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 ºC
• 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

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

*: 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

*: 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.

* 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.

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.

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

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.

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). 

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 °ºC
• 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.

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

*: 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.

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.

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.

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.

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.

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.

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 ºC with one exact solubility of 0.6 mg/l at 24 ºC. 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 ºC. 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 ºC
• 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

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

*: 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.

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.

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.

 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.

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 irrita-tion 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.

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).

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

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 compatibility 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

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

*: 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.

* 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.

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.

5.5.2 Health assessment

Key toxicity data on TETM are presented Table 5.39.

Table 5.39 Selected toxicity data on TETM.

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.

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)

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.

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.

*: 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.

* 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.

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.

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.

* 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

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.

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.

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.

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 LD₅₀ in 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.

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

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

*: 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.

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.

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.

* 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^m g/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

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