Appendix 4. Physical-chemical, emission, exposure, health and environmental data, Danish Environmental Protection Agency

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

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 avail-able 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

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