(2-ethylhexyl) phosphate

Worker

Production of cables – open tube after the extruders

Consumer

Exposure from cables in private houses

2,2,4-trimethyl 1,3-pentandiol diisobutyrate

Worker

Production of cables – open tube after the extruders

Consumer

Exposure from cables in private houses

Alkylsulfonic acid ester

Worker

Production of cables - open tube after the extruders

Consumer

Exposure from cables in private houses

Dipropylene glycol dibenzoate

Worker

Production of fillers

Consumer

Daily use of a bathroom with fillers

Dioctyl sebacate

Worker

Production of printing inks

Consumer

Daily reading of printed advertisement

Appendix 3 Organisations contacted
Authorities
The Danish Environmental Protection Agency, Copenhagen, Denmark
Swedish National Chemicals Inspectorate, Stockholm, Sweden
National Working Environment Authority, Copenhagen, Denmark
The Medicines Agency, Copenhagen, Denmark
The Danish Veterinary and Food Administration, Copenhagen, Denmark
Occupational Health Inspectorate, Copenhagen, Denmark
National Environmental Research Institute, Copenhagen, Denmark
Trade organisations
The Danish Plastics Federation, Denmark
Members of the Danish Paintmakers Association
European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC),
Brussels, Belgium
The Graphic Association of Denmark (GA)
PVC Information Council Denmark
Federation of Danish Textile and Clothing (FDTC)
European Counsel for Plasticisers and Intermediates, Brussels, Belgium
Association of Plasticisers Manufacturers in Europe, Brussels, Belgium
Industries
AEC Rådgivende Ingeniører, Vedbæk, Denmark
AKV Gummi, Laasby, Denmark
Akzo Nobel Chemicals, Skovlunde, Denmark
Aalborg Gummivarefabrik, Aalborg, Denmark
Alifix, Kolding, Denmark
A-Trading Fugekemi, Nr. Sundby, Denmark
BASF Danmark, Copenhagen, Denmark
Bayer DK, Lyngby, Denmark
Berner, Nørresundby, Denmark
Bjørn Thorsen Polymer, Copenhagen, Denmark
CASCO, Fredensborg, Denmark
Ciba Special Chemicals, Virum, Denmark
Clariant, Glostrup, Denmark
CODA GUMMI, Køge, Denmark
DAFA, Brabrand, Denmark
DANA LIM, Køge, Denmark
DAN-KIT, Græsted, Denmark
DOW, Stockholm, Sweden
DOW CORNING, Stockholm, Sweden
DOW CORNING, United Kingdom
DTI, Taastrup, Denmark
EniChem, Copenhagen, Denmark
Exxon Chemicals, Göteborg, Sweden
Exxon Chemicals, Copenhagen, Denmark
Hempel, Lyngby, Denmark
Henkel Byggeteknik, Vejle, Denmark
ICI Norden, Göteborg, Denmark
KEMOPLAST, Hvidovre, Denmark
Kondor Kemi, Glostrup, Denmark
LIP, Nr. Åby, Denmark
Mont Oil, Stockholm, Sweden
Neste Oxo AB, Stenungsund, Sweden
NKT Cables, Kalundborg, DK
Nordisk Byggekemi, Rødekro, Denmark
Norsk Hydro, Copenhagen, Denmark
Optirock, Karlslunde, Denmark
PCI Augsburg, Germany
Reilly Chemical, Brussels, Belgium
Rodia (tidligere Rhône Poulenc), Søborg, Denmark
Sika-Beton, Lynge, Denmark
Sika, Zürich, Switzerland
Sveda Kemi, Frederiksberg, Denmark
TOTALFINA, Paris, France
W.R. Grace & Co, Maryland, US
Åffa, Ishøj, Denmark
Appendix 4. Physical-chemical, emission, exposure, health and
environmental data
The complete result of the screening for environmental and health data
is given in the data sheets presented in the appendix. Each data
collection has been based primarily on review literature, handbooks and
electronic databases and for selected key studies on the original paper,
if available. The first page of each data sheet presents a short summary
of the most important findings and if relevant a remark regarding special
properties of the compound.
The information marked by ¨in the data
sheets of appendix 4 is considered key data for the assessment.
The list of literature represents the sources of information, which
have been consulted. Not necessarily all references are quoted in each
table.

Diethylhexyl adipate

CAS number: 103-23-1

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

The reviewed data on diethylhexyl adipate (DEHA) indicates that
the substance is non-volatile and slightly flammable compound with
low water solubility. Further, the available data on LogP_ow
indicates strong lipophilicity and partitioning to particles and
biota. DEHA has a migration potential in PVC films, which in several
cases exceeds the Danish limit of 4 mg/dm².

Emission

DEHA is according to the available estimates released during
production, and from consumer products.

Exposure

DEHA has been found in the aquatic environment, in drinking water
and in sewage sludge. DEHA has also been found to migrate into food,
which has been in contact with cling films.

Occupational exposures occur during the production.

Health

The lowest LD₅₀ was 7,392 mg/kg bw in rat in acute
oral tests. Acute effects were not observed from DEHA in inhalation
studies nor was DEHA shown to be sensitising. DEHA was slightly
irritating to skin and eyes in rabbits.

The subacute NOAEL was 610 mg/kg bw in rat and more than 3,100 ppm
in mouse.

DEHA was only slightly mutagenic in in vitro tests. Studies
on dominant lethal mutations in mouse showed a LOAEL on 450 mg/kg
bw. Metabolites showed no mutagenic effects in Ames tests with Salmonella
typhimurium.

DEHA shows limited evidence of carcinogenicity in animals (IARC,
category 3).

NOAEL was 170 mg/kg bw/day for both the parent and the F₀
generation in reproductive toxicity studies in rats. The NOAEL was
170 mg/kg/day and LOAEL was 1,080 mg/kg/day to rat in reproductive
toxicity tests.

Critical effect: NOAEL, foetotoxicity was 28 mg/kg bw/d.

Several hexyl carboxylic acid derivated metabolites have been
identified in humans. Elimination half-life of DEHA was only 1½
hour. Distribution of DEHA was highest in body fat, liver and kidney
when administered once intravenous or intragastrically to mouse and
rat. No DEHA was observed in mouse after 4 days.
Based on the available data, DEHA does not fulfil the criteria
for classification according to the Substance Directive /EU 1967/
for any of the described effects.

Environment

According to the available biodegradation data there is good
evidence of ready biodegradability of DEHA.

In one study DEHA is very toxic to D. magna with 50%
mortality slightly below 1 mg/l. The available ecotoxicological data
on DEHA from several other experiments show no mortality in algae,
crustaceans, and three fish species at concentrations up to 100
times the water solubility of DEHA. The maximum acceptable toxicant
concentration in a chronic test on reproduction in D. magna
was 0.024-0.052 mg/l. Bioaccumulation was 27 in test with bluegills,
100 times less than predicted from LogP_ow.

Diethylhexyl adipate

Identification of the substance

CAS No.

103-23-1

EINECS No.

203-090-1

EINECS Name

Bis(2-ethylhexyl) adipate

Synonyms

Adipic acid bis(2-ehtylhexyl) ester, adipol 2 EH, AI3-28579,
BEHA, bis(2-ehtylhexyl) adipate, bis(2-ethylhexyl)ester adipic acid,
bis(2-ethylhexyl)ester hexandioic acid, bis(2-ehtylhexyl)
hexanedioate, bisoflex DOA, D, DEHA, di-2-ethylhexyl adipate,
di(2-ethylhexyl) adipate, diethylhexyl adipate, di-octyl-adipat,
diisooctyladipat, dioctyl adaipate, DOA, Effemoll DOA, Effomoll DA ,
Effomoll DOA, ergoplast ADDO, flexol A 26, flexol plasticiser 10-A,
Flexol plasticiser A-26, Flexol plasticiser A 26, hexanedioic acid,
bis(2-ehtylhexyl) ester, exanedioic acid, bis(2-ehtylhexyl) ester
(9CI), hexanedioic acid, di(2-ehtylhexyl) ester, hexanedioic acid,
dioctyl ester, Kemester 5652, Kodaflex DOA, Lankroflex DOA, Mollan
S, Monoplex, Monoplex DOA, NCI-C54386, NSC 56775, octyl adipate,
Plastomoll, Plastomoll DOA, PX-238, Reomol DOA, Rucoflex plasticiser
DOA, Sicol, Sicol 250, Staflex DOA, Truflex DOA, Uniflex DOA,
Vestinol OA, Wickenol 158, Witamol, Witamol 320.

Molecular Formula

C₂₂H₄₂O₄

Structural Formula

Illustration. Structural Formula CAS No.103-23-1(2 Kb)

Major Uses

Plasticiser in PVC and other polymers processing.

Hydraulic fluid.

Plasticiser or solvent in cosmetics.

Plasticiser in PVC films.

Aircraft lubrication.

Application of paints and coatings.

[3]

[3]

[3]

[3]

[12]

[12]

IUCLID

The compound is included on the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

Colourless or very pale amber liquid.

Light-coloured, oily liquid.

Clear colourless liquid.

Colourless liquid

[3]

[6]

[6]

[15]

Molecular Weight (g/mole)

370.57

Melting Point/range (° C)

¨-67.8

–65 to –79

–65

–76 (DIN-ISO 3016)

[13]

[1,10,12]

[15]

[16]

Boiling Point/range (°C)

210-218

¨417

214 (at 5 mm Hg)

210-218 (DIN 53171, at 20.7 mm Hg)

210-220 (at 14.8 mm Hg)

210-218 (at 5.5 mm Hg, DIN 53171)

[1]

[13]

[3,12]

[10]

[15]

[16]

Decomposition Temperature (°C)

No data found

Vapour Pressure (mm Hg at °C)

1.58 (100 ° C)

2.4 (200 ° C)

8.5´ 10^-7 (20 °
C)

<0.01 (20 ° C)

2.35´ 10^-6(calculated, 25°
C)

¨ 8.50´ 10^-5
(20 ° C)

2.6 (20 ° C)

0.03 (20 ° C)

0.016 (100 ° C)

[1]

[2]

[3]

[8]

[8]

[10]

[12]

[15]

[16]

Density (g/cm³at ° C)

0.924 (DIN 51757, 20 ° C)

0.922 (25 ° C)

0,9268 (20 ° C)

0.923-0.926 (20 ° C)

[1,10,16]

[3]

[6]

[15]

Vapour Density (air=1)

12.8

[3]

Henry’s Law constant (atm/m³/mol at °
C)

4.34´10^-7 (measured, 20 °
C)

4.34´10^-7 (measured, 25 °
C)

2.13´ 10^-5 (estimated, 25°
C)

[3]

[10]

[8]

Solubility (g/l water at ° C)

<0.1 (20 ° C)

<0.1 (22 ° C)

¨ 0.00078 (22 °
C)

0.1 (estimated, 25 ° C)

0.2 (20 ° C)

[1,16]

[6]

[3,6]

[10]

[10]

Partition Coefficient (log P_ow)

¨ 8.114 (estimated)

¨ > 6.11 (measured)

4.2 (estimated)

¨ 8.1-8.114 (estimated)

6.114-8.2 (estimated)

¨ 8.1 (estimated)

[1]

[3]

[8]

[10]

[10]

[12,15]

pK_a

Not applicable

Flammability

Slightly flammable when exposed to heat

¨ Must be preheated before ignition

[3]

[6]

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

From PVC films to isooctane:

8.1-48.1 mg/dm²

From PVC to olive oil:

8.2-41.3 mg/dm² (reduced 2.6-41.3 mg/dm²)

[14]

[14]

Emission Data

During production

Estimated:

¨ Ca. 1 % to atmosphere of treated
amount of plastizicer

0.001 % to hydrosphere of total production amount

[10]

[10]

Exposure Data

Aquatic environment, incl. sediment

Measured:

Rw winter 0.08-0.3 ppb

Rw 1-30 ppb

Lw 35-130 ng/l

Fw 0.2-1.0 m g/l

Lw 0.01 –7.0 m g/l

Untreated dw 0.02 mg/l

Rw 1 m g/l

Indust. effluent 8.2 m g/l

Sediment 0.1 mg/kg

Lake sediment 3 mg/kg dry weight

[3,12]

[3]

[3,10]

[3]

[10]

[10]

[10]

[10]

[10]

[10]

Terrestrial environment

No data found

Sewage treatment plant

Measured:

Effluent 2-70 ppb

Effluent 2000 ppb

Effluent 10 m g/l

Influent 90 m g/l

Influent 0.1-3 m g/l

[3]

[3]

[10]

[10]

[10]

Working environment

Measured:

Indoor, office 2 ng/m³Indoor, packing room max 214 m g/m³Indoor, laboratory 0.001-0.0014 m
g/m³

Indoor, telephone exchange 0.002 m g/m³

Indoor, meat packing room av. 11.7 m g/m³

Indoor, meat packing room max 14.7 m g/m³

[3]

[10]

[10]

[10]

[10]

[10]

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

Measured:

Dw 77 ppb

Dw 0.002 ppb

Dw 0.1 m g/l

Dw 20.0 m g/l

Fruits/vegetables 0.2-6.4 mg/kg

Sandwich 30-325 mg/kg

Cheese 28-2,100 mg/kg

Fresh pork 1.8-64 mg/kg

Fresh lamb 2.9-11 mg/kg

Fresh beef 1.0-8.0 mg/kg

Fresh chicken 8.5-53 mg/kg

Draught beer 0.01-0.07 mg/kg

Bottled beverage 0.01-0.1 mg/kg

PVC wrapped food 41-362 mg/kg

Mango slices 0.2 mg/kg

Cabbage 4.8 mg/kg

Cake slices 200 mg/kg

55 % Minced beef 81.8 mg/kg

Olive oil 192-391 mg/kg

Chocolate 0.38 mg/kg

Biscuits 0.11 mg/kg

Cheese 15-2100 mg/kg

Fresh meat 49-151 mg/kg

Boiled meat 40 mg/kg

Dialysis patients (1-5h.) 2.7-9.7 mg/l perfusate

Oxplasma (5h.) 80-90 mg/l

Human plasma 50-100 mg/l blood

[3]

[3,10]

[3]

[3]

[3]

[3,10]

[3]

[3]

[3]

[3]

[3]

[3]

[3]

[3]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

Atmosphere

Measured:

Coal smoke 73 m g/Nm³

Estimated:Rain 1 m g/l

Air 15–20 pg/m³

[10]

[10]

[10]

Dermal

No data found

Toxicological data

Observations in humans

Irritation and sensitisation:

The concentration of DEHA in working environment was at 4 workplaces
below detection limit. Only one worker reported having difficulties
with the respiratory passages.

[1,10]

¨ In the meatpacking industry 685
workers were investigated. The average DEHA concentration in the
rooms was 11.7 m g/m³to 14.6 m
g/m³. Workers with asthma or allergy seemed to have more
pronounced reactions.

[1]

0.01-0.225% (4 testrows) 370 persons. One incidence of mild skin
reaction.

[10]

0.175% to 9% DEHA in cosmetic products151 subjects mild skin
irritation was observed in two subjects in induction tests with.
(CFTA 1976).

[29]

Cosmetic products containing 0.175% to 9% of DEHA. Mild
irritation was observed in two of 151 human subjects at the
induction tests. Repeated insult patch test.

[10]

9% DEHA in cosmetic product (3 times per w for 3 w) 209 subjects.
Light to strong erythema was observed in 4 of 209 subjects
(BIBRA/CFTA 1978A).

[10,31]

Undiluted DEHA. Not sensibility observed.

[10]

9% (repeated treatment) 25 subjects. No photo-sensibilisating
reactions observed.

[10]

ADI:

¨ ADI for man : 0.3 mg DEHA/kg bw/d

[23]

Toxicokinetics

50 mg H2 marked DEHA in 6 test persons. 2-ethyl-5-hydroxyhexanoic
acid was observed as the main metabolite in the urine.

[1,10]

¨ 46 mg/person (once) administration
in an oral gelantine capsule. Metabolites in blood (up to 31 h after
administration) and urine (up to 96 h after administration)
investigated. The main metabolite in blood was 2-ethylhexyl acid.
Elimination half time was 1.65 h. In urine the observed metabolites
were 2-ethylhexylanoic acid (8.6%), 2-ethyl-5-hydroxyhexanoic acid
(2.6%) 2-ethyl-1,6-hexandioicacid (0.7%), 2-ethyl-5-ketohexanoic
acid (0.2%) and 2-ethylhexanol (0.1%). Half life time was approx.
1.5 h. After 36 h no metabolites were found in the urine.

[10,40]

50 mg (single) oral administration. Metabolites after 24 h in
humans investigated in urine and faeces. 1.5-8 %
2-ethyl-5-hydroxyhexanacid, 0.5-1.5% 2-ethyl-5-ketohexanacid.
0.15-1% 2-ethyl-1,6-hexandiacid. In faeces di-(2-ethylhexyl)adipate
and mono-(2-ethyl-hexyl)adipate were found.

[10,41]

Acute toxicity

Oral

Rat:

Test dose not given. LD₅₀ was 45,000 mg/kg bw.

Test dose not given. LD₅₀ was 24,600 mg/kg bw.

Test dose not given. LD₅₀ was 14,800 mg/kg bw.

¨ Test dose not given. LD₅₀
was 7,392 mg/kg bw.

Test dose not given. LD₅₀ was 9,110 mg/kg bw.

Test dose not given. LD₅₀ was 20,290 mg/kg bw.

Test dose not given. LD₅₀ was 20,000-50,000 mg/kg bw.

Test dose not given. LD₅₀ was 9,110 mg/kg

Test dose not given. LD₀ was 6,000 mg/kg
Mouse:

Test dose not given. LD₅₀ was 15,000 mg/kg bw.

Test dose not given. LD₅₀ was 24,600 mg/kg bw.
Guinea pig:

Dose£14 ml/kg. Effects: 50% died after
2-3 d

Test dose not given. LD₅₀ was 12,900 mg/kg bw.

[1,10]

[1,10]

[1,10]

[1,10, 24]

[1,10]

[1,10]

[1,10]

[6,10]

[10]

[1,10]

[1,10]

[3]

[1,10]

Dermal

¨ Test dose not given. LD₅₀
was 8,410 mg/kg

Test dose not given. LD₅₀ was 15,100 mg/kg

[1,6,10,26]

[1]

Inhalation

Rat:

8h exposure, no effects observed
¨ 900 g/m³ (4 hours). No
effects

[1]

[27]

Other routes

Rat:

i.v., LD₅₀=900 mg/kg bw
Rabbit:

¨ i.v., LD₅₀=540 mg/kg bw

[1,6,10]

[1,6,10,28]

Rat:

Test dose not given. i.p., LD₅₀>6,000 mg/kg bw

Test dose not given. i.p., LD₅₀>46,000 mg/kg bw

Test dose not given. i.p., LD₅₀>47,000 mg/kg bw

[1,10]

[1]

[1]

Mouse:

¨ Test dose not given. i.p., LD₅₀ca.
150 mg/kg bw

Test dose not given. i.p., LD₅₀>5,000, mg/kg bw, GLP

Test dose not given. i.p., LD₅₀>5,000 mg/kg bw

Test dose not given. i.p., LD₅₀>9,240 mg/kg bw

Test dose not given. i.p., LD₅₀>92,400 mg/kg bw

Test dose not given. i.p., LD₅₀app. 150,000 mg/kg bw

[1,25]

[1]

[1]

[1]

[1]

[1]

Rabbit:

Test dose not given. i.p., LD₅₀>38,000 mg/kg bw

[1,10]

Skin irritation

Rabbit:

Test dose not given. Not irritating (5 studies)

¨ 500 mg; Test dose not given. Slightly
irritating (2 studies)

[1,10]

[1,10,26]

Eye irritation

Rabbit:

No dose specified. Not irritating, BASF test.

0.1 ml (92.4 mg). Not irritating.

No dose specified. Not irritating, Draize test.

¨ 0.5 ml (462 mg) test substance. Small
foci with necroticism.

500 mg. Slightly irritating.

Test dose not given (24 h) particular attention to cornea. Degree of
injury rated 1. Most severe injury has been rated 10.

No dose specified. Temporary redness of conjunctive. No effects
observed after 24 hours.

[1]

[1,10]

[1]

[1,10,20]

[1,10]

[3, 19]

[10]

Irritation of respiratory tract

No data found

Skin sensitisation

Guinea pig:

Application of o.05ml/0.1% and weekly o.1ml/0.1% over (3 w). Not
sensitising, Draize test

[1,10]

¨ First application 0.05 ml 0.1%
solution, thereafter 0.1 ml 0.1 % solution 3 times/w (3 w) 10 males.
Not sensitising, patch test.

[1,10,30]

Subchronic and Chronic Toxicity

Oral

Many other studies found.
Mouse:

700 and 1,500 mg/kg/d (2-year) feeding. Dose related depression of
weight gain.

¨ B6C3F1 mice: 240-3,750 mg/kg bw
(13 w) feeding. Decrease in weight gain in male mice at 465 mg/kg
bw.

[4]

[1,10,21]

Rat:

0.5, 2, 5% (500 to 5,000 mg/kg, one month) in diet. Growths effect
at 5 %.

Fisher 344 rats: 0.25, 0.5, 1.0, 2.0 % (250 to 2,000 mg/kg,
one month) in diet, males. Enlargement of liver at 2 % doses.

Wistar rats: 2% (2 w) in diet, males. Hepatic peroxisome
proliferation, increased liver size, enzyme catalase and cartinine
acetyltranferase and hypolipidemia

0, 0.1, 0.6, 1.2, 2.5% (21 d) in diet. Differences in Bw, in liver
weights, kidney weights. Increases in different liver lipids, minor
differences between male and females. Dose related increase in
peroxisome proliferation at doses above 0.1%, except in female group
0.6 and 1.2% (equivocal).

¨ 700 and 1,500 mg/kg/d (2-year)
feeding. Dose related depression of weight gain, NOAEL = 700
mg/kg/d, LOAEL = 1,500 mg/kg/d.

Fisher 344 rats: 1,600, 3,100, 6,300, 12,500, 25,000 ppm
(approx. 160-2,500 mg/kg/d; 13-w) oral feeding. NOAEL >
12,500 ppm

0.16 to 4.7 g/kg/d (90 d) in food. Reduced growth and altered liver
and kidney weights in dose groups between 2.9 to 16-4.74 g/kg/d.
Death produced at 4.74 g/kg. No effect in animals dosed 0.16 g/kg.

¨ 610-4,760 mg/kg (90 d). NOAEL=610
mg/kg

100 mg/kg (19 months), oral. NOAEL>100 mg/kg

[3,10]

[1]

[3]

[3]

[3,4,21]

[1, 4]

[3]

[1,10,20]

[1,20]

Dog:

2 g/kg (2 month) in diet. Transient loss of appetite.

[3]

Inhalation

No data found

Dermal

No data found

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Mouse:

Mutational effect in spermatogenesis and adverse effects in
premeiotic stage

5 g/kg/d (one or two d) i.p. 6 animals/sex. No significant
difference in incidence of polychromatic erythrocytes. Micronucleus
test.

¨ 0, 0.45, 0.9, 4.6, 9.2 g/kg bw (single
dose) intraperitoneal injection to male mice (10/dose), thereafter
fertilisation of 2 female/male. Dose related decrease in fertility,
dose related increase in dominant-lethal mutations (early foetal
deaths). LOAEL was 450 mg/kg bw.

[3]

[1,3]

[4,10,22]

Mouse lymphoma cell:

Up to 1,000 nl/ml. Not mutagenic without activation up to 1,000
nl/ml, or at concentration ranging from 15.6 to 250 nl/ml in the
presence of activation. Growth parameters was 21.4% at the high dose
level in absence of activation and 69.6 to 19.7% at the levels
tested in the presence of activation. With and without metabolic
activation.

[1,3]

Drosophila melanogaster:

5,000 ppm (injection) and 20,000 ppm (feeding) male.
Canton-S-wild-type males were treated and then mated with 3 harems
of virgin females. No sex-linked recessive lethal mutation. 30%
mortality in males.

[1,3]

Salmonella typhimurium:

¨ 0.025-10.0 mg/plate. Test strains:
TA 1535, TA 1537, TA 1538, TA 98, TA 100. Not mutagenic, with or
without activation. Preliminary range finding study non-toxic in
levels up to 10 mg/plate.

Up to 2 ml of urine from rats dosed 2,000 mg/kg (15d) gavage. Test
strains: TA 1535, TA 1537, TA 1538, TA 98, TA 100. No mutagenicity.
Modified Ames test, with and without metabolic activator.

0.15-150.0 m l/plate. Test strains: TA
1535, TA 1537, TA 1538, TA 98, TA 100. Not mutagenic. Ames
Salmonella/Microsome plate test, with or without activation.
Preliminary range finding study non-toxic in levels up to 150 m
l/plate.

Up to 1000 m g /plate, test strains:
TA97, TA98, TA100, TA102. Negative. Ames assay with and without
metabolic activation.

[3,4,10,

32]

[3]

[1,3,10]

[3]

Saccharomyces cerevisiae:

Not mutagenic in test.

[3]

Rat:

Negative, bioassay test

No dose specified (single) oral gavage dose, ability of different
tumor promoters to DNA synthesis. Test positive, stimulation of DNA
synthesis occurred.

5-1,000 nl/ml (20-24 h) closed culture vessels. No change in nuclear
labelling, slight decrease in relative survival at 1,000 nl/ml dose
level (84%). DNA repair assay.

[3]

[3]

[3]

Chromosome abnormalities

No data found.

Other genotoxic effects

Human Lymphocytes

¨ 10, 50, 100 µg/ml. Negative. OECD
guideline no. 473, with and without metabolic activation.

CHO cells

¨ <400 m
g/ml. A weak positive effect without S9 fraction. Not mutagenic with
the S9 fraction. With and without metabolic activation system.

[1,10,33]

[1,10,34]

Other toxic effects

Mouse cell line

3.38, 6.75, 13.5, 27.0 nl/ml in 0.5% acetone (72 h) mouse cell line.
No induction change of appearance of number of transformed foci.
Cell survival ranged from 89-37.7% relative to control. Cell
transformation Assay.

0.07, 0.7, 7, 28, 42 nl/ml in 0.5% acetone (48 h) mouse cell line.
No induction change of appearance of number of transformed foci.
Cell survival ranged from 52.3 to 11.5% relative to control. Cell
transformation Assay.

0.003, 0.01, 0.1, 0.3 nl/ml in 0.5% acetone (48 h) mouse cell line.
No induction change of appearance of number of transformed foci.
Cell survival ranged from 99.7 to 43.5% relative to control. Cell
transformation Assay.

[3]

[3]

[3]

Carcinogenicity

Mouse

¨ B6C3F1 mice: 1,800, 3,750
mg/kg/d (103 w) 50 animals/sex/dose group. Carcinogenic to female
mice, incidence of hepatocellular liver tumors in female mice.

LD₅₀= 47 ml /kg, ip. Carcinogenic bioassay.

¨ Test dose not given, oral gavage. LD_50,male=15 g/kg. Carcinogenic bioassay.

Test dose not given, oral gavage. LD_50,female=25
g/kg. Carcinogenic bioassay.

B6C3F1 mice: 0, 12,000, 25,000 ppm (104 w) oral in diet. Test
substance related liver carcinoma or adenoma observed.

[1,3,10,

21]

[3]

[3,21]

[3]

[4]

Rat

LD₅₀=0.9 ml/kg, i.v. Carcinogenicity bioassay.

LD₅₀=5.6 g/kg, oral. Carcinogenicity bioassay.

LD₅₀=47 ml/kg, ip. Carcinogenicity bioassay.

LD_50,male=45 g/kg, oral gavage.
Carcinogenicity bioassay.

LD_50,female=25 g/kg, oral gavage.
Carcinogenicity bioassay.

Male Wistar rats: Hepatic microsomal lauric acid hydroxylase
activity and peroxisome proliferation in liver, phenobarbital and
3-methylcholanthrene total cytochrome P450 was 1.7-2.7 times
induced.

Fisher 344 rats: 1.2, 2.5, 1.5%, to males in diet.
Significant increase in 8-hydroxydeoxyguanosine levels in liver
after 1 and 2 weeks of treatment. Indicates involvement of oxidative
DNA damage in hepatocarcinogenesis by peroxisome proliferation.

Fisher 344 rats: 0, 12,000, 25,000 ppm (103 w) oral in diet.
Test substance related liver carcinomas or adenomas were not
observed.

¨ Fisher 344 rats: 600, 1,250
mg/kg/d (103 w) oral feed 1-3 times/w, 50 animals/sex. Not
potentially carcinogenic to rats.

[3,21]

[3]

[3]

[3]

[3]

[3]

[3]

[4]

[1,10,21]

Mouse and rat

¨ Fisher 344 rats and B6C3F1
mice: 2.5 g/kg/d. Dose related increase in liver weight, palmitoyl
CoA oxidation markedly increased, some glycogen loss, dose-related
hypertrophy, increased eosinophilia in both mice and rats,
peroxisome proliferation combined with reduction of lipid in the
centrilobar hepatocytes. Indication of higher sensitivity for rats
than mice to hepatic peroxisome proliferation due to DEHA.

No dose specified (2 year). Hepatocarcinogenesis in female mice.

[3]

Male Fisher 344 rats and female B6C3F1 mice: 2 g/kg
(14 d). Significant increase in perixomal-acyl-CoA and catalase,
decrease in glutathione peroxidase in rats and mice. Increase in
steady state hydrogen concentration in liver homogenates.

Fisher 344 rats and female B6C3F1 mice: 12,000 and
25,000 ppm (103 w) oral, 50 animals per dose group. Decrease in BW
in high dose groups. Not carcinogenic.

Carcinogenic to rats. Carcinogenic to mice, especially female mice.
Dose related occurrence of adenomas and hepatocellular carcinomas in
mice, significant in males in high dose group and in females in low
and high dose groups. Carcinogenic bioassay.

[3,35]

[3,4]

[3,4]

Cancer Review

IARC - Not classifiable as a human carcinogen. Limited evidence
of carcinogenicity in animals.

[6]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity/teratogenicity

Many studies present.

Mouse:

Test dose not given, single IP doses to males, mated with untreated
females. Dose-dependent antifertility, dominant lethal mutation
indicated by reduced the % of pregnancies and increased number of
early foetal deaths.

[3,4]

Rat:

¨ Alpk:APfSD rats: 0, 300, 1,800,
12,000 ppm (28, 170 1,080 mg/kg/d; 10 w). No treatment related
effects on male or female fertility. Fertility study (OECD
415/1988). NOAEL, parental= 1,800 ppm, NOAEL, F0 offspring= 1,800.

[46]

¨ Alpk:APfSD rats: 0, 28, 170,
1080 mg/kg/d, 24 pregnant females/dose, in diets on gestation days
1-22. Changes in maternal bw gain, and food consumption, reduced
ossification, Kinked and dilated uterus in foetuses, developmental
study (OECD 414/1981). NOAEL

(foetotoxicity) = 28 mg/kg bw/d. Not significant.

[4,10]

¨ Sprague Dawley rats: 0.9,
4.6, 9.2 g/kg (on day 5, 10 and 15 of gestation) i.p. 5 pregnant
rats. Reduced foetal weight in dose groups 4.6 and 9.6 g/kg.
Developmental/teratogonicity study. NOAEL (maternal toxicity) = 0.9
g/kg bw/d, NOAEL (teratogenicity) = 0.9 g/kg bw/d (higher values in
ref. [46]).

[4,10]

Toxicokinetics

Toxicokinetics

Rat:

¨ In vivo - different doses of
DEHA and mono-(2-ethylhexyl)-adipate (5d) gavage, in vitro – hepatocytes.
No DEHA in urine after 24 h. Adipic acid was main metabolite,
2-ethylhexanol pathway showed further metabolites, mainly
2-ethylhexanoic acid which was conjugated or submitted to other
pathways, 2-ethylhexanoic acid glucoronidation appeared dose and
time dependent, 2-ethylhexanol glucoronidation was more stable. In
vitro, first hydrolysis of DEHA a rate limiting step, when
adding mono-(2-ethylhexyl)adipate all in vivo metabolites
were found, Glucoronidation of 2-ethylhexanol and 2- ethylhexanoic
acid was dose and time dependent.

[3,38]

Mouse, rat, guinea pig, marmoset:

¨ Up to 5 mM, metabolites of DEHA,
potential as peroxisome proliferators. In mice
mono(2-ethylhexyl)adipate and 2-ethylhexanol equipotent in inducing
oxidation, 2-ethylhexanoic acid increased oxidation by 25 fold at
1mM, other metabolites smaller increases in oxidation. Concentration
of respectively 2-ethylhexanoic acid, 2-ethylhexanol and
mono(2-ethylhexyl)adipate above 1mM resulted in cytotoxic signs
(blebbing, rounding of cells, detachment from the cultured flasks).
No peroxisomal beta-oxidation at up to 5 mM DEHA in rats hepatocytes
and at up to 2 mM in guinea pig or marmoset hepatocytes.

[3,39]

Mouse and rat:

Test dose unspecified, 14C-labelled (carbonyl or alcohol moiety)
DEHA (once) on day 17 of gestation, male rats, male mice and
pregnant female mice, i.v., in dimethyl sulfoxide and
intragastrically. Distribution highest in body fat, liver, kidney
when administered i.v. or intragastrically, 14C activity in bronchi
of male mice (alcohol labelled), in pregnant mice DEHA observed in
foetal liver, intestine, bone marrow during the first 24 h when
carbonyl labelled. Very little in mice foetuses when alcohol
labelled. No DEHA in mice after 4 d. Blood DEHA in rats 2-3 times
higher when given in DMSO than in corn oil. Sign. amount of DEHA
excreted in bile in rat when treated with DEHA in DMSO, alcohol
labelled. DEHA excreted in urine, vehicle little effect on amount
excreted. DEHA poorly absorbed from an oil solution.

[3]

Intestinal homogenates from rats:

Hydrolysis was rapid, estimated half-life of 6.0 min.

[3]

Ecotoxicity Data

Algae

Selenastrum capricornutum:

EC₅₀(72h)>500 mg/l, EPA-600/9-78-018

EC₅₀(96h)> 100´ S_w,
EPA-test

¨ LC₅₀(96h)=0.78 mg/l

Scenedesmus subspicatus:

EC₅₀(72h)>500 mg/l, DIN 38412/11

EC₅₀(72h)=400 mg/l, DIN 38412/11

[1]

[10]

[11,18]

[10,16]

[10]

Crustacean

Daphnia magna (fw):

EC₅₀(24h)>1000 mg/l

EC₅₀(24h)>500 mg/l, Dir. 84/449/EEC

EC₅₀(24h)>2.1 mg/l, DIN 38412/11

EC₅₀(24h)>500 mg/l, OECD 202

EC₀(24h)=500 mg/l, OECD 202

EC₅₀(48h)>500 mg/l, Dir. 84/449/EEC

EC₅₀(48h)>500 mg/l, OECD 202

LC₅₀(48h)=0.66 mg/l (range: 0.48-0.85 mg/l)

¨ EC₅₀(48h)=0.66 mg/l,
EPA-66013-75-009

EC₀(48h)=250 mg/l, OECD 202

EC₅₀(96h)= 0.66 mg/l, EPA-66013-75-009

[15]

[1]

[1]

[10,16]

[10]

[1]

[10]

[11]

[18]

[10]

[1,10]

¨ NOEC(96h)<0.32 mg/l,
EPA-6603-75-009
MATC(21d)=0.024-0.052 mg/l (geometric mean 0.035 mg/l),
Reproduction test according to ASTM E 47.01

[1,10,18]

[1,11,10, 18]

Chaetogammarus marinus (sw):

LC₀(96 h)=100 mg/l

[10]

Nitocra spinipes (sw):

LC₁₀₀(96 h)<100 mg/l

[10]

Fish

Lepomis machrochirus (fw):

¨ LC₅₀(96h) >100´ sol_w EPA-66013-75-009

[18]

Onchorhynchus mykiss (fw):

LT₅₀(96h)=110 mg/l

¨ LC₅₀(96h) >100´
sol_w,
EPA-66013-75-009

EC₅₀(96h)=54-150mg/l

[10]

[18]

[16]

Pimephales promelas (fw):

¨ LC₅₀(96h) >100´
sol_w,
EPA-66013-75-009

[1,10,18]

Poecilia reticulata (fw):

LC₅₀(96h)>100´ sol_w

[10]

Salmo gairdneri (fw):

LC₅₀(72h)>1 mg/l

LC₅₀(96h)=54-150 mg/l

LC₅₀(96h)>100´ sol_w,
EPA-66013-75-009

[1,10]

[1,15]

[1]

Bacteria

Pseudomonas putida:

EC₅₀>10,000 mg/l, DIN 38412
Inhibition of activated sludge:

EC₂₀>350 mg/l , OECD 302C/209

[1,15,16]

[16]

Terrestrial organisms

No data found

Other toxicity information

No data found

Environmental Fate

BCF

2700 (estimated)

2264 (estimated)

2692 (estimated)

Lepomis macrochirus (fw):

¨ 27 (28d, measured)

[1]

[8]

[10]

[2,10,16, 18]

Aerobic biodegradation

Aquatic – ready biodegradability tests:

¨ 66 % at 100 mg/l in 28 d, OECD 301 C

¨ 68 % at 100 mg/l in 28 d, OECD 301 C

<60 % in 28 d, OECD 301 C

¨ >98% in 28 d, OECD 301 F

¨ 93.8 at 20,1 mg/l in 35 d, Modified
Sturm-Test

>60% in 28 d (OECD 301)

67-74 % at 100 mg/l in 28 d, OECD 301 C

[1,10,42]

[1,10,43]

[1]

[10,44]

[1,9,10,44

[15,16]

[17]

Aquatic – other tests:

65-81 % in 1 d, SCAS

88-96 % in 1 d, SCAS

Ca. 73 % at 20 mg/24h. in 1 d, SCAS

Ca. 92 % in at 5 mg/24h. in 1 d, SCAS

81.6 % at 37.4 mg/l in 35 d, Shake-flask-system

94% after 35 d, Sturm-test

94 % in 35 d

81.6 % in 14 d, 14 d die-away test

[1,10]

[1,10]

[1,8,9,10]

[1,8,9,10]

[1,9,10]

[1]

[3,10]

[8]

Terrestrial environment:

> 50 % in 30 d, Sandy loam

[10]

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

K_oc=50,468

[10]

Conclusion

Physical-chemical

Reviewed data on diethylhexyl adipate (DEHA) indicates that the
substance is non-volatile and non-flammable compound with low water
solubility. Further the available data on LogP_ow
indicates strong lipophilicity and partitioning to particles and
biota.

DEHA has a migration potential in PVC films, which in several cases
exceeds the Danish limit of 4 mg/dm².

Emission

DEHA is according to the available estimates released during
production. Concentrations

Exposure

DEHA has been found in the aquatic environment and in drinking
water. DEHA has also been found to migrate in food, which has been
in contact with cling films,

Patients treated using plastic tubing, which has been produced using
DEHA, could be exposed to DEHA.

Health

LD₅₀ was 7,392 mg/kg bw in rat in acute oral tests.
Acute effects were not observed from DEHA in inhalation studies nor
was DEHA shown to be sensitising. DEHA was slightly irritating to
skin and eyes.

The subacute NOAEL was 610 mg/kg bw in rat and more than 3,100 ppm
in mouse.

DEHA was only slightly mutagenic in in vitro tests. Studies
on dominant lethal mutations in mouse showed a LOAEL on 450 mg/kg
bw. Metabolites showed no mutagenic effects in Ames tests with Salmonella
typhimurium.

DEHA shows limited evidence of carcinogenicity in animals (IARC,
group 3).

NOAEL was 1,200 ppm for both the parent and the F₀
generation in reproductive toxicity studies on mouse. The NOAEL was
170 mg/kg/d and LOAEL was 1,080 mg/kg/d to rat in reproductive
toxicity tests.

Critical effect: NOAEL, foetotoxicity was 28 mg/kg bw/d.

In rat adipic acid was the main metabolite. In human blood the main
metabolite was 2-ethylhexane acid. The metabolites
2-ethyl-5-hydroxyhexane acid, 2-ethyl-5-ketohexane acid,
2-ethyl-1,6-hexandiacid were found in human urine and
di-(2-ethylhexyl)adipate and mono-(2-ethyl-hexyl)adipate were found
in human faeces. Elimination half-life of DEHA was only 1½ hour.
Distribution of DEHA was highest in body fat, liver and kidney when
administered once intravenous or intragastrically to mouse and rat.
No DEHA was observed in mouse after 4 days.

Environment

According to the available biodegradation data there is good
evidence of ready biodegradability of DEHA.

In one study DEHA is very toxic to D. magna with 50%
mortality slightly below 1 mg/l. The available ecotoxicological data
on DEHA from several other experiments show no mortality in algae,
crustaceans, and three fish species at concentrations up to 100
times the water solubility of DEHA. The maximum acceptable toxicant
concentration in a chronic test on reproduction in D. magna
was 0.024-0.052 mg/l. Bioaccumulation was 27 in test with bluegills,
100 times less than predicted from LogP_ow.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

Bayer A/S (1999): Sicherheitsdatenblatt – Adimoll DO. Bayer,
Leverkusen, Germany

16

BASF (2000): Leveradørbrugsanvisninger – PLASTOMOLL* DOA. BASF
A/S Denmark

17

Chemicals Inspection and Testing Institute (1992): Biodegradation
and bioaccumulation Data of existing Chemicals based on the CSCL
Japan. Japan Chemical Industry Ecology and Toxicology and
Information Center. ISBN 4-89074-101-1.

18

Felder, J.D., Adams, W.J. & Saeger, V.W. (1986): Assessment
of the Safety of Dioctyl adipate in Freshwater Environments. Environ.
Toxicol. Chem. 5(8):777-784. Quoted in ref. 11.

19

Grant, W. M (1986): Toxicology of the eye. 3 rd ed. Springfield,
IL: Charles C. Thomas Publisher 1030. Quoted in ref 3.

20

Smyth et al.: (1951): Range finding toxicity data List IV.
Arch. Ind. Hyg. Occup. Med. 4, 199-122 Quoted in BUA.

21

DHHS/NTP (1981): Carcinogenesis bioassay of di-2-ethylhexyl
adipate in F344 rats and B6C3F1 Mice, p.2. Technical Rpt Series
No. 212 NIH Pub No. 81-1768. NTIS/PB 82-109166. US Department of
Cemmerce, Springfield, VA.

22

Singh et al. (1975): Dominant lethal mutations and
antifertility effects of di-2-ehtylhexyl adipate and diethyl adipate
in male mice. Toxicol. Appl. Pharmacol. 32, 566-576.

23

SCF (1991): Draft consolidated report of the Scientific
Committee for Food on certain additives used in the manufacture of
plastic materials intended to come into contact with foodstuffs. CEC
Draft report CS/PM/664 dated 15 January. Qouted in TNO BIBRA
International Ltd. Toxicity profile on Di-(2-ethylhexyl) adipate
(1991).

24

Kolmar Res. Ctr. (1967): : The toxicological examination of
di-a-ethyl-hexyl-adipate. (Wickenol 158). NTIS/OTS
286-1#FYI-OTS-0684-0286, US Department of Commerce, Springfield, VA.
Qouted in ref. 10.

25

BASF AS Ludwigshafen qouted in EUCLID (7/2-96) and ref. 10.

26

Union Carbide quoted in Sax, N.J. and Lewis, R.J. Jr. (eds);
1989): Dangerous Properties of Industrial Materials, Vol. 1.
7^th ed. Van Nostrand Reinhold, New York pp. 87, 748.

27

Vandervort and Brooks (1977). NOISH HEalth Hazard Evaluation
Determination Report No 74-24, 92. 95 cited in vandervort and Brooks
(1977): J. Occup.Med 19,188. Quoted in TNO BIBRA International Ltd. Toxicity
profile on Di-(2-ethylhexyl) adipate (1991).

28

Edgewood Arsenal (1954) quoted cited in Sax, N.J. and Lewis, R.J.
Jr. (eds); 1989): Dangerous Properties of Industrial Materials,
Vol. 1. 7^th ed. Van Nostrand Reinhold, New York pp. 87,
737.

29

Unpublished data from CFTA (1976). Cosmetic, Toiletry and
Fragrance Association. Modified Draize-Shelenski test cited in CIR.
Quoted in TNO BIBRA International Ltd. Toxicity profile on
Di-(2-ethylhexyl) adipate (1991)..

30

Kolmar Res. Ctr. (1967): : The toxicological examination of
di-a-ethyl-hexyl-adipate. (Wickenol 158). NTIS/OTS
286-1#FYI-OTS-0684-0286, US Department of Commerce, Springfield, VA.
Quoted in ref. 10.

31

Unpublished data from CFTA (1978a). Cosmetic, Toiletry and
Fragrance Association. Modified Draize-Shelenski test cited in CIR.
Quoted in TNO BIBRA International Ltd. Toxicity profile on
Di-(2-ethylhexyl) adipate (1991).

32

Zeiger et al. (1982): Phthalate ester testing in national
Toxicological Program's environmental mutagenesis test development
program. Environ. Health Perspect. 45, 99-101. Quoted in ref.10.

33

ICI PLC (1989b): Di(2-ethylhexyl) adipate: An evaluation in
the in vitro cytogenetic assay in human lymphocytes. Report No.
CTL/P/2519. Quoted in ref. 10.

34

Galloway et al (1987): Chromosome aberrations and sister
chromatid exchanges in chinese hamster ovary cells: Evaluation of
108 chemicals. Environ. Mol. Mutagen. 10, 1-15, 21, 32-36, 65,
109, 136, 137. Quoted in ref. 10.

35

Tomaszewski KE et al (1986): Carcinogenesis 7 (11): 1871-6.

36

Tinston DJ (1988): Di(2-ethylhexyl) adipate (DEHA): Fertility
study in rats. Unvceröffentlichte studie des ICI central toxicology
laboratory report bi CTL/P/2229. Quoted in ref. 10.

37

Hodge (1991): Di(2-ethylhexyl) adipate: Teratogenicity study
in the rat. ICI central Toxicology laboratory report No.
CTL/P/2119. NTIS/OTS 0533689 # 88-910000259. US Department of
Commerce, Springfield, VA. Quoted in ref. 10.

38

Cornu MC et al (1988): Arch Toxicol (suppl 12, The target organ
and the toxic Process): 265-8.

39

Cornu MC et al (1992): Biochem Pharmacol 43 (10): 2129-34. Quoted
in ref. 3.

40

Loftus et al (1993): Metabolism and pharmacokinetics of
deuterium labelled di(2-ethylhexyl) adipate in humans. Food Chem
Toxicol 31, 609-614.

41

Loftus et al (1990): The metabolism and pharmacokinetics of
deuterium labelled di(2-ethylhexyl) adipate in human volunteers
following oral administration. Hum. Exp. Toxical 9, 326-327.

42

ICI (1984): Letter from ICI Brixham Laboratory to ICI
Petrochemicals & Plastics Division dated 31. January 1984.

IUCLID Datasection 03.06.1994

43

ICI (1990): Letter from ICI Group Environmental Laboratory to ICI
Chemicals & Polymers Limited dated 15. August 1990.

IUCLID Datasection 03.06.1994

44

BASF AG (1987a): Labor für Umweltanalytik und Ökologie;
Unveröffentlichte Untersuchung 287356 Quoted in ref. 10.

45

Saeger, V.W., Kaley II, R.G., Hicks, O., Tucker, E.S., &
Mieure, J.P. (1976): Activated sludge degradation of selcted
phophate esters. Environ. Sci. Technol. 13, 840-482. Quoted in ref.
10.

46

SIDS dossier Cas No. 103-23-1. HEDSET datasheet. 18 September
1998.

O-acetyltributyl citrate

CAS number: 77-90-7

Physical-chemical, emission, exposure,
health and environment data

Summary

Physical-chemical
Indications are available that O-acetyltributyl citrate is
non-volatile and non-flammable compound with low water solubility.
Further the available data indicates that this compound
bioaccumulates. ATBC will migrate from cling film to food.

Emission

No data found.

Exposure

Human occupational exposure may occur through inhalation of dust
particles and dermal contact when working at places where O-acetyl
tributyl citrate is handled. General exposure of the population may
occur through dermal contact with consumer products containing O-
acetyl tributyl citrate and ingestion of contaminated food.

O-acetyl tributyl citrate has been found in the aquatic environment.

Health

Sufficient data were not found.

LD₅₀to rat was 31,4 g/kg in acute tests which indicated
very low toxicity. O-acetyl tributyl citrate was not found to be
irritant to skin or sensitising. Moderate eye irritation has been
observed. O-acetyl tributyl citrate was not mutagenic and did not
cause chromosomal aberrations in rat lymphocytes or unscheduled DNA
synthesis in rats treated by gavage. The negative UDS study indicated
that the in vivo genotoxic potential of ATCB is low or absent

The carcinogenic potential could not be evaluated from the reviewed
study. Decreased body weights were observed in a 2-generation study
(NOAEL 100 mg/kg bw/day). Based on limited data available the critical
effect appears to be reproductive toxicity and repeated dose toxicity.

Sufficient data are not available to evaluate the classification of
the substance for all effects (EU, 1967).

Environment

Only ecotoxicological data for fish were found. Acute mortality in
two freshwater fish were 38-60 mg/l.

According to the available biodegradation data there is no evidence of
ready biodegradability of ATBC.

O-acetyltributyl citrate

Identification of the substance

CAS No.

77-90-7

EINECS No.

201-067-0

EINECS Name

Tributyl O-acetylcitrate

Synonyms

1,2,3-Propanetricarboxylic acid, 2-(acetyloxy)-tributyl ester;
acetyl tri-n-butyl citrate, acetylcitric acid tributyl ester,
blo-trol, citric avid tributyl ester acetate, citroflex A, citroflex A
4, tributyl acetylcitrate, tributyl
2-acetoxy-1,2,3-propanetricarboxylate, tributyl acetylcitrate,
tributyl O-acetylcitrate, tributyl
2-(acetyloxy)-1,2,3-propanetricarboxylic acid, tributyl acetate

Molecular Formula

C₂₀H₃₄O₈

Structural Formula

Illustration. Structural Formula. CAS nr. 77-90-7 (2 Kb)

Major Uses

Flavour ingredient

Plasticiser for vinyl resins, rubber and cellulosic resins

Plasticiser for cellulose nitrate, ethyl cellulose, polystyrene
acetate, polyvinylchloride, vinylchloride copolymers

[3]

[3]

[3]

IUCLID

The substance is not included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

Colourless liquid

[3,6]

Molecular Weight (g/mole)

¨ 402.48

402.88

[1]

[3]

Melting Point/range (° C)

¨ -80

[3,6]

Boiling Point/range (° C)

172-174 ° C at 1 mm Hg

[1,3,6]

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

¨ 1 at 173 °
C

¨ 4.6´ 10^-6
(estimated)

1

5.2´ 10^-2

[3]

[3]

[6]

[16]

Density (g/cm³at ° C)

1.05

1.046 at 25° C

1.048

[1]

[3]

[6]

Vapour Density (air=1)

No data found

Henry’s Law constant (atm/m³/mol at °
C)

3.8´ 10^-6 (estimated,
unknown temperature)

[3]

Solubility (g/l water at ° C)

¨ 0.005 (unknown temperature)

Insoluble in water (unknown temperature)

[3]

[6]

Partition Coefficient (log P_ow)

¨ 4.31 (estimated)

[3]

pK_a

Not applicable

Flammability

No data found

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

Household cling film:

Sunflower oil (10d, 40 ° C)=4.7 mg/dm²Acetic acid (10d, 40 ° C)=2.8 mg/dm²

Migrated amount to cheese was 1-6% of plasticiser amount in film
corresponding to 0.1-0.7 mg/dm².
PVC transfusion tubing:

Studies on the migration potential of O-acetyltributyl citrate has
shown that O-acetyltributyl citrate is extractable from PVC tubing
using distilled water as a solvent.

Extraction studies of Poretex PVC transfusion tubing resulted
O-acetyltributyl citrate concentrations after 2 h. of 100 m
g/l.

Perfusion studies of the same PVC tubing resulted in an average
O-acetyltributyl citrate concentrations (mean of extract concentration
after 2-10 h. extraction) of ~ 6 m
g/l.

[15]

[15]
[20]

[17]

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

O-acetyltributyl citrate was found in 2 water samples taken from
River Lee (UK) at trace levels.

[3]

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

No evidence of sensitisation and irritation in a sensitisation
test.

[22]

Acute toxicity

Oral

Rats and cats

Single oral doses, 10-30 ml/kg. No marked effect observed.
¨ Rat

LD₅₀=31.4 g/kg

[3]

[3]

Dermal

No data available

Inhalation

No data available

Other routes

¨ Rabbit

Local anaesthetic action.

Blocks neural transmission in rats when placed in contact with a nerve
trunk.

0.1 g/kg i.v. caused increased motor activity and respiration.
Unspecified dosed had a depressive effect on the blood pressure.

¨ Mouse and rat

0.4 g/kg increased respiration and induced severe signs of central
nervous system toxicity.

[3]

[3]

[21]

[21]

Skin irritation

¨ Rabbit

Not a skin irritant.

[22]

Eye irritation

¨ Rabbit

5% suspension instilled in the eye caused temporarily abolished
corneal reflex action.

¨ Rat

Moderate eye irritation.

[21]

[22]

Irritation of respiratory tract

No data available

Skin sensitisation

¨ Guinea pig

Not a sensitiser in guinea pig maximisation test.

[22]

Subchronic and Chronic Toxicity

Oral

Rats

5 or 10% in the diet (6-8 w) in male rats. The lower dose had no
deleterious effect on growth whereas the high dose produced frequent
diarrhoea and markedly depressed growth.

1000 (1%), 2,700 (2.5%) and more mg/kg bw/d in the diet (4 w).
Decreased body weights and changes in organ weights from 2.5% onwards.
No effects at 1%. Range finding study.

¨ 100, 300, 1,000 mg/kg bw/d (90 d) in Wistar
rats. Haematological and biochemical changes from 300 mg/kg bw/d.
Increased lever weights at 1,000 mg/kg bw/d. NOAEL 100 mg/kg bw/d.
(OECD 408)

[21]

[22]

[22]

Inhalation

No data available

Dermal

Mice

900 mg/kg (14 d), i.p. No other effects than decreased red blood cell
count were observed.

[3]

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Salmonella typhimurium

¨ No dose mentioned. Not mutagenic.

[5]

Gene Mutation

¨ Not mutagenic
Mouse lymphoma

No dose mentioned. Test strain: L5178Y. No gene mutations were
observed. Suspension/plate with and without metabolic activation.

Salmonella typhimurium

¨ No dose mentioned, test strain: TA98,
TA100, TA 1535, TA1537 and TA1538. No gene mutations were observed.
Standard plate with metabolic activation). Ames test.

[3]

[5]

[5]

Chromosome Abnormalities

Rats

¨ Single doses by gavage of 800 or 2,000
mg/kg did not produce unscheduled DNA systhesis.
Rat lymphocytes

¨ Dose levels not reported. No chromosomal
aberrations were observed in the absence or presence of activation.

[22]
[22]

Other Genotoxic Effects

Human KB cells:

50% inhibited growth= 44.7 m g/Ml

[3]

Monkey Vero cells:

¨ 50% inhibited growth = 39.9 m
g/mL

[3]

Canine MDCK cells:

50% inhibited growth = 42.1 m g/mL
Rat liver microsomes:

Laurate 12-hydroxylase activity in acetyl-tributyl-citrate rats = 4,4
nmol (controls = 2.8 nmol). Cytochrome p450-mediated fatty acid
omega-hydroxylation system.

[3]

[3]

Carcinogenicity

¨ Rat (Sherman)

0, 200, 2000, 20000 ppm (1000 mg/kg bw/d) (2 years). No significant
findings. Not according to modern guidelines. ATBC not a potent
multi-site carcinogen.

[22]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

Rat, Sprague Dawley

¨ 0, 100, 300, 1000 mg/kg bw/d in the
diet. 2-generation reproduction study (OECD 416). Decreased body
weights in F1 males from 300 mg/kg bw/d and F0 males at 1000 mg/kg
bw/d- NOAEL 100 mg/kg bw/d.

[22]

Teratogenicity

No data found

Other Toxicity Studies

No data found

Toxicokinetics

ATBC is rapidly absorbed after oral administration. Half-life = 1
hour. >67% is absorbed and primarily excreted into urine (approx.
64%). Excretion in faeces amounts to approx. 32% and 2% in air.

[22]

Ecotoxicity Data

Algae

No data found

Crustacean

No data found

Fish

Lepomis macrochirus

LC₅₀ (96h) = 38-60 mg/l

Fundalus heteroclitus

LC₅₀ (96h) = 59 mg/l

[23]

[23]

Bacteria

No data found

Terrestrial organisms

No data found

Other toxicity information

No data found

Environmental Fate

BCF

¨ 1,100 (estimated)

[18]

Aerobic biodegradation

Aquatic – other tests:

80 % at 30 mg/l in 28 d, modified MITI Test

[19]

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

K_oc»5100 (estimated)

[3]

Conclusion

Physical-chemical

Indications are available that O-acetyltributyl citrate is
non-volatile and non-flammable compound with low water solubility.
Further the available data indicates that this compound
bioaccumulates.

Emission

No data available

Exposure

Human occupational exposure may occur through inhalation of dust
particles and dermal contact when working at places where O-acetyl
tributyl citrate is handled. General population exposure may occur
through dermal contact with consumer products containing O- acetyl
tributyl citrate and ingestion of contaminated food. O-acetyl tributyl
citrate has been found in the aquatic environment.

Health

Sufficient data were not found.

LD₅₀to rat was 31,4 g/kg in acute tests.

O-acetyl tributyl citrate was not found to be irritant to skin or
sensitising. Moderate eye irritation has been observed.

O-acetyl tributyl citrate was not mutagenic and did not cause
chromosomal aberrations in rat lymphocytes or unscheduled DNA
synthesis in rats treated by gavage. The negative UDS study indicated
that the in vivo genotoxic potential of ATCB is low or absent

The carcinogenic potential could not be evaluated from the reviewed
study.

Decreased body weights were observed in a 2-generation study (NOAEL
100 mg/kg bw/d).

Based on limited data available, the critical effect appears to be
reproductive toxicity and repeated dose toxicity.

Sufficient data are not available to evaluate the classification of
the substance for all effects (EU, 1967).

Environment

According to the available biodegradation data there is no evidence
of ready biodegradability of O-acetyltributyl citrate.
Acute mortality in two freshwater fish were 38-60 mg/l.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

Plastindustrien i Danmark (1996): Redegørelse om phthalater i
blød PVC – Acetyl Tribtutyl Citrate Dossier for evaluation. ATBC
Industry Group (1992). pp VI

16

Reilly Chemicals: CitroflexÒ - Citric
Acid Estres – Technical Bulletin 101. Received from MST (2).

17

Hollingsworth, M. (1975): Pharmacologi-cal Properties of the
Plasticiser, Acetyl N-tributyl citrate, and its Extraction from
Poly(vinyl Chloride) Tubing. J. Biomed. Mater. Res. Vol. 9, pp.
687-697

18

Meyland W M, Howard P H (1995). J Pharm Sci 84: 83-92.

19

Chemicals Inspection and Testing Institute (1992): Biodegradation
and bioaccumulation Data of existing Chemicals based on the CSCL
Japan. Japan Chemical Industry Ecology and Toxicology and
Information Center. ISBN 4-89074-101-1

20

Castle, L., Mercer, A.J., Startin, J.R. & Gilbert, J. (1988)
Migration from plasticised films into foods. 3. Migration of
phthalate, sebacate, citrate and phosphate esters from films used for
retail food packaging. Food Addit. Contam. 5(1), pp 9-20

21

TNO BIBRA International Ltd (1989): Toxicity profile - Acetyl
tributyl citrate.

22

Scientific Committee on Toxicity, Ecotoxicity and the Environment
(CSTEE) (28 September 1999): Opinion on the toxicological
characteristict and risks of certain citrates and adipates used as a
subatitute for phthalates as plastosisers in certain soft PVC
products.

23

Ecosystems Laboratory (1974) Report on the potential
environmental impact of Citroflexes. Information from Reilly
Chemicals, Oct. 2000.

Di(2-ethylhexyl) phosphate

CAS number: 298-07-7

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

Di(2-ethylhexyl) phosphate is a slightly flammable compound when
exposed to heat. It has a low water solubility and vapour pressure.

Emission

No data found

Exposure

No data found

Health

Inhalation of 2 ppm caused weakness, irritability and headache in
humans.

Acute oral toxicity (LD₅₀) of di(2-ethylhexyl) phosphate to
rat was 4,940 mg /kg bw whereas the LD₅₀ in an acute dermal
application test on rat was 1,200 mg/kg bw. The i.p. LD₅₀ for
rat was 1,200 mg/kg bw.

Di(2-ethylhexyl) phosphate exhibit strong corrosive effect in cornea at
5 m l doses (1% solution) as well as skin
irritating effects. No mutagenic activity has been observed.
All endpoints have not been sufficiently investigated. Dermal
toxicity and local corrosive effects on skin and eyes seems to be the
most severe effects. Sufficient data are not available for
classification. DEHPA has been classified by Bayer AG in 1993 as C (Corrosive);
R34 (Causes burns) and Xn (Harmful); R21 (Harmful in
contact with skin.

No data found to determine reproductive toxicity or teratogenicity.

Environment

Conflicting data on the biodegradability of di(2-ethylhexyl)
phosphate are available. The compound is here evaluated as inherently
biodegradable.

The BCF values indicates that di(2-ethylhexyl) phosphate does not
bioaccumulate.

The available ecotoxicological data indicates that di(2-ethylhexyl)
phosphate is harmful to algae, crustaceans and fish.

Di(2-ethylhexyl) phosphate

Identification of the substance

CAS No.

298-07-7

EINECS No.

206-056-4

EINECS Name

Bis(2-ethylhexyl) hydrogen phosphate

Synonyms

Bis(2-ethylhexyl) hydrogenphosphate, Bis(2-ethylhexyl)
orthophosphoric acid, Bis(2-ethylhexyl) phosphoric acid, D2EHPA, DEHPA,
DEHPA extractant, Di-(2-ethylhexyl) acid phosphate, Di-2-ethylhexyl
hydrogen phosphate, Di-(2-ethylhexyl) phosphoric acid, Di(2-ethylhexyl)
orthophosphoric acid, Di(2-ethylhexyl) phosphate, Di-(2-ethylhexyl)
phosphoric acid, ECAID 100, 2-ethyl-1hexanol hydrogen phosphate, HDEHP,
hydrogen bis(2-ethylhexyl) phosphate, phosphoric acid bis(ethylhexyl)
ester, phosphoric acid bis(2-ethylhexyl) ester.

Molecular Formula

C₁₆H₃₅O₄P

Structural Formula

Illustration. Structural Formula. CAS nr. 298-07-7 (2 Kb)

Major Uses

Additive to lubrication oils, corrosion inhibitors and antioxidants.

Metal extraction and separation.

Intermediate for wetting agents and detergents.

Extraction of drugs from aqueous phase.

[3]

[3]

[3]

[3]

IUCLID

The compound is not listed as HPVC.

EU classification

The compound is not included in Annex I to 67/548/EEC

[10]

Physico-chemical Characteristics

Physical Form

Colourless Liquid

[3,15]

Molecular Weight (g/mol)

322.48

[3]

Melting Point/range (° C)

-60 ° C

~ 50 ° C

[3]

[15]

Boiling Point/range (° C)

¨ 48 at 12 mm Hg

Decomposition occurs prior to boiling

[1]

[10]

Decomposition Temperature (° C)

240

[10]

Vapour Pressure (mm Hg at ° C)

¨ 4.65´ 10^-8
(estimated)

< 0.003

[3]

[15]

Density (g/cm³at ° C)

0.97

0.96 at 20 ° C

[1]

[10,15]

Vapour Density (air=1)

No data found

Henry’s Law constant (Pa/m³/mol at °
C)

4.16´ 10^-3 (estimated)

[3]

Solubility (g/l water at ° C)

0.1 (20 ° C)

[3]

Partition Coefficient (log P_ow)

6.07 (estimated)

¨ 2.67, MITI

[3]

[10]

pK_a

¨ 1.72 (estimated)

2.17 (estimated)

[10]

[10]

Flammability

¨ Slightly flammable when exposed to
heat.

[3]

Explosivity

May form flammable hydrogen gas.

[3]

Oxidising Properties

No data found

Migration potential in polymer

No data found

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

No data found

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found concerning concentration in the working environment.

Potential working groups to be exposed: workers in the radiochemical
industry where bis(2-ethylhexyl) hydrogen phosphate is used to extract
radioactive metals; workers using bis(2-ethylhexyl) hydrogen phosphate
during manufacture of certain lubricating oils, wetting agents and
detergents.

[3]

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

Bis(2-ethylhexyl) hydrogen phosphate is a liquid used for the
extraction of heavy metals as an additive for lubricating oil and as an
intermediate for manufacture of wetting agents and detergents, the most
probable route of exposure is by skin absorption.

[3]

Toxicological data

Observations in humans

Smarting of skin and first degree burns on short exposure. May cause
second degree burn on long term exposure. Irritating to skin and eyes.
Inhalation of 2 ppm caused weakness, irritability and headache.

[3]

[3]

Acute toxicity

Oral

Rat:

¨ LD₅₀=4,742 mg/kg

LD₅₀=4,940 mg/kg

[10]

[10]

Dermal

Rabbit:

¨ LD₅₀=1,200 mg/kg bw (1.25
ml/kg; 24 h)

LD₅₀=1,250 mg/kg bw

[10]

[3]

Inhalation

Rat:

Saturation concentration < 1,300 mg/m³?
Dogs:

8 hours exposure of 380 ppm caused death.

[10]

[3]

Other routes

Mouse:

I.p. study. LD₅₀= 62.5 mg/kg bw
Rat:

I.p. study. LD₅₀= 50-100 mg/kg, 50% mortality was observed in
dose group 500 mg/kg bw. Adhesion in inner organ of animals from the 50
mg/kg bw group.

I.p. study. LD₅₀ varied between less than 50 mg/kg to more
than 5,000 mg/kg.

[10]

[10]

[3]

Skin irritation

10 µL undiluted (24 h), 5 animals. Necrosis was observed after 24 h.
Intact skin, occlusive test.

500 µl (4-8 h).

[10]

[10]

Eye irritation

Rabbit:

100 m l, 2 young animals, application in eye.
Corrosive to cornea and irritating to mucous membrane.

¨ 5 µl (1% solution) young animals. Strong
corrosive effects in cornea.

[10]

[10]

Irritation of respiratory tract

No data found

Skin sensitisation

No data found

Subchronic and Chronic Toxicity

Oral

Rat:

Sprague Dawley rats: 0.25%, 1%, 3% (25, 100, 200 mg/kg bw) (5 d),
feed. Significant increases in the relative liver weight in the 1% and
3% dose groups. Test substance was a potent inductor of the P450b+e
system.

Mouse:

C57B1/6: 1,500 mg/kg bw (4 d), 3 animals. Significant increases
in liver weights. Increases in the perixomale enzymes carnitine
acetyltranferase and palmitoyl CoA-oxidase.

[10]

[10]

Inhalation

No data found

Dermal

No data found

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Salmonella typhimurium:

¨ 4-2,500 m
g/plate, strain: TA98, TA100, TA1535, TA1537, all strain tested both
with and without metabolic activation. No mutagenicity was observed.

0.001-5 m l/plate, strain: TA98, TA100,
TA1535, TA1537, TA1538, all strain tested both with and without
metabolic activation. No mutagenicity was observed.

[10]

[10]

Saccharomyces cerevisiae:

¨ 0.001-5 m
l/plate. Tested both with and without metabolic activation. No
mutagenicity was observed.

[10]

Mouse lymphoma:

¨ 0.05 - 0.095 m
l/ml. No metabolic activation. No mutagenicity was observed.

¨ 0.01 - 0.095 m
l/ml. With metabolic activation. No mutagenicity was observed.

[10]

[10]

Gene Mutation

No data found

Chromosome Abnormalities

No data found

Other Genotoxic Effects

No data found

Carcinogenicity

No data found

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

No data found

Teratogenicity

No data found

Other Toxicity Studies

No data found

Toxicokinetics

Toxicokinetics

No data found

Ecotoxicity Data

Algae

Chlorella emersonii:

Growth inhibition at conc.= 0.3-100 mg/l

¨ EC₅₀(48h)=50-100 mg/l

[3]

[10]

Crustacean

Daphnia magna:

EC₅₀(24h)=42.0 mg/l

LC₅₀(24h)>42 mg/l

¨ EC₅₀(48h)=42.0 mg/l

¨ EC₅₀(48h)=60.7 mg/l

¨ EC₅₀(48h)=75.0 mg/l

¨ EC₅₀(48h)=76.9 mg/l

¨ EC₅₀(48h)=83.7 mg/l

¨ LC₅₀(48h) > 42 mg/l

EC₅₀(72h)=24.5 mg/l

EC₅₀(72h)=29.0 mg/l

EC₅₀(72h)=30.2 mg/l

EC₅₀(72h)=40.2 mg/l

EC₅₀(72h)=46.8 mg/l

EC₅₀(72h)=47.4 mg/l

EC₅₀(72h)=47.9 mg/l

LC₅₀(72h)=36.5 mg/l

LC₅₀(72h)=46.8 mg/l

EC₅₀(96h)=11.1 mg/l

EC₅₀(96h)=12.1 mg/l

EC₅₀(96h)=18.4 mg/l

EC₅₀(96h)=26.0 mg/l

EC₅₀(96h)=27.2 mg/l

EC₅₀(96h)=28.7 mg/l

EC₅₀(96h)=28.2 mg/l

LC₅₀(96h)=16.5 mg/l

LC₅₀(96h)=27.2 mg/l

[11]

[10]

[11]

[11]

[11]

[11]

[11]

[10]

[11]

[11]

[11]

[11]

[10]

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[10]

[10]

Other invertebrates

No data found

Fish

Salmo gairdneri (fw):

Inhibited growth at conc.= 0.3-100 mg/l

¨ LC₅₀(96h)=48-54 mg/l

Oncorhynchus mykiss (fw):

LC₅₀(48h)=22-43 mg/l

¨ LC₅₀(96h)=20-36 mg/l

LC₅₀(120h)=20-34 mg/l

Danio rerio (fw):

¨ LC₅₀(96h)=56 mg/l

[3]

[10]

[10]

[10]

[10]

[11]

Bacteria

Pseudomonas flourescens:

EC₀(48h)=2,340 mg/l, DEV L8

Thiobacillus ferooxidans:

IC₆₈(3h)=443 mg/l, respiration

Cellulomonas and sporocytophaga myxococcoides:

Inhibited growth at conc.= 0.3-100 mg/l

[10]

[10]

[3]

Terrestrial organisms

No data found

Other toxicity information

No data found

Environmental Fate

BCF

37 (estimated)

Cyprius carpio (fw):

¨ 1.1-6, MITI test

[10]

[10]

Aerobic biodegradation

Aquatic – ready biodegradability tests:

¨ 75 % at 100 mg/l in 28 d, modified MITI
Test
Aquatic – other tests:

¨ 0-17 % at 30 mg/l in 28 d, modified MITI
Test

[9,10,15]

[10]

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

No data found

Conclusion

Physical-chemical

Di(2-ethylhexyl) phosphate is a slightly flammable compound when
exposed to heat with a low water solubility and vapour pressure.

Emission

No data found

Exposure

No data found

Health

Inhalation of 2 ppm caused weakness, irritability and headache in
humans.

Acute oral toxicity to rat expressed as LD₅₀ was 4,940 mg
di(2-ethylhexyl) phosphate /kg bw and the LD₅₀ in an acute
dermal application test on rat was 1,200 mg di(2-ethylhexyl)
phosphate/kg bw. The i.p. LD₅₀ for rat was 1,200 mg
di(2-ethylhexyl) phosphate/kg bw.

Di(2-ethylhexyl) phosphate exhibit strong corrosive effect in cornea at
5 m l doses (1% solution) as well as skin
irritating effects. No mutagenic activity was observed.

All endpoints have not been sufficiently investigated. Dermal toxicity
and local corrosive effects on skin and eyes seems to be the most severe
effects. Sufficient data are not available for classification. DEHPA has
been classified by Bayer AG in 1993 as C (Corrosive); R34 (Causes
burns) and Xn (Harmful); R21 (Harmful in contact with
skin.

No data found to determine reproductive toxicity or teratogenicity.

Environment

Conflicting data on the biodegradability of di(2-ethylhexyl)
phosphate are available. The compound is here evaluated as inherently
biodegradable.

The BCF values indicates that di(2-ethylhexyl) phosphate does not
bioaccumulate.

The available ecotoxicological data indicates that di(2-ethylhexyl)
phosphate is harmful algae, crustaceans and fish.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)phoisphat/
Tri-(2-ethylhexyl)phoisphat, BUA-Stoffbericht 172. S. Hirzel,
Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører –
Migration fra plast og generel baggrundsforurening. Ph.D Thesis. The
Danish Veterinary and Food Administration.

15

Bayer A/S (1999): Sicherheitsdatenblatt – BAYSOLVEX D2EHPA. Bayer,
Leverkusen, Germany

Tri(2-ethylhexyl) phosphate

CAS number: 78-42-2

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

Tri(2-ethylhexyl) phosphate (TEHPA) is a slightly flammable
compound when exposed to heat. It has a low water solubility and
vapour pressure. THEPA has a high fat solubility

Emission

No data found

Exposure

TEHPA has been found fresh water, in seawater and in sewage
treatment plant influents, effluents and sludge.

TEHPA has also been found in several types of food and in drinking
water.

Health

Tri(2-ethylhexyl) phosphate appears to have only slight acute oral
toxicity. LD₅₀in rats was more than 37.08 g/kg and LD₅₀
was approx. 46.0 g/kg in rabbits. In connection with inhalation the
toxicity expressed as LC₅₀ were 450 mg/m³/30
minutes. Tri(2-ethylhexyl) phosphate produces moderate erythema in
skin irritation test and slight irritation to eyes at doses from 0.01
ml to 0.05 ml. No sufficient data were found on skin sensitisation.
In subchronic and chronic toxicity tests NOEL for TEHPA in mouse
was less than 500 mg/kg bw, NOEL for male rats was 100 mg/kg and NOEL
for rats was 430 mg/kg. In an inhalation test 10.8 mg/m3 produced high
mortality. Dose related effects on trained behaviour were observed.
TEHPA was not mutagenic and was not found genotoxic in chromosome
aberration test and micronuclei assays. Slight evidence of
carcinogenicity was observed in mouse, but it has been concluded that
the substance is not likely to cause cancer in humans. No data were
found on reprotoxicity, embryo toxicity and teratogenicity. Slight
neurotoxic effects were observed in dogs.
Based on the available data the critical effect appears to be
repeated dose toxicity after oral administration and local effects.
Bayer AG has classified TEHPA according to the substance directive in
1993 as follows: Xi (Irritant); R36/38 (Irritating to skin
and eyes).

Environment

The available data on biodegradation do not indicate that TEHPA
biodegrades readily. The only measured BCF value indicates that TEHPA
does not bioaccumulate. It should be noted that the measured Log Pow
indicates a potential for bioaccumulation. The available
ecotoxicological data indicate, that tri(2-ethylhexyl) phosphate is
harmful to algae. The available data on crustaceans are insufficient
to make a classification. A low range result (10 mg/l) exists from a
ciliate test.

Tri(2-ethylhexyl) phosphate

Identification of the substance

CAS No.

78-42-2

EINECS No.

201-116-6

EINECS Name

Tris(2-ethylhexyl) phosphate

Synonyms

Trioctyl phosphate, phosphoric acid tris(2-ethylhexyl) ester,
2-ethylhexanol phosphate triester, 2-ethyl-1-hexanol phosphate,
triethylhexyl phosphate, TOF, Disflamoll TOF, Flexol TOF, Kronitex
TOF, NCI-C54751, TOF, tris(2-ethylhexyl) phosphate.

Molecular Formula

C₂₄H₅₁O₄P

Structural Formula

Illustration. Structural Formula. CAS no. 78-42-2 (2 Kb)

Major Uses

Flame retardant plasticiser for polyvinyl chloride resins.

Solvent, anti foaming agent and plasticiser.

Colour carrier in polymer colouring.

Viscosity increaser.

[3]

[3]

IUCLID

The compound is not included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

[10]

Physico-chemical Characteristics

Physical Form

Viscous colourless liquid

[3,15]

Molecular Weight (g/mole)

434.72

Melting Point/range (° C)

-74

<70

-70 to –90

[3]

[15]

[10]

Boiling Point/range (° C)

220 at 5 mm Hg

210-220 at 37.5-49.5 mm Hg

210 at 14.8 mm Hg

[3]

[10]

[15]

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

0.23 at 150 ° C

1.9 at 200 ° C

¨ 8.3´ 10^-7
at 25 ° C

1.4´ 10^-4at 25 °
C

[3]

[6]

[10]

[15]

Density (g/cm³at ° C)

0.92 (unknown temperature)

0.92-0.926 (unknown temperature)

0,92 at 20 ° C

[6]

[10]

[15]

Vapour Density (air=1)

No data

Henry’s Law constant (atm/m³/mol at °
C)

0.008 (estimated, unknown temperature)

[10]

Solubility (g/l water at ° C)

<0.1 at 20 ° C

<0.001 at 18 ° C

< 0.0005 at 20 ° C

¨ 0.0006 at 24 °
C

[3]

[6]

[10]

[10]

Partition Coefficient (log P_ow)

4.23

0.8-4.22

4.22

¨ 4.1-5.04

5,04

[8]

[12]

[16]

[10]

[15]

pK_a

¨ 1.72 (estimated) at 25 °
C
¨
2.12 (estimated)

[10]

[10]

Flammability

Slightly flammable when exposed to heat or flame.

[3]

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

No data found

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

Estuary 1-5 ng/l

Rw 20-290 ng/l

Sediment 2-70 m g/kg

Dw 0.3 ng/l

Fw (maximum measurements) 40-120 ng/l

[10]

[10]

[10]

[10]

[10]

Terrestrial environment

No data found

Sewage treatment plant

Influent:

7-144 ng/l
Effluent:

0.5 ng/l

[10]

[10]

Working environment

Indoor, office 5-6 ng/m³

[10]

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

Oil and grease (food for children) 38.5 m
g/kg

Meat, oil and greases 6.7 m g/kg

[10]

[10]

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

A 24 hours exposure of the underarm on six test persons did not
result in any irritation of the skin.

[10]

Acute toxicity

Oral

Tri(2-ethylhexyl)phosphate appears to have only slight acute oral
toxicity.
Mouse

LD₅₀> 12,800 mg/kg bw

[3]

[3]

Rat:

No specific doses and duration specified. LD₅₀= 37 g/kg.

LD₅₀> 2,000 mg/kg bw

¨ LD₅₀= 37,080 mg/kg bw

LD₅₀= 39,800 mg/kg bw

¨ 18,400 and 36,800 mg/kg bw. Mortality in
animals dosed 18,400 mg/kg bw where 1 of 6 animals died and in dose
group 36,800 mg/kg bw where 2 of 6 animals died.

LD₅₀>9,200 mg/kg bw (> 10 ml/kg bw)
Rabbit:

No doses specified, gavage. LD₅₀ approx. 46.0 g/kg.

No specific doses and duration specified. LD₅₀= 46 g/kg.

¨ LD₅₀= 46,000 mg/kg bw

[10]

[10]

[10, 17]

[10]

[6,10]

[10]

[3]

[6]

[10]

Dermal

Rabbit:

No specific doses and duration specified. LD₅₀= 20 g/kg.

LD₅₀= 18,400 mg/kg bw

[6]

[10]

Inhalation

Rat

¨ 450 mg/m³. No mortality was
observed.
Rat and rabbit:

Dose and duration not specified. No toxic effects were observed.
Guinea pig:

No specific doses and duration specified. LD₅₀= 450 mg/m³/30
minutes.

¨ 448 mg/m³ (1,5 h), average
particle size=1.5µm. 6 of 10 animals died.

[10]

[3]

[6,10]

[10]

Other routes

Mouse

¨ LD₅₀= 7,200 mg/kg bw, route
unknown.
Rat and rabbit:

Dose and duration not specified, intravenously. No toxic effects were
observed.

Dose and duration not specified, intratracheally. No toxic effects
were observed.
Rabbit

¨ 358 mg/kg bw. 2 of 6 animals died.

1,811 mg/kg bw. 1 of 6 animals died in the dose range from 690 to
1,811 mg/kg bw.

[10]

[3]

[3]

[10]

[10]

Skin irritation

Rat and rabbit

Single application of TEHPA resulted in hyperglycemia, reduced growth
of hair, hair loss and dryness of the skin.
Rabbit

¨ 250 mg (24 h) applied to shaved skin.
Moderate erythema was observed within 24 h and lasted one week.

No dose specified (24 h), occlusive application in ear. Swelling and
redness of skin.

¨ 10-20 ml, single application on skin on
the back of young rabbits. Mortality was observed after single
application of test substance.
No evidence of systematic intoxication.

[10]

[3,10]

[10]

[10]

[10]

Eye irritation

Rabbit

No dose specified (24 h). Rated one on a numerical scale from 1 to 10
according to degree of injury. Particular attention to condition of
cornea. Most severe injury observed was rated 10.

0.1-0.5 ml (24 h), young animals tested. Moderate conjunctivitis that
cleared up after 24 h.

¨ 0.01-0.05 ml application in eye of young
animals. Light irritation was observed.

Dose not specified, young animals tested. Flood of tears, darkening of
the cornea and hair loss in the eye surroundings.
No evidence of systematic intoxication.

[3]

[3,10]

[10]

[10]

[3]

Irritation of respiratory tract

No data found.

Skin sensitisation

Guinea pig

Not sensitising.

[10]

Subchronic and Chronic Toxicity

Oral

Of low toxicity to mice and rat

[10]

Mouse:

Up to 3,000 mg/kg bw (14 d) oral probe. No toxic effects were
observed.

¨ B6C3F1 mice: 0, 500,
1,000, 2,000, 4,000, 8,000 mg/kg bw/d (13 w, 5 d/w) oral probe.
NOEL<500 mg/kg bw. Gastritis was dose dependent and lowest dose
observation was in the 500 mg/kg bw group and isolated incidences of
ulceration was observed in dose groups from 2,000 mg/kg bw group.
Decrease in bw was observed in the female 4,000 mg/kg bw dose group
and in the male 8,000 mg/kg bw.

B6C3F1 mice: 0, 375, 750, 1,500, 3,000, 6,000 mg/kg bw/d
(14 d) 5 animals/sex/dose group, oral probe. NOEL = 3,000 mg/kg bw.
Decrease in bw in 6,000 mg/kg bw males and in 3,000 mg/kg bw females.
Decreased activity and raw throat.
Rat:

Fisher 344 rats: 0, 375, 750, 1,500, 3,000, 6,000 mg/kg bw/d
(14 d) 5 animals/sex/dose group, oral probe. NOEL, males =750 mg/kg
bw. Decrease in bw in 1,500 mg/kg bw males and in 3,000 mg/kg bw
females after 14 d.

¨ (Crj: CD(SD)) rats: 30, 100, 300,
1,000 mg/kg bw/d (28 d, thereafter 14 d observation) 6
animals/sex/dose group, oral probe. NOEL=100 mg/kg bw. 300 mg/kg bw
females had decreased prothrombin time and decreased partial
thromboplastin time in 1,000 males. Decrease in serum choline esterase
activity in male 300 mg/kg.

¨ Sherman rats: 110-1,550 mg/kg
bw/d (30 d) 5 animals/sex/dose group. NOEL 430 mg/kg bw. Decrease in
bw in the 1,550 dose groups (LOEL).

0, 250, 500, 1,000, 2,000, 4,000 mg/kg bw/d (13 w) 10 animals/sex/dose
group, oral probe. NOEL, female =1,000 mg/kg bw. Decrease in growth
was observed in the female 2,000 mg/kg bw dose group and in the male
4,000 mg/kg bw after 13 w.

[10]

[10]

[10]

[10]

[10]

[3,10]

[10]

Inhalation

Rat:

0.23, 0.63 mg/m³ (16 w, 4 h/d) 30 females. Dose group 0.23
mg/m³ showed decrease in choline esterase activity in
blood. Decrease in Beta-globuline in serum. Dose group 0.63 mg/m³
showed change in content of hippurie acid in the leucocyte number. The
study does not comply with OECD study criteria.

[10]

Guinea pig:

Hartley: 1.6, 9.6 mg/m³ (12 w, 5 d/w, 6 h/d), 20
males, average particle size = 3.8 µm. Decrease in kidney weight.
Increased bw in 9.6 mg/m³. Several histopathological
changes. Several other observations but the study does not comply with
modern study criteria.

¨ 10.8, 26.4, 85 mg/m³ (12 w, 5
d/w, 6 h/d), 10 animals/dose group, average particle size = 4.4 µm.
High mortality in all dose groups due to lung infections. Increase in
relative lung and kidney weights in the highest dose groups.
Dog:

10.8, 26.4, 85 mg/m³ (12 w, 5 d/w, 6 h/d), 1
animal/sex/dose group, average particle size = 4.4 µm. Minor chronic
infection in lungs. Slight behavioural changes.
Monkey:

Rhesus: 10.8, 26.4, 85 mg/m³ (12 w, 5 d/w, 6 h/d), 1
animal/sex/dose group, average particle size = 4.4 µm. No effects
were observed.

[10]

[10]

[10]

[10]

Dermal

Rabbit:

92 mg/animals/d (5 d/w, observation period after treatment: 3-17 d) 10
and 20 applications. Hyperkeratose, mild parakeratose, acute
dermatitis and mild thickening of the epidermis. The effects
disappeared 17 days after the 10^th application. No systemic
changes.

[10]

Other routes

Chicken:

Doses not specified, route and duration unspecified. No demyelinating
action found. Positive control: Tri-ortho-cresyl phosphate.

Doses not specified, route and duration not specified. No
neuropathological or inhibition of cholineesterase.
Cat:

920 mg/kg bw/d (1 ml/kg bw)(4 w, 5 d/w), 2 cats. No decrease in the
cholineesterase activity in the erythrocytes.
Dog:

¨ Doses not specified, route and duration
unspecified. Dose related effect on trained behaviour of dogs.
Monkey:

Doses not specified, route and duration unspecified. No effect on
trained behaviour of monkeys.

[3]

[3]

[10]

[3]

[3]

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Salmonella typhimurium:

No dose specified, strain indicators: TA98, TA100, TA1535, TA1537.
Not mutagenic. All strains tested both with and without metabolic
activation.

100-10,000 m g/plate, strain: TA98, TA100,
TA1535, TA1537. Not mutagenic. All strains tested both with and
without metabolic activation.

¨ 20-12,500 m
g/plate, strain: TA98, TA100, TA1535, TA1537. Not mutagenic. All
strains tested both with and without metabolic activation.

100-10,000 m g/plate, strain: TA98, TA100,
TA1535, TA1537. Not mutagenic. All strains tested both with and
without metabolic activation.

312.5-5,000 m g/plate, strain: TA98, TA100,
TA1535, TA1537. Not mutagenic. All strains tested both with and
without metabolic activation.

Escherichia coli:

¨ 312.5-5,000 m
g/plate. Not mutagenic. All strains tested both with and without
metabolic activation.

Mouse lymphoma:

¨ Up to 74.1 m
l/ml. All strains tested both with and without metabolic activation.
No metabolic activation.

Drosophila melanogaster:

¨ 50,000 ppm in a sugar solution (3
d). No sex-linked recessive lethal mutations.

50,000 ppm in 0.7% NaCl, injection. No sex-linked recessive lethal
mutations.

[3,5]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

Gene Mutation

No data found

Chromosome Abnormalities

CHO:

Up to 1670 m g/ml. No chromosome
aberration.

Up to 839 m g/ml. No sister chromatide
exchange.
CHL:

3 -11 m g/ml. No chromosome aberration. No
metabolic activation system.

1,100 -4,400 m g/ml. No chromosome
abbreviation. No metabolic activation system.

[10]

[10]

[10]

[10]

Other Genotoxic Effects

Mouse:

0, 500, 1,000, 1,500, 2,000, 3,000 mg/kg bw (3 d) daily i.p. No
micronuklei observed.
Rat:

0, 0.25, 0.50 mg/lair (2 w, 5 d/w, 6 h/d) altogether 9 exposures. No
micronuclei observed.
Chicken:

Doses not specified. No demyelinating action found. Positive control:
Tri-ortho-cresyl phosphate.

Doses not specified. No neuropathological or inhibition of
cholineesterase.

[10]

[10]

[3]

[3]

Carcinogenicity

Mouse:

B6C3F1 mice: 500 and 1,000 mg/kg bw; (103 w, 5 d/w), 50
animal/dose group, in corn oil by gavage. Increased incidence of
folicular cell hyperplasia of the thyroid. In females significant
increase of hepatocellular carcinomas in the high dose group. Decrease
in hemangiosarcomas of the circulatory system in males and
hematopoietic system in females. Some incidence of carcinogenicity in
the 1,000 mg/kg female group. No evidence of carcinogenicity in males.

¨ B6C3F1 ♀ mice 0, 500 and
1,000 mg/kg bw (102-104 w) females, in corn oil by gavage, 5 d/w.
Carcinoma and adenoma in liver. Evidence of carcinogenicity.
Rat:

Fisher 344 rats: 2,000, 4,000 mg/kg bw male; 1,000, 2,000 mg/kg
bw female; (103 w, 5 d/w), 50 animals/dose group, in corn oil by
gavage. Results - male: Bw gain was depressed. Dose related increase
in pheochromocytoma of adrenal glands. 2 malignant pheochromocytoma in
the high dose group. High increase compared to control, but incidence
in this group unusually low. Decreased incidence of acinar cell adomas
of the pancreas. Evidence of carcinogenicity was equivocal in dose
group 2,000 and 4,000 mg/kg. Results - female: Decreased incidence of
fibroadenomas of mammary glands in low dose groups. No evidence of
carcinogenicity in female rats.

0, 2,000, 4,000 mg/kg bw (102-104 w), males, in corn oil by gavage, 5
d/w. Results: No evidence of carcinogenicity.

0, 1,000, 2,000 mg/kg bw (102-104 w), males, in corn oil by gavage, 5
d/w. Results: No evidence of carcinogenicity.

[3,5,6,10]

[5]

[3,5,6,10]

[5]

[5]

Human:

Based on the slight carcinogenicity and no mutagenicity and
genotoxicity, TEPH is evaluated as unlikely to be carcinogenic to
humans by an ECETOC working group.

[10]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

No data found.

Teratogenicity

No data found.

Other Toxicity Studies

No data found.

Neurotoxicity and Toxicokinetics

Neurotoxicity

Chicken:

500, 2,500 mg/kg bw, 8 animals. Result: One animal of 8 died in the
high dose group.

250, 500, 2,500 mg/kg bw. Result: No observed effects.
Dog and monkey:

¨ 10.8, 26.4, 85 mg/m³ (12 w, 6
h/d, 5 d/w) 2 animals/dose group. Result: Dog - Decreased results of
the multiple stimuli conditioned avoidance test. Monkey - no effects
were observed in the ability of visual discrimination.

[10]

[10]
[10]

Toxicokinetics

Rat:

¨ TEHPA metabolised to at least one other
compound.

[3]

Other effects

HeLa cell:

144 and 320 mg/ml. Result: No effects observed in the low dose group.
TEHPA precipitated at 320 mg/ml. Metabolic inhibition test.

Ecotoxicity Data

Algae

Chlorella emersonii:

¨
EC₅₀(48h) =50-100 mg/l

[10]

Crustacean

Culex tarsalis:

LC₅₀(24h)>1 mg/l
Daphnia magna:

EC₅₀(48h)>0,08 mg/l

[10]

[15]

Fish

Brachydanio rerio (fw):

LC₀(96h) >100 mg/l

[12,15]

Bacteria

Activated sludge:

EC₅₀(3h)>100 mg/l

[15]

Terrestrial organisms

No data found.

Other toxicity information

Tetrahymena pyriformis:

¨ EC₅₀(24h) =10 mg/l

[18]

Environmental Fate

BCF

251 (estimated)

251-3,837 (estimated)

¨ 2.4-22 Cyprius carpio, MITI

2-22 (42h)

[10]

[10]

[19]

[15]

Aerobic biodegradation

Aquatic – ready biodegradability tests:

¨ 0 % at 100 mg/l, in 28 d, OECD 301C

¨ 0 % at 4.76 mg/l, in 28 d, OECD 301D
Aquatic – other tests:

40-60 % in 2 d, activated sludge

20 % in 1 d, activated sludge

20 % in 1 d, adapted activated sludge

0-90 % at 3.22 mg/l, in 30 d, RDA

0 % in 28 d, waste water

55 % in 2 d, activated sludge

60 % in 2 d, adapted activated sludge

20 % at 2 mg/l/24h, in 238 d, SCAS

0 % at 100 mg/l in 28 d, SCAS

0 % at 8 mg/kg in 7 d, mesophile sludge stabilisation

20.4-35.9 % at 1-20 mg/l in 7 d, river water

20.0-42.2 % at 1-20 mg/l in 14 d, river water

65.5 % at 1-20 mg/l in 15 d, river water

9.9 % at 1 mg/l in 7 d, sea water

1.2 % at 1 mg/l in 8 d, sea water

32.5-73.2 % at 1 mg/l in 14 d, sea water

12-28 % at 3-13 mg/l/24h, in 34 d, SCAS

[19]

[19]

[9]

[9]

[9]

[9,10]

[9]

[12]

[12]

[10,12]

[10,12]

[10]

[10]

[10]

[10]

[10]

[10]

[10]

[16]

Anaerobic biodegradation

25 % at 1.4 mg/l in 70 d, mesophile sludge stabilisation.

[10]

Metabolic pathway

No data found.

Mobility

No data found.

Conclusion

Physical-chemical

Tri(2-ethylhexyl) phosphate (TEHPA) is a slightly flammable
compound when exposed to heat. It has a low water solubility and
vapour pressure. THEPA has a high fat solubility

Emission

No data found.

Exposure

TEHPA has been found fresh water, in seawater and in sewage
treatment plant influents, effluents and sludge.

TEHPA has also been found in several types of food and in drinking
water.

Health

Tri(2-ethylhexyl) phosphate appears to have only slight acute oral
toxicity. LD₅₀was more than 37 g/kg in rats and approx. 46
g/kg in rabbits. In connection with inhalation the toxicity expressed
as LD₅₀ were 450 mg/m³/30 minuttes.
Tri(2-ethylhexyl) phosphate produces moderate erythema in skin
irritation test and slight irritation to eyes at doses from 0.01 ml to
0.05 ml. No sufficient data were found on skin sensitisation.
In subchronic and chronic toxicity tests NOEL for TEHPA in mouse
was less than 500 mg/kg bw, NOEL for male rats was 100 mg/kg and NOEL
for rats was 430 mg/kg. In an inhalation test 10.8 mg/m³
produced high mortality. Dose related effects on trained behaviour
were observed.
TEHPA was not mutagenic and was not found genotoxic in chromosome
aberration test and micronuclei assays. Slight evidence of
carcinogenicity was observed in mouse. No data were found on
reprotoxicity, embryo toxicity and teratogenicity. Slight neurotixic
effects were observed in dogs.
Based on the slight carcinogenicity and no mutagenicity and
genotoxicity, TEPHA is evaluated as unlikely to be carcinogenic to
humans by an ECOTOC working group.
Based on the available data the critical effect appears to be
repeated dose toxicity after oral administration and local effects.
TEHPA has been classified according to the substance directive by
Bayer AG in 1993 as follows: Xi (Irritant); R36/38 (Irritating
to skin and eyes).

Environment

The available data on biodegradation do not indicate
that TEHPA biodegrades readily.

The only measured BCF value indicates that TEHPA does not
bioaccumulate. It should be noted that the measured Log P_ow
indicates a potential for bioaccumulation.

The available ecotoxicological data indicate, that tri(2-ethylhexyl)
phosphate is harmful to algae. The available data on crustaceans are
insufficient to make a classification. A low range result (10 mg/l)
exists from a ciliate test.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)phoisphat/
Tri-(2-ethylhexyl)phoisphat, BUA-Stoffbericht 172. S. Hirzel,
Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

Bayer A/S (1999): Sicherheitsdatenblatt – DISFLAMOLL TOF. Bayer,
Leverkusen, Germany

16

Saeger, V.W., Kaley II, R.G., Hicks, O., Tucker, E.S., &
Mieure, J.P. (1976): Acti-vated sludge degradation of selected
phosphate esters. Environ. Sci. Technol. 13, 840-482.

17

MacFARLAND, H.N. et al (1966): Toxicological Studies on
Tri-(2-Ethylhexyl)-Phosphate. Arch Environ Health-Vol 13, July 1966.

18

Yoshioka,Y., Ose, Y., & Sato, T. (1985): Testing for the
Toxicity of Chemicals with Tetrahymena pyriformis. Sci. Total
Environ. 43(1-2): 149-157.

19

Chemicals Inspection and Testing Institute (1992); Biodegradation
and bioaccumulation Data of existing Chemicals based on the CSCL
Japan. Japan Chemical Industry Ecology and Toxicology and
Information Center. ISBN 4-89074-101-1.

Tri-2-ethylhexyl trimellitate

CAS number: 3319-31-1

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

Tri-2-ethylhexyl trimellitate is a compound with low water
solubility and, low vapour pressure a high fat solubility. Migration
from PVC to sunflower oil, isooctane or ethanol was 1,280; 1,220 and
450 mg/dm2 respectively, which is relatively high.

Emission

No data found

Exposure

No data found

Health

Sufficient data were not found for a profound assessment but data
indicate that the substance is moderately irritating towards skin,
eyes and respiratory tract and harmful by inhalation.
Concerning sensitisation animal experiments indicate that it does
not induce sensitisation in Guinea-pigs.

Data on mutagenicity indicate that tri-2-ethylhexyl trimellitate is
not mutagenic to Salmonella typhimurium.

The identified critical effect is related to systemic effects from
inhalation of the substance. Based on the available information
tri-2-ethylhexyl trimellitate should be classified Xn (Harmful);
R20 (dangerous by inhalation).

Environment

The available data indicate that tri-2-ethylhexyl trimellitate does
not biodegrade readily or inherently.

The only available measured Log P_ow value, indicates that
tri-2-ethylhexyl trimellitate bioaccumulates.

The available acute 50 % effect concentrations are all given as
ranges, and it therefore not possible to evaluate the acute
ecotoxicity of tri-2-ethylhexyl trimellitate. A NOEC based on chronic
data for crustaceans was 0.082 mg/l.

[1a, 17]

[1a]

Tri-2-ethylhexyl trimellitate

Identification of the substance

CAS No.

3319-31-1

EINECS No.

222-020-0

EINECS Name

Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate

Synonyms

Tris(2-ethylhexyl) trimellitate, trioctyl, trimellitate
tris(2-ethylhexyl) ester, Kodaflex TOTM, tri(2-ethylhexyl)trimellitate
ester, 2-ethylhexyl trimellitate,
tris(2-ethylhexyl)benzenetricarboxylate, Bisoflex TOT,
tri-2-ethylhexyl trimellitate.

Molecular Formula

C₃₃H₅₄O₆

Structural Formula

Illustration. Structural Formula. CAS no. 3319-31-1 (3 Kb)

Major Uses

No data found

IUCLID

The substance is included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

Yellow oily liquid

[6]

Molecular Weight (g/mole)

546.79

Melting Point/range (° C)

-35 – -30 ° C

[1a]

Boiling Point/range (° C)

414

[15]

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

¨ 5.5´ 10^-5
at 20 ° C

3.94´ 10^-11

[1a]

[15]

Density (g/cm³at ° C)

0.985-0.992 at 20 ° C

0.989 (unknown temperature)

[1a]

[2]

Vapour Density (air=1)

No data found

Henry’s Law constant (atm/m³/mol at °
C)

4.45´ 10^-7 (estimated,
unknown temperature)

[8,15]

Solubility (g/l water at ° C)

<1 mg/l at 20 ° C

¨ 0.00039 mg/l at 25 °
C

0.1 mg/l at 25 o C

[1a,6]

[1a]

[15]

Partition Coefficient (log P_ow)

¨ 4.35 at 25 °
C

12.41 (estimated)

11.59 (estimated)

[1a]

[8]

[15]

pK_a

No data found

Flammability

No data found

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

¨ Migration from PVC to sunflower oil,
isooctane or ethanol was 1,280; 1,220 and 450 mg/dm²
respectively in studies over 1-3 days at the same, corresponding to
30-80% of the total TETM amount in the PVC piece.

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

No data found

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

Mist and fumes from hot processing may cause irritation to eyes,
nose throat and upper respiratory tract, nausea and vomiting.
Significant absorption through the skin is unlikely.

[1a, 17]

Acute toxicity

Oral

Rat

LD₅₀ rat >3.2 g/kg bw.

LD₅₀ rat = 9850 mg/kg bw
Mouse

LD₅₀ mouse > 3.2 g/kg bw.

[1, 17]

[1a]

[1a, 17]

Dermal

Rabbit

LD₅₀(24 hour covered) >1.98 g/kg bw

LD₅₀(OECD 402/1981) > 1.97 g/kg bw

[17]

[1a]

Inhalation

Rat:

¨ LC₅₀ = 2.6 mg/l (4 hours)

[1a]

¨ Moderate irritation resulted from a 6
hours exposure to 16 ppm (probably in rats) but a concentration on
2640 mg/m³ in 6 hours exposure caused severe irritation
(probably the respiratory tract) and death. No death occurred at a
concentration equal to 230 mg/m³.

[17]

Other routes

Rat

i.p LD₅₀> 3200 mg/l
Mouse

i.p LD₅₀> 3200 mg/l

[1a]

[1a]

Skin irritation

Rabbit

0.5 ml neat substance (occlusive, 4 hours). Slightly irritating, not
classifiable. (OECD 404/1984)

0.5 ml neat substance (occlusive 24 hours). Slightly irritating, not
classifiable. (FHSAR - 16FSR)
Guinea pig

0.5 ml neat substance (occlusive, 24 hours). Slightly irritating.

0.5 ml neat substance (occlusive, 24 hours). Not irritating. (Buehler)

[1a]
[1a]

[1a]
[1a]

Eye irritation

Rabbit

0.1 ml. Slightly irritating, not classifiable. (OECD 405/1984)

0.1 ml neat substance. Slightly irritating, not classifiable. (FHSAR -
16FSR)

[1a]
[1a]

Irritation of respiratory tract

Rats exposed to an estimated concentration of 230 mg/m³
for 6 hr. showed minimal irritation.
See also "Inhalation"

[17]

Skin sensitisation

Guinea pig

0.5 ml neat substance (occlusive, 24 hours, 10 applications).
Challenge after 2 weeks. Not sensitising. (OECD 406/1981)

[1a, 17]

Subchronic and Chronic Toxicity

Oral

Rat

¨ Fisher 344: 0, 0.2% (184 mg/kg
bw/d), 0.67% (650 mg/kg bw/d) and 2% (1826 mg/kg bw/d) in diet for 28
days. LOAEL = 184 mg/kg bw. Slightly increased liver weights and liver
enzymes, decreased erythrocytes, increased leucocytes, and raised
cholesterole levels at 0.67%. Increased palmitoyl CoA at 0.2%. Slight
peroxisome proliferation at 2%.

[1a]

Fisher 344: 0, 200 mg/kg bw/d, 700 mg/kg
bw/d and 2000 mg/kg bw/d per gavage for 21 days. LOAEL = 200 mg/kg bw.
Slight increase in hepatic peroxisomes in males at top dose level.
Increased enzyme activity in males and females at 200 and 2000 mg/kg
bw.

[1a]

Fisher 344: 0 and 1000 mg/kg bw/d per
gavage for 28 days. LOAEL = 1000 mg/kg bw. Non-significant liver
effects.

[1a]

(Albino rats) 0 and 985 mg/kg bw/d injections for 7 days. No
effects. NOAEL = 985 mg/kg bw.

[1a]

Mouse

14 and 42 mg/kg bw/d injections for 14 days. Increased relative spleen
and liver weights in top dose group. LOAEL = 42 mg/kg bw. (Limited
data)
Dog

14 and 42 mg/kg bw/d injections for 14 days. Increased relative spleen
and liver weights in top dose group. LOAEL = 42 mg/kg bw. (Limited
data)

[1a]

[1a]

Inhalation

No relevant data found.

Dermal

No relevant data found.

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Salmonella typhimurium:

¨ 0, 100, 333, 1000, 3333, 10000 m
g/plate. Test strain: TA100, TA1535, TA97 or TA 98. No mutagenicity
was observed. Ames, pre-incubation, test with and without metabolic
activation.

Neat urine from male Sprague-Dawley rats gavaged daily for 15 days
with 2 g/kg bw. Test strain: TA97, TA98, TA 100 or TA1535. No
mutagenicity was observed. Ames with and without metabolic activation.
Chinese hamster ovary cells:

¨ 5 - 200 nl/ml (6 concentrations).
Unschedules DNA synthesis without metabolic activation. No
mutagenicity observed.
Primary rat hepatocytes:

¨ 250 - 5000 nl/ml. HGPRT assay with and
without metabolic activation. No indication of UDS observed.

[1a]

[1a]

[1a]

[1a]

A dose of approximately 1400 mg/kg bw was not mutagenic in a
dominant lethal test in mice.

[1a, 17]

Chromosome Abnormalities

No relevant data found.

Other Genotoxic Effects

No relevant data found.

Carcinogenicity

Mouse (strain A):

Approx. 1400 mg/kg bw (possibly per day). Tests in mouse with a
propensity to form pulmonary adenoms were negative. No further
details.

[1a]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

No relevant data found.

Teratogenicity

No relevant data found.

Other Toxicity Studies

No relevant data found.

Toxicokinetics

Toxicokinetics

Metabolic studies in rats have shown that following the
administration of 100 mg/kg bw by stomach tube , about 64% was
excreted unchanged in the faeces, 11% and 16% were excreted as
metabolites in the faeces and urine respectively, and less than 0.6%
remained in the tissues after 6 days.

Is the substance given intravenously, it will mainly accumulate in
the liver (72%), lungs and spleen.

Ecotoxicity Data

Algae

No data found.

Crustacean

Daphnia magna (fw):

EC₅₀(48h)>1 mg/l

¨ NOEC(21d)<= 0.082 mg/l

[1a]

[1a]

Fish

Salmo gairdneri (fw):

LC₅₀(96h)>1 mg/l

[1a]

Bacteria

No data found.

Terrestrial organisms

No data found.

Other toxicity information

No data found.

Environmental Fate

BCF

No data found.

Aerobic biodegradation

Aquatic – ready biodegradability tests:

¨ 14 % at 100 mg/l in 28 d, OECD 301 C
Aquatic – other tests:

4.2 % at 30 mg/l in 28 d, OECD 301C or 302C

[1a]

[16]

Anaerobic biodegradation

No data found.

Metabolic pathway

No data found.

Mobility

No data found.

Conclusion

Physical-chemical

Tri-2-ethylhexyl trimellitate is a compound with low water
solubility and, low vapour pressure a high fat solubility. Migration
from PVC to sunflower oil, isooctane or ethanol was 1,280; 1,220 and
450 mg/dm² respectively, which is relatively high.

Emission

No data found.

Exposure

No data found.

Health

Not sufficient data. Data on mutagenicity indicate that
tri-2-ethylhexyl trimellitate is not mutagenic to Salmonella
typhimurium.

The identified critical effect is related to systemic effects from
inhalation of the substance.
Classification Based on the available information TETM should be
classified Xn (Harmful); R20 (dangerous by inhalation).

Environment

The available data indicate that tri-2-ethylhexyl trimellitate does
not biodegrade readily or inherently.

The only available measured Log P_ow value, indicates that
tri-2-ethylhexyl trimellitate bioaccumulates.
The available acute 50 % effect concentrations are all given as
ranges, and it therefore not possible to evaluate the acute
ecotoxicity of tri-2-ethylhexyl trimellitate. A NOEC based on chronic
data for crustaceans was 0.082 mg/l.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

1a

European Commission Joint Research Centre (2000): International
Uniform Chemical Information Database. IUCLID CD-ROM. Year 2000
Edition. ISBN 92-828-8641-7.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3^rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

PhysProp - Syracuse Research Corporation. Interactive PhysProp
Database

http://esc.syrres.com/interkow/physdemo.htm

16

Chemicals Inspection and Testing Institute (1992) ; Biodegradation
and bioaccumulation Data of existing Chemicals based on the CSCL
Japan. Japan Chemical Industry Ecology and Toxicology and
Information Center. ISBN 4-89074-101-1.

17

TNO BIBRA International Ltd (1993): TOXICITY PROFILE
Tris(2-ethylhexyl) trimellitate. TNO BIBRA International

18

Hamdani, M. and A. Feigenbaum (1996) Migration form plasticised
poly/vinyl chloride) into fatty media: importance of simulant
selectivity for the choice of volatile fatty simulants. Food Additives
and Contaminants 13, pp 717-730.

o-Toluene sulphonamide

CAS number: 88-19-7

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

o-Toluene sulphonamide is a compound with a low water solubility,
moderate fat solubility and a low vapour pressure.

Emission

No data found

Exposure

No data found

Health

No data found on acute toxicity, subchronic and chronic toxicity.

o-Toluene sulphonamide is reported as teratogenic in rats, but no
detailed descriptions of the study design is available. Only weak
mutagenic activity is shown.

There is limited evidence that OTSA is carcinogenic when administered
orally to rats. This has been suggested as the cause of
carcinogenicity of saccharin. The available data suggest that OTSA
impurities at the levels normally found in commercial saccharin do not
contribute to the carcinogenicity of saccharin.
Based on very limited data the critical effect has been identified
as possible teratogenicity.

It is not possible to evaluate the data against the classification
criteria for teratogenicity, as information is too sparse. Other
described effects are not classifiable.

Environment

The available data on biodegradation indicate that o-toluene
sulphonamide does not biodegrade readily.

The available BCF values indicate that o-toluene sulphonamide do not
bioaccumulates.

o-Toluene sulfonamide

Identification of the substance

CAS No.

88-19-7

EINECS No.

201-808-8

EINECS Name

Toluene-2-sulphonamide

Synonyms

2-methyl-benzenesulphonamide, o-methylbenzenesulphonamide,
2-methylbenzensulphonamide, toluene-2-sulphonamide, o-toluene
sulfonamide.

Molecular Formula

C₇H₉NO₂S

Structural Formula

Illustration. Structural Formula. CAS no. 88-19-7 (2 Kb)

Major Uses

Plasticiser in the saccharin and amino resins production.

Reactive plasticiser.

Plasticiser for hot-melt adhesives.

Fluorecent pigment.

[3]
[3]

[3]

[3]

IUCLID

The substance is not included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

Colourless octahedral crystals.

[3]

Molecular Weight (g/mole)

171.23

Melting Point/range (° C)

156.3

Boiling Point/range (° C)

214 ° C at 997.5 mm Hg

[3]

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

¨ 6´ 10^-5
(estimated) at 25 ° C

[3,15]

Density (g/cm³at ° C)

No data found

Vapour Density (air=1)

No data found

Henry’s Law constant (atm/m³/mol at °
C)

4.7´ 10 ^–7

[3,15]

Solubility (g/l water at ° C)

¨ Slightly soluble in water (unknown
temperature)

1.62 at 25° C

[3]

[15]

Partition Coefficient (log P_ow)

¨ 0.84 (measured)

[3,15]

pK_a

No data found

Flammability

No data found

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

Less than 0.2 mg/kg (detection limit) migrated from package
material containing 0.96-3.3 mg/dm² to food

[20]

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

No data found

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

¨ A 2-month old infant developed no
symptoms of toxicity following inadvertently uptake of a 1500 mg dose
of sulfasalazine (same group as o-toluene sulphonamide)
One patient developed seizures, coma, hypoxia, hyperglycemia,
metabolic acidosis and methemoglobinemia after an oral dose of 50 mg
sulfasalazine and 50 mg paracetamol. Effects (except
methemoglobinemia) could be secondary to acetmenophen toxicity.
Overdose of sulfasalazine result in coma in one patient and tremor
in another.

[3]

[3]

[3]

Acute toxicity

Oral

No relevant data found

Dermal

No relevant data found

Inhalation

No relevant data found

Other routes

No relevant data found

Skin irritation

No relevant data found

Eye irritation

No relevant data found

Irritation of respiratory tract

No relevant data found

Skin sensitisation

No relevant data found

Subchronic and Chronic Toxicity

Oral

No relevant data found

Inhalation

No relevant data found

Dermal

No relevant data found

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Salmonella typhrimurium:

Negative. Histidine reverse gene mutation,
Ames assay.

Salmonella:

Up to 1 mg/plate and 2.5 mg/plate. Not mutagenic. Microsome plate
with and without arochlor 1254-induced rat liver 9000 XG supernatant.

¨ No test dose mentioned. Weak mutagenic
effects. Modified Salmonella/microsome test.

Saccharomyces cericisiae:

¨ Up to 1 mg/plate. No gene
conversion. Test both with and without metabolic activation.

Drosophila melanogaster:

No test dose mentioned. No conclusion. Sex-linked recessive lethal
gene mutation.

0.2 µl or feeding 5 mmol. No sex-linked recessive lethal mutation.

¨ 0.05% (3 d). Larger scale feeding study
than previous study. Significant doubling of frequency of sex-linked
lethal mutation.

¨ No test dose mentioned. Weak mutagenic
effects.

[7]

[17]

[3]

[17]

[7]

[17]

[3]

[19]

Chromosome Abnormalities

Drosophila melanogaster:

Mammalian polychromatic erythrocytes. No conclusion. Micronucleus
test, chromosome aberrations.
0.9-400 µg/ml (24 h). No increase in number of breaks, gaps, and
other aberrations.

[7]

[3]

Other Genotoxic Effects

No relevant data found

Carcinogenicity

Mouse:

2x1g/kg bw, oral and ip. No micronuclei in bone marrow cells.
BHK 21/CL 13 cell:

0.025-2500 µg/ml. No morphological transformation in cells.

[3]

[3]

Rat

0, 20 and 200 mg/kg bw (lifetime). No increase in incidence of
malignant tumors.

2.5, 25 and 250 mg/kg bw. Benign bladder tumor in f0 (one in control
group, one in both group 2.5 and 250 mg/kg bw) and in f1 (2 in the 2.5
mg/kg bw).

0 or 1% in drinking water or 90 mg/kg. (2 year). No difference in
overall tumor incidence (2 year).

0.15 ml NMU/N-methyl-N-nitrosourea, 2 weeks later 0, 0.08 mg
o-toluenesulphonamide /kg bw in diet or 0.1% o-toluenesulphonamide in
drinking water (2 years). No difference in overall tumour incidence
was observed.
¨ There is limited evidence that
o-toluenesulphonamide is carcinogenic when given orally to rats.

[3]

[3]

[3]

[3]

[17]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

¨ In connection with assessment of
saccharine and its impurities, among others o-toluenesulphonamide, it
has been found that these impurities are responsible for the
reproductive effects of impure saccharine.

[18]

Rat:

250 mg/kg bw. Lower feed consumption. 2-generation study.

[3]

Teratogenicity

Rat:

¨ Found to be teratogenic.
0-250 mg/kg, gavage throughout gestation and lactation, also
puppets. Dose-response for incidence of bladder calculi in 21-day-old
pups and 105-day old rats.

No dose mentioned, dietary treatment during mating, gestation and
lactation and after weaning. Renal calculi and bladder lesions were
observed in 8-day old pups.

[3]
[3]

[3]

Other Toxicity Studies

No relevant data found.

Toxicokinetics

Toxicokinetics

Rat:

20, 125 or 200 mg/kg bw. Single oral doses. Result: Main metabolites
in the urine were 2-sulfamoylbenzyl alcohol and it sulfate or
glucuronic acid conjugates (80%), n-acetyltoluene-2-sulphonamide (6%),
saccharin (3%) and 2-sulfamoylbenzoic acid (2%). 79, 58 and 36% of
activity recovered in urine after 24 h, 7, 14 and 33% of the dose in
the urine from 24-48 h, respectively. After 7 d 4.5, 5.9 and 7% of
activity was recovered from faeces.

[3]

Human:

0.2-0.4 mg/kg bw, oral doses. Result: Excreted more slowly in humans
than in rats. 50% excreted after 24 h. and 80% within 48 h. less than
1% was found in the faeces. Main urine metabolites were
2-sulfamoylbenzyl alcohol and its sulfates and glucoronic conjugates
(35%), saccharin (35%), 2-sulfamoylbenzoic acid (4%) and
N-acetyltouluene-2-sulphonamide (2%).

[3]

Ecotoxicity Data

Algae

No data found

Crustacean

No data found

Fish

No data found

Bacteria

No data found

Terrestrial organisms

No data found

Other toxicity information

No data found

Environmental Fate

BCF

¨ 0.4-2.6

2.5 (estimated)

[16]

[3]

Aerobic biodegradation

Aquatic – ready:

¨ 0 % in 14 d, OECD 301C

[16]

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

K_oc=68 (estimated)

[3]

Conclusion

Physical-chemical

o-toluensulphonamide is a compound with a low water solubility, low
fat solubility and a low vapour pressure.

Emission

No data found

Exposure

Not data found

Health

No data found on acute toxicity, subchronic and chronic toxicity.

o-Toluensulphonamide is reported as teratogenic in rats, but no
detailed descriptions of the study design is available. Only weak
mutagenic activity is shown.

There is limited evidence that OTSA is carcinogenic when administered
orally to rats. This has been suggested as the cause of
carcinogenicity of saccharin. The available data suggest that OTSA
impurities at the levels normally found in commercial saccharin do not
contribute to the carcinogenicity of saccharin.

Based on very limited data the critical effect has been identified as
possible teratogenicity.

It is not possible to evaluate the data against the classification
criteria for teratogenicity, as information is too sparse. Other
described effects are not classifiable.

Environment

The available data on biodegradation indicate that
o-toluensulphonamide do not biodegrades readily.

The available BCF values indicate that o-toluensulphonamide do not
bioaccumulates.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

PhysProp - Syracuse Research Corporation. Interactive PhysProp
Database

http://esc.syrres.com/interkow/physdemo.htm

16

Chemicals Inspection and Testing Institute (1992); Biodegradation
and bioaccumulation Data of Existing Chemicals based on the CSCL
Japan. Japan Chemical Industry Ecology and Toxicology nad
Information Center. ISBN 4-89074-101-1

17

IARC MONOGRAPHS, vol 22

18

Lederer, L.(1977): La Saccharine, ses Pollutants et leur Effet
Tératogène, Louvaine Méd. 96 : 495-501, 1977

19

Eckardt, K. et al (1980): Mutagenicity study of Remsen-Fahlberg
Saccharin and Contaminants, Toxcology Letter, 7 (1980),
Elsevier/North-Holland Biomedical Press.

20

Nerín, C., Cacho, J., Gancedo, P. (1993) Plasticisers from
printing inks in a selection of food packagings and their migration to
food. Food Additives and Contaminants 10, pp 453-460.

2,2,4-trimethyl-1,3-pentandioldiisobutyrate

CAS number: 6846-50-0

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

2,2,4-trimethyl-1,3-pentandioldiisobutyrate (TXIB) is a compound
with a low water solubility (1-2 mg/l).

The Log P_ow value of 4.1 indicates lipophillic properties.

Emission

No data found.

Exposure

No data found.

Health

The available data indicate that TXIB is a substance of low
toxicity. Results from animal tests do not fulfil the classification
criteria with regard to acute toxicity, skin and eye irritation and
skin sensitisation. Reversible liver changes were found rats in a
chronic study whereas chronic toxicity testing in beagles did not
reveal any significant findings.

TXIB is eliminated via urine and faeces. Half to two-thirds are
excreted in urine (about two-thirds within 48 hours, about 90% by 5
days and almost complete in 10 days). Faecal elimination appeared to
take 2-4 days.

Environment

According to the available data on biodegradation there is no
evidence of ready biodegradability of TXIB.
The available 50 % effect concentrations are above tested ranges,
and the NOECs are assigned to the maximum tested concentration of TXIB
(~1.5 mg/l).

2,2,4-trimethyl-1,3-pentandioldiisobutyrate

Identification of the substance

CAS No.

6846-50-0

EINECS No.

229-934-9

EINECS Name

1-isopropyl-2,2-dimethyltrimethylene diisobutyrate.

Synonyms

2,2,4-Trimethyl-1,3-pentanediol diisobutyrate, Kodaflex, TXIB,
2,2,4-Trimethylpentanediol diisobutyrate,
(1-isopropyl-2,2-dimethyl-1,3-propandiyl) diisobutyrate.

Molecular Formula

Illustration. Structural Formula. CAS nr. 6846-50-0 (2 Kb)

Structural Formula

C₁₆H₃₀O₄

Major Uses

No data found.

IUCLID

The substance is included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

No data found.

Molecular Weight (g/mole)

286.41

Melting Point/range (° C)

-70 ° C

[1a,15]

Boiling Point/range (° C)

280 ° C

[1a,15]

Decomposition Temperature (° C)

No data found.

Vapour Pressure (mm Hg at ° C)

No data found (0.009 reported in [1a] but no unit given).

[1a]

Density (g/cm³at ° C)

0.945 at 20 ° C

0.94

0.944

[1a]

[2]

[15]

Vapour Density (air=1)

No data found.

Henry’s Law constant (atm/m³/mol at °
C)

No data found.

Solubility (g/l water at ° C)

¨ 0.001-0.002

Immiscible with water

[1a]

[15]

Partition Coefficient (LogP_ow)

4.1 (measured)

[1a]

pK_a

No data found.

Flammability

No data found.

Explosivity

No data found.

Oxidising Properties

No data found.

Migration potential in polymer

No data found.

Emission Data

During production

No data found.

Exposure Data

Aquatic environment, incl. sediment

No data found.

Terrestrial environment

No data found.

Sewage treatment plant

No data found.

Working environment

No data found.

Consumer goods

No data found.

Man exposed from environment

No data found.

"Secondary poisoning"

No data found.

Atmosphere

No data found.

Dermal

No data found.

Toxicological data

Observations in humans

No data found.

Acute toxicity

Oral

Rat

¨ LD₅₀ > 3,200 mg/kg bw.
Mouse

LD₅₀ > 6,400 mg/kg bw.

[1a]

[1a]

Dermal

Guinea pig

¨ LD₅₀ > 20 ml/kg.

[1a]

Inhalation

Rat

¨ 6 hour exposure to 0.12 mg/l or 5.3
mg/l. LC₅₀ > 5.3 mg/l.

[1a]

Other routes

Rat

¨ LD₅₀ approx. 3,200 mg/kg
bw. i.p.

[1a]

Skin irritation

Guinea pig

No information on test material and exposure time. Slight skin
irritant when covered and more irritating when uncovered.

[1a]

Eye irritation

Rabbit

0.1 ml. Not irritating, not to be classified. (OECD 405/1990)

[1a]

Irritation of respiratory tract

No data found.

Skin sensitisation

Guinea pig

No detailed information. (Test protocol similar to OECD 406).
Injection via footpad. Not sensitising.

[1a]

Subchronic and Chronic Toxicity

Oral

Rat

Albino rats. 0.1% and 1% w/w in the diet for 103 d. No significant
changes. NOAEL = 0.1%, LOAEL = 1%
Sprague Dawley rats. 0.1% and 1% w/w in the diet for 52 or 99 d.
Statistically significant higher liver weight in the top dose group.
Liver changes appeared reversible. NOAEL = 0.1%, LOAEL = 1%.
Dog, beagle

0.1%, 0.35%, and 1% in the diet for 13 weeks. No significant
findings.

[1a]

[1a]

[1a]

Inhalation

No data found.

Dermal

No data found.

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

No data found.

Chromosome Abnormalities

No data found.

Other Genotoxic Effects

No data found.

Carcinogenicity

No data found.

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

No data found.

Teratogenicity

No data found.

Other Toxicity Studies

No data found.

Toxicokinetics

Toxicokinetics

Metabolic studies in rats indicated that hydrolysis to the parent
glycol (TMPD) is a major pathway in the disposal of the
diisobutyrate. The substance is rapidly absorbed from the gut. No
elimination via lungs. From half to two-thirds excreted in urine
(about two-thirds within 48 hours, about 90% by 5 d and almost
complete in 10 d). Faecal elimination appeared to take 2-4 d.

[1a]

Ecotoxicity Data

Algae

No data found.

Crustacean

Asellus intermedius:

LC₅₀(96h)>1.55 mg/l

NOEC(96h)=1.55 mg/l

Daphnia magna (fw):

LC₅₀(96h)>1.46 mg/l

NOEC(96h)=1.46 mg/l

Gammarus fasciatus:

LC₅₀(96h)>1.55 mg/l

NOEC(96h)=1.55 mg/l

[1a]

[1a]

[1a]

[1a]

[1a]

[1a]

Fish

Pimephales promelas (fw):

LC₅₀(96h)>1.55 mg/l

NOEC(96h)=1.55 mg/l

[1a]

[1a]

Bacteria

No data found.

Terrestrial organisms

No data found.

Other toxicity information

Dugesia tigrina:

LC₅₀(96h)>1.55 mg/l

NOEC(96h)=1.55 mg/l

Lumbriculus variegatus:

LC₅₀(96h)>1.55 mg/l

NOEC(96h)=1.55 mg/l

Helisoma trivolvis:

LC₅₀(96h)>1.55 mg/l

NOEC(96h)=1.55 mg/l

[1a]

[1a]

[1a]

[1a]

[1a]

[1a]

Environmental Fate

BCF

No data found.

Aerobic biodegradation

Aquatic – other tests:

99.9 % at 650 mg/l (incomplete information)

[1a]

Anaerobic biodegradation

No data found.

Metabolic pathway

No data found.

Mobility

No data found.

Conclusion

Physical-chemical

2,2,4-trimethyl-1,3-pentandioldiisobutyrate (TXIB) is a compound
with a low water solubility (1-2 mg/l).

The Log P_ow value of 4.1 indicates lipophillic
properties.

Emission

No data found.

Exposure

No data found.

Health

The available data indicate that TXIB is a substance of low
toxicity. Results from animal tests do not fulfil the classification
criteria with regard to acute toxicity, skin and eye irritation and
skin sensitisation. Reversible liver changes were found rats in a
chronic study whereas chronic toxicity testing in beagles did not
reveal any significant findings.

TXIB is eliminated via urine and faeces. Half to two-thirds are
excreted in urine (about two-thirds within 48 hours, about 90% by 5
days and almost complete in 10 days). Faecal elimination appeared to
take 2-4 days.

Environment

According to the available data on biodegradation there is no
evidence of ready biodegradability of TXIB.
The available 50 % effect concentrations are above tested ranges,
and the NOECs are assigned to the maximum tested concentration of
TXIB (~1.5 mg/l).

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

1a

European Commission Joint Research Centre (2000): International
Uniform Chemical Information Database. IUCLID CD-ROM. Year 2000
Edition. ISBN 92-828-8641-7.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

Astill, B. D., Terhaar, C. J. and Fassett, D. W. (1972): The
Toxicology and Fate of 2,2,4-Trimethyl-1,3-Pentanediol
Diisobutyrate. Toxicology and applied pharmacology 22, pp
387-399.

Epoxidized soybean oil

CAS number: 8013-07-8

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

Sufficient data not available.

Emission

No data found

Exposure

No data found

Health

ESBO is only slightly acute toxic. In the acute oral tests LD₅₀to rat ranged between 21,000-40,000 mg/kg bw and were not
irritating to skin.

ESBO was not mutagenic in Ames test. Based on the limited data
available ESBO was not found to be a potential carcinogen or to
exhibit reproductive toxicity or teratogenitity. In reproductive
toxicity tests in mouse and rat the NOAEL for the parental group was
1,000 mg/kg bw and the NOAEL for the F1 offspring were 1,000 mg/kg
bw.

Environment

According to the available biodegradation data there is good
evidence of ready biodegradability of epoxidized soybean oil.

The available ecotoxicological data indicates that epoxidized
soybean oil is toxic to crustaceans.

Epoxidized soybean oil

Identification of the substance

CAS No.

8013-07-8

EINECS No.

232-391-0

EINECS Name

Soybean oil, epoxidized

Synonyms

Soybean oil epoxidized, Epoxidised soyabean oil, ESBO, Epoxidised
soy bean oil.

Molecular Formula

No data found

Structural Formula

No data found

Major Uses

Softener.

Solvent.

Construction material additive.

Viscosity adjusters.

Stabiliser.

Plasticiser processing aid.

[1]

[1]

[1]

[1]

[1]

[3]

IUCLID

The substance is included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

No data found

Molecular Weight (g/mole)

No data found

Melting Point/range (° C)

No data found

Boiling Point/range (° C)

No data found

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

No data found

Density (g/cm³at ° C)

0.994-0.998

[1]

Vapour Density (air=1)

No data found

Henry’s Law constant (atm/m³/mol at °
C)

No data found

Solubility (g/l water at ° C)

Low (unknown temperature)

[1]

Partition Coefficient (log P_ow)

> 6 (estimated)

[1]

pK_a

No data found

Flammability

No data found

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

No data found

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

No data found

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

¨ Asthma developed in a worker
exposed to vapour from heated polyvinyl chloride film containing
ESBO. Challenge with ESBO vapour of unspecified concentration
produced asthmatic symptoms within 5 min.

[1]

Acute toxicity

Oral

Rat:

21,000-40,000 mg/kg bw. Single dose of 5.000 mg/kg caused dispnoea
and diarrhoea. (must be 5,000).

¨ LD₅₀>5,000 mg/kg bw.

[1]

[1]

Dermal

Rabbit:

No dose mentioned (24 h) occlusion. LD₅₀>20,000 mg/kg
bw.

[1]

Inhalation

No data found

Other routes

No data found

Skin irritation

Rabbit:

¨ Moderately irritating (24 h)
occlusion.

Slightly irritating. EPA, Federal reg., Vol 43, No. 163

[1]

[1]

Eye irritation

Rabbit:

0.5 ml. Not irritating. Instillation of 0.5 ml of undiluted
substance.

¨ Not irritating. EPA, Federal Register,
Vol. 43, No. 163.

[1]

[1]

Irritation of respiratory tract

No data found

Skin sensitisation

Guinea pig:

¨ Induction phase of 8 intracutaneous
injection of diluted product (no further information). 3 weeks later
challenge with 0,1 ml of 0.1% Reoplast 39%. Rechallange after 2
weeks with patch test 30% Reoplast 39 in 1:1 propylene glycol:saline
cover for 24 h, 20 animals/group. No sensitisation was observed.
Optimisation test.

[1]

Subchronic and Chronic Toxicity

Oral

Rat

¨ 0.25% and 2.5% Reoplast 39 (2 years)
oral feed, 48 animals/dose group. NOAEL: Approx. 1.3 mg/kg bw.
Slight injury in uterus at 2.5% (ca. 1.4 g/kg bw/d).

Approx. 10 g/kg bw/d, epoxide numbers 14.6-111.5 (10 w). Slow
growth, death in groups receiving compound with epoxide number 49.7
or more. Water intake increased with epoxide number while food
intake and protein utilisation decreased. Feeding with epoxy number
105 and 111.5 - severe degeneration of testes. Fatty degeneration in
the controls and in the group fed ESBO with epoxide numbers
14.6-49.7.

1.4 g/kg/application, 2 applications/w (16 months). NOAEL= 1,400
mg/kg bw.

[1]

[1]

[1]

Dog

Up to 5% paraplex G-60 and paraplex G-62 (ca. 1.25 g/kg/d)(one year)
oral feed. Food intake and bw decrease (5%) in all dose groups.
Slight liver change in 5% paraplex G-62.

¨ 1.4 g/kg (12 months) 2 applications/w.
NOAEL= 1,400 mg/kg.

[1]

[1]

Inhalation

No data found

Dermal

No data found

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

Salmonella typhimurium:

Up to 2,025 µg/plate. Test strain: TA98, TA100, TA1535, TA1537. No
mutagenicity was observed. Ames test, Ciba methode nach B. N. Ames
1973 u. 1975 with and without metabolic activation.

4, 20, 100 ,500, 2,500, 12,500 µg/plate. Test strain: TA98, TA100,
TA1535, TA1537 and TA 1538. No mutagenicity was observed. Ames test,
Henkel-method "Salmonella typhimurium reverse mutation
assay" with and without metabolic activation, GLP.

Up to 5,000 µg/plate. Test strain: TA98, TA100, TA1535, TA1537 and
TA102. No mutagenicity was observed. Ames test, Siehe RE with and
without metabolic activation. GLP.

[1]

[1]

[1]

Mouse:

Up to 5,000 µg/l. No mutagenicity was observed. Mouse lymphona
assay , Siehe RE, with and without metabolic activation., GLP

[1]

Chromosome Abnormalities

No data found

Other Genotoxic Effects

Humane lymphocytes:

No doses specified (20 to 44 h without, 3 h with metabolic
activation). No evidence of clastogenic effect or induced
aneuploidy. Cytogenetic assay Siehe Re.

[1]

Carcinogenicity

Mouse:

¨ No dose specified undiluted ESBO
(whole life) 3timesw, 40 animals. No skin tumors.

Total dose 2.15 g/kg bw (3 w), i.p. once/w. No incidence of lung
tumors after 16 weeks.
Rat:

Up to 2.5% (1.4 g/kg bw/d) Paraplex G-60 and Paraplex G-62 (2 years)
oral feed. No evidence of carcinogenicity.

Up to 5% paraplex G-60 and Paraplex G-62 (1 or 2 years) oral feed.
No evidence of carcinogenicity.

[1]

[1]

[1]

[1]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

Rat:

¨ 100, 300, 1,000 mg/kg bw/d (21 d
post-partum) gavage. NOAEL, parental = 1,000 mg/kg bw, NOAEL, F1
offspring = 1,000 mg/kg bw. OECD 415.

20% (ca. 10 g/kg bw/d; 7 w), epoxide number 15 and 50. No
histological changes of the testes in animals treated with epoxide
number 15 to 50. Severe degeneration in testes of animals tested
with ESBO with epoxide number between 105 or 111.5.

[1]

[1]

Teratogenicity

Rat:

¨ 100, 300, 1,000 mg/kg bw/d (6. to 15.
day of the pregnancy) gavage, 25 females/dose group. NOAEL, parental
= 1,000 mg/kg bw, NOAEL, F1 offspring = 1,000 mg/kg bw. OECD 414.

[1]

Other Toxicity Studies

No data found

Toxicokinetics

Toxicokinetics

No data found

Ecotoxicity Data

Algae

No data found

Crustacean

Artemia salina:

EC₅₀(24h) = 240 mg/l, unspecified static test

Daphnia magna:

¨ EC₅₀(24h) = 8 mg/l, Dir.
87/302/EEC, part C

NOEC(24h) = 0.7 mg/l, Dir. 87/302/EEC, part C

[1,11]

[1]

[1]

Fish

Leuciscus idus (fw):

¨ LC₅₀(48h) = 900 mg/l, DIN
38412-L15

LC₅₀(48h) = >10,000 mg/l, DIN 38412-L15

[1]

[1]

Bacteria

Activated sludge:

EC₅₀(3h)>100 mg/l, OECD 209

Pseudomonas putida:

EC₀(0.5h)>10,000 mg/l, DIN 38412-L27

[1]

[1]

Terrestrial organisms

No data found

Other toxicity information

Water transpiration of Vicia faba (pea) sprayed with a 10
% suspension of epoxidized soybean oil was reduced by 30 %. A slight
increase in grain yield (g dry weight/plant) of maize or no effect
(dependent on water supply of plants) when sprayed onto soil or
plant was observed itself as a 0,05 - 0,1 % suspension was further
observed.

[1]

Environmental Fate

BCF

No data found

Aerobic biodegradation

Aquatic – ready biodegradability tests:

¨ 79 % at 10 mg/l in 28 d, OECD 301 B

¨ 78 % at 2 mg/l in 28 d, OECD 301 D
Aquatic – other tests:

20 % at 10 mg/l in 20 d, unspecified BOD test

[16]

[17]

[1]

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

No data found

Conclusion

Physical-chemical

No data found

Emission

No data found

Exposure

No data found

Health

ESBO is only slightly acute toxic. In the acute oral tests LD₅₀in rats ranged between 21,000-40,000 mg/kg bw. ESBO was only
slightly irritating to skin.

ESBO was not mutagenic in Ames test. Based on the limited data
available ESBO was not found to be carcinogen or to exhibits
reproductive toxicity or teratogenitity. In reproductive toxicity
tests in mouse and rat the NOAEL for the parental group were 1,000
mg/kg bw and the NOAEL for the F1 offspring were 1,000 mg/kg bw.

Environment

According to the available biodegradation data there is good
evidence of ready biodegradability of epoxidized soybean oil.

The available ecotoxicological data indicates that epoxidized
soybean oil is toxic to crustaceans.

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

1a

European Commission Joint Research Centre (2000): International
Uniform Chemical Information Database. IUCLID CD-ROM. Year 2000
Edition. ISBN 92-828-8641-7.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

Ciba Additive GmbH Lambertheim (1988) not published. Quoted in
ref 1.

16

Henkel KGaA (Pruefnr. 7014), not published. Quoted in ref. 1.

Dipropyleneglycol dibenzoate

CAS number: 27138-31-4

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

Dipropyleneglycol dibenzoate is a compound with low water
solubility (15 mg/l) and a low vapour pressure. The estimated Log P_ow
value of 3.88 indicates lipophillic properties.

Emission

No data found.

Exposure

No data found.

Health

No data found.

Environment

No data found.

Dipropyleneglycol dibenzoate

Identification of the substance

CAS No.

27138-31-4

EINECS No.

248-258-5

EINECS Name

Oxydipropyl dibenzoate

Synonyms

Propanol, oxybis-, dibenzoate

Molecular Formula

C₂₀H₂₂O₅

Structural Formula

Illustration- Structural Formula. CAS nr. 27138-31-4 (2 Kb)

Major Uses

No data found

IUCLID

The substance is not included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

No data found

Molecular Weight (g/mole)

342.4

Melting Point/range (° C)

No data found

Boiling Point/range (° C)

No data found

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

¨ 4.6´ 10^-7
at 25 ° C

[15]

Density (g/cm³at ° C)

No data found

Vapour Density (air=1)

No data found

Henry’s Law constant (atm/m³/mol at °
C)

1.38´ 10^-8 at 25 °
C

[15]

Solubility (g/l water at ° C)

¨ 0.015 (at 25 °
C)

[15]

Partition Coefficient (log P_ow)

¨ 3.88 (estimated)

[15]

pK_a

No data found

Flammability

No data found

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

No data found

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

No data found

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

No data found.

Acute toxicity

Oral

No data found.

Dermal

No data found.

Inhalation

No data found.

Other routes

No data found.

Skin irritation

No data found.

Eye irritation

No data found.

Irritation of respiratory tract

No data found.

Skin sensitisation

No data found.

Subchronic and Chronic Toxicity

Oral

No data found.

Inhalation

No data found.

Dermal

No data found.

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

No data found.

Chromosome Abnormalities

No data found.

Other Genotoxic Effects

No data found.

Carcinogenicity

No data found.

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

No data found.

Teratogenicity

No data found.

Other Toxicity Studies

No data found.

Toxicokinetics

Toxicokinetics

No data found.

Ecotoxicity Data

Algae

No data found.

Crustacean

No data found

Fish

No data found

Bacteria

No data found

Terrestrial organisms

No data found

Other toxicity information

No data found

Environmental Fate

BCF

No data found

Aerobic biodegradation

No data found

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

No data found

Conclusion

Physical-chemical

Dipropyleneglycol dibenzoate is a compound with low water
solubility (15 mg/l) and a low vapour pressure. The estimated Log P_ow
value of 3.88 indicates lipophillic properties.

Emission

No data found

Exposure

No data found

Health

No data found

Environment

No data found

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

1a

European Commission Joint Research Centre (2000): International
Uniform Chemical Information Database. IUCLID CD-ROM. Year 2000
Edition. ISBN 92-828-8641-7.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB - Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS - Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS - Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox - Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg - Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

PhysProp - Syracuse Research Corporation. Interactive PhysProp
Database

http://esc.syrres.com/interkow/physdemo.htm

Dioctyl sebacate

CAS number: 122-62-3

Physical-chemical, emission, exposure, health and
environment data

Summary

Physical-chemical

Dioctyl sebacate is a compound with a low estimated vapour
pressure and water solubility.

The estimated Log P_ow value indicates that dioctyl
sebacate may bioaccumulate.

Emission

No data found

Exposure

No data found

Health

Only a limited data set were found.

The acute toxicity for rats was as LD₅₀ 1,280 mg/kg bw
and for rabbit 540 mg/kg bw.

Based on the available data dioctyl sebacate is not considered a
potential carcinogen, and has not been shown to produce any
reproductive toxicity.

Environment

No data found

Dioctyl sebacate

Identification of the substance

CAS No.

122-62-3

EINECS No.

204-558-8

EINECS Name

Bis(2-ethylhexyl) sebacate

Synonyms

Decanedionic acid bis(2-Ethylhexyl) ester, octyl Sebacate,
sebacic acid bis(2-ethylhexyl) ester, bis(2-ethylhexyl) sebacate,
bisoflex dos, DOS, 2-ethylhexyl sebacate, 1-hexanol
2-ethyl-sebacate, monoplex dos, octoil s, PX 438, Staflex dos,
Plexol 201, bis(2-ethylhexyl) decanedioate, Edenol 888, Ergoplast
sno, Reolube dos, DEHS.

Molecular Formula

C₂₆H₅₀O₄

Structural Formula

Illustration. Structural Formula. CAS nr. 122-62-3 (2 Kb)

Major Uses

Synthetic lubricant for reaction motor

Plasticiser for poly(methyl methylacrylate) and cyclonite.

[3]

[3]

IUCLID

The substance is not included in the IUCLID HPVC list.

EU classification

The compound is not included in Annex I to 67/548/EEC

Physico-chemical Characteristics

Physical Form

Pale straw coloured liquid.

Oily colourless liquid.

Pale yellow liquid.

Clear light coloured liquid.

[3]

[3]

[6]

[6]

Molecular Weight (g/mole)

426.68

Melting Point/range (° C)

-67 ° C

¨ –48 ° C

[2]

[3,6]

Boiling Point/range (° C)

248 at 4 mm Hg

256 ° C at 5 mm Hg

[2,6]

[3]

Decomposition Temperature (° C)

No data found

Vapour Pressure (mm Hg at ° C)

¨ 1.0´ 10^-7
(estimated, 25 ° C)

[15]

Density (g/cm³at ° C)

0.914

0.912 at 25 ° C

0.91 at 25 ° C

[2]

[3]

[6]

Vapour Density (air=1)

14.7

[3]

Henry’s Law constant (atm/m³/mol at °
C)

No data found

Solubility (g/l water at ° C)

Insoluble (temperature unknown)

¨ 3.5´ 10^-7
(estimated, 25 ° C)

[6]

[15]

Partition Coefficient (log P_ow)

¨ 10.08 (estimated)

[15]

pK_a

No data found

Flammability

Slightly flammable when exposed to heat.

[3]

Explosivity

No data found

Oxidising Properties

No data found

Migration potential in polymer

76-137 mg/kg Dioctyl sebacate

[17]

Emission Data

During production

No data found

Exposure Data

Aquatic environment, incl. sediment

No data found

Terrestrial environment

No data found

Sewage treatment plant

No data found

Working environment

No data found

Consumer goods

No data found

Man exposed from environment

No data found

"Secondary poisoning"

No data found

Atmosphere

No data found

Dermal

No data found

Toxicological data

Observations in humans

Volunteers did not generate sensitisation during 48 hour covering
and patch tests.
DOS aerosols have been used to demonstrate particle deposition in
lung and respiratory tract without apparently producing overt toxic
effects.

[16]

Acute toxicity

Oral

Rat

¨ LD₅₀=1,280 mg/kg

[6]

LD₅₀(rat)=1,700 mg/kg bw
LD₅₀(mouse)=9,500 mg/kg bw

[16]
[16]

Exposure to DOS may produce reduced coordination, laboured
breathing and diarrhoea, with tissue damage in the liver, spleen,
brain and heart.

[16]

Dermal

LD₅₀(guinea-pig) > 10 g/kg bw

[16]

Inhalation

No adverse effects were seen in a 13-week study where 12 rats
exposed to 250 mg/m³.
No seen effects on lung or liver below saturating concentrations
but saturated mist may cause lung toxicity. When DOS is heated to
371 °C decomposition products can lead
to death of rabbits and rats.

[16]

Other routes

Rat

LD₅₀= 900 mg/kg , i.v.
Rabbit

¨ LD₅₀= 540 mg/kg, i.v.

[16]

[16]

Skin irritation

¨ Not a skin irritant or absorbed
through skin.
Not a skin irritant during 48 hour tests

[3]
[16]

Eye irritation

Above 60 mg/m³ for 1 minute it is irritating

[16]

Irritation of respiratory tract

Above 60 mg/m³ for 1 minute it is irritating

[16]

Skin sensitisation

Not sensitising in rabbits

[16]

Subchronic and Chronic Toxicity

Oral

No data found

Inhalation

Rat

Exposed to air bubbled through a column of liquid at 100 °C (6 h).
No toxic effects and no mortality were observed.

[3]

Dermal

No data found

Mutagenicity, Genotoxicity and Carcinogenicity

Mutagenicity

¨ Salmonella typhimurium

No dose specified. Test strains: TA100, TA 1535, TA1537, TA98.
No mutagenicity were observed. Preincubation with and without
metabolic activation system.

[5]

Chromosome Abnormalities

No data found

Other Genotoxic Effects

No data found

Carcinogenicity

Rat

¨ 200 mg/kg bw (19 months). Result: No
effects observed. No carcinogenic potential.
Rats fed with a diet containing 10 mg/kg bw for up to 19 month
showed no carcinogen effects and the reproduction were normal in a 4
generation study of rats fed with about 10 mg/kg bw.

[3]
[16]

Reproductive Toxicity, Embryotoxicity and
Teratogenicity

Reproductive Toxicity

Rat

¨ 200 mg/kg bw (19 months). No effects
observed in growth, pathology, reproduction, or during parturition
or nursing in several generations.

[?]

Rats fed with a diet containing 10 mg/kg bw for up to 19 month
showed that the reproduction were normal in a 4 generation study of
rats fed with about 10 mg/kg bw.

[16]

Teratogenicity

No data found

Other Toxicity Studies

No data found

Toxicokinetics

Toxicokinetics

Not absorbed through skin.

[3]

Ecotoxicity Data

Algae

No data found

Crustacean

No data found

Fish

No data found

Bacteria

No data found

Terrestrial organisms

No data found

Other toxicity information

No data found

Environmental Fate

BCF

No data found

Aerobic biodegradation

No data found

Anaerobic biodegradation

No data found

Metabolic pathway

No data found

Mobility

No data found

Conclusion

Physical-chemical

Dioctyl sebacate is a compound with a low estimated vapour
pressure and water solubility.

The estimated Log P_ow value indicates that dioctyl
sebacate may bioaccumulate.

Emission

No data found

Exposure

No data found

Health

Only a limited data set were found.

The acute toxicity for rats was as LD₅₀ 1,280 mg/kg bw
and for rabbit 540 mg/kg bw.

Based on the available data dioctyl sebacate is not considered a
potential carcinogen, and has not been shown to produce any
reproductive toxicity.

Environment

No data found

References

1

European Commission Joint Research Centre (1996): International
Uniform Chemical Information Database. IUCLID CD-ROM – Existing
Chemicals – 1996.

2

Chemfinder – Cambridge Soft.

http://www.chemfinder.com

3

HSDB – Hazardous Substances Data Bank

http://toxnet.nlm.nih.gov

4

IRIS – Integrated Risk Information System

http://toxnet.nlm.nih.gov

5

CCRIS – Chemical Carcinogenesis Research Information System

http://toxnet.nlm.nih.gov

6

NTP – National Toxicology Program, Chemical Health & Safety
Data

http://ntp-server.niehs.nih.gov

7

Genetox – Genetic Toxicology

http://toxnet.nlm.nih.gov

8

Chemfate – Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

9

Biodeg – Syracuse Research Corporation. Environmental Fate
Database

http://esc.syrres.com

10

Betratergremium für umweltrelevante Altstoffe (1996): Di-(2-ethylhexyl)adipat,
BUA-Stoffbericht 196. S. Hirzel, Frankfurt am Main.

11

ECOTOX – US. EPA . ECOTOX database system

http://www.epa.gov

12

Verschueren, K. (1996) Handbook of Environmental Data on Organic
Chemicals. 3rd Ed. Van Nostrand Reinhold. New York.

13

Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72^nd
ed. Boca Raton, FL: CRC Press 1991-1992.

14

Petersen, J., H. (1999): Forurening af fødevarer med blødgører
– Migration fra plast og generel baggrundsforurening. Ph.D Thesis.
The Danish Veterinary and Food Administration.

15

PhysProp – Syracuse Research Corporation. Interactive PhysProp
Database

http://esc.syrres.com/interkow/physdemo.htm

16

BIBRA (1996): TOXICITY PROFILE di(2-ethylhexyl)sebacate. TNO
BIBRA International Ltd., 1996.

17

Castle, L., Mercer, A.J., Startin, J.R. & Gilbert, J. (1988)
Migration from plasticised films into foods. 3. Migration of
phthalate, sebacate, citrate and phosphate esters from films used
for retail food packaging. Food Addit. Contam. 5(1), pp 9-20

[Front page]
[Top]}}}

Environmental and Health Assessment of Alternatives to Phthalates and to flexible PVC

Contents

Appendix 1 Abbreviations used

Authorities

Trade organisations

Industries

Environmental and Health Assessment of Alternatives to Phthalates and
to flexible PVC