APPENDIX 6. TOXICOLOGICAL DATA FOR CLASS 3 SOLVENTS

Transcription

1 APPENDIX. TOXICOLOGICAL DATA FOR CLASS SOLVENTS draft page 1

2 ACETIC ACID Genotoxicity Negative results in Ames tests. Refs. Zeiger E et al., Environ. Mol. Mutagen. 1 1 (suppl1) -1 Mut. Res Carcinogenicity No relevant data available Reproductive Toxicity Doses up to 1. g/kg administered by gavage to rabbits from days -1. No material toxicity and no adverse effects on the offspring NOEL 1.g/kg.. Ref. 1 FDA Internal report Ref. GRM :0 100 x 0. x x 1 x 1 x 1 00 x 00 = 00 mg / day = 0,000 ppm Animal Toxicity Oral LD0 in rats is. g/kg. Ref. Merck Index th Edn 1 Acetic acid is a permitted direct food additive. Ref. 1CFR 1.0 (10) 1 Conclusion The PDE for acetic acid is 00 mg/day. draft page

3 1 1 1 ACETONE Genotoxicity Negative in vitro results in Ames test, sister chromatid exchange assay, SHE cell transformation assay and in DNA repair-deficient bacterial tests. Also negative in vivo in micronucleus test. Refs. De Flora S et al., Mut. Res. 1 1 () -. Zeiger E et al., Environ. Mol. Mutagen. 1 1 (Suppl 1) 1-. Mut. Res. 1. Mut. Res Mut. Res. -. Mut. Res Carcinogenicity No increase in tumour incidence when 0. ml applied weekly to skin of CF1 mice for years. Ref. Zakova N et al., Fd. Chem. Toxicol ml = 0. x 0. = 1 mg 1 1 For continuous dosing = 1 x 1 =. mg 1 0 Daily dose =. x 00 = 0 mg / kg 1 0 x 0 1 x x 1 x 1 x 1 = mg / day x 00 =,00 ppm draft page

4 Reproductive toxicity No suitable data available. Animal toxicity Oral LD0 in rats is. ml/kg. Ref. Smyth HF et al., Ind. Hyg. J. 1. Rats given 1,000 ppm by inhalation h/day, days/week for weeks showed no evidence of toxicity. Ref. Bruckner JV and Peterson RG. Toxicol. Appl. Pharmacol ppm = 1,000 x. =,0 mg / m =.1 mg / L 1 1 For continuous dosing =.1 x x x =.0 mg / L 1 1 Daily dose =.0 x 0 0. = 0 mg / kg x 0 x x x 1 x 1 = mg / day 1 1 x 00 =,00 ppm 0 1 F rats given,00;,000;,000, 0,000 and 0,000 ppm in drinking water for 1 weeks. Weight gain was depressed and kidney changes were noted at the two highest concentrations and at 0,000 ppm hypogonadism occurred in the testes. NEL,000 ppm (equivalent to 0 mg/kg - time weighted average). Ref. Dietz DD et al., Fund. Appl. Toxicol draft page

5 0 x 0 x x x 1 x 1 = mg / day x 00 = 1,000 ppm Conclusion The PDE for acetone is.0 mg/day. draft page

6 ANISOLE Genotoxicity Carcinogenicity Reproductive Toxicity Toxicity Oral LD0 in rats reported as. g/kg and. g/kg. Refs. Jenner PM et al., Food Cosmet. Toxicol. 1 () - Smyth HF et al., Arch. Ind. Hyg. Occup. Med Oral LD0 in mice. g/kg. Ref. J. Pharmacol. Exp. Ther Human Anisole has GRAS status and is permitted for food use as an artificial flavouring substance. Ref. 1 CFR 1.1 draft page

7 1 1 1-BUTANOL Genotoxicity Negative results in Ames and SCE assays. Refs. Jung R et al., Mut. Res. 1 () -0 Conners T H et al., Toxicol. Lett. 1 (1) -0 Mut. Res Mut. Res. 1- Carcinogenicity Reproductive toxicity Teratogenic when administered into yolk sac of chick embryos. Ref. McLaughlin J et al., Am. Ind. Hygien. Assoc. J. 1 () Animal toxicity Oral LD0 is. g/kg. Ref. Smyth HF et al., Am. Ind. Hygien Occup. Med. J Butanol is a permitted direct food additive. Ref. 1 CFR 1.1 (1). draft page

8 -BUTANOL Genotoxicity Negative in Ames and CHO assays. Ref. Brook TM et al., Mutagen. 1 - Carcinogenicity No data available Reproductive Toxicity Wistar rats given 0., 1.0 or.0% in drinking water, equivalent to or 000mg/kg, for weeks then mated. The Fia generation was used for a toxicity study (see below). The foetuses of the Flb generation were examined at the end of pregnancy. (Dosing of generation continues throughout.) No maternal effects were noted but foetal weight was slightly reduced at the high dose level only and there was evidence of retarded skeletal development. NOEL is 100mg/kg. Ref. 1 Internal FDA document. ASP x 0 x x x 1 x 1 = 00 mg / day x 00 = 0,000 ppm 0 1 Animal Toxicity A parent generation of Wistar rats was given 0., 1.0 or.0% in drinking water, equivalent to 00, 100 or 000 mg/kg, for weeks then mated. Dosing continued throughout pregnancy and weaning. The F1 generation was treated for weeks then mated. Daily continued throughout pregnancy at the end of which the F1 generation was killed and examined (routine laboratory examinations were performed and tissues were examined microscopically). Kidney changed comprising tubular degeneration and microcysts in the papilla were noted at the high draft page

9 dose level only. NOEL 1%, equivalent to 100 mg/kg. Ref. 1 internal FDA document x 0 x x x 1 x 1 = 00 mg / day 00 x 00 = 0,000 ppm Oral LD0 in rats is.g/kg. Ref. Merck index th Edn (1) - Butanol is a permitted direct food additive. Ref. 1CFR 1.1 (10) 1 CONCLUSION The PDE for -butanol is 00 mg/day. draft page

10 BUTYL ACETATE Genotoxicity Negative in Ames tests. Ref. shimizu H et al., Sangyo lgaku Carcinogenicity No data available Reproductive Toxicity No data available Animal Toxicity CD-1 mice were given 00, 00 or 000mg/kg in the diet daily for 0 days. Reduced motor activity, prostration, and laboured breathing were noted at the high dose level only and serum cholesterol was reduced in this group. Not microscopic changes were noted at any dose level. NOEL 00mg/kg. Ref. 1 Internal FDA report Ref. FAP A0 : x 0 1 x x x 1 x 1 =. mg / day 0 1. x 00 =,00 ppm Sprague-Dawley rats were given 00, 000 or 000 mg/kg daily by gavage for 0 days. All rats salivated after dosing but this was considered a response to the test of the material rather than toxicity. Reduced motor activity was seen at the intermediate and high levels with lachrymation and prostration in a few high dose animals only. High dose level animals draft page

11 showed reduced weight gain. Stomach lesions were noted in the inter and high dose level animals. NOEL 00 mg/kg. Ref. 1 Internal FDA report Ref. FAP A0 : 00 x 0 x x x 1 x 1 = 10 mg / day 10 x 00 = 1,000 ppm Oral LD0 in rats is 1.1g/kg. Ref. Merck index th Edn 1 Butyl acetate is a permitted direct food additive. Ref. 1 CFR 1.1 (10) 1 Conclusion The PDE for butyl acetate is. mg/day. draft page

12 TERT-BUTYLMETHYL ETHER Genotoxity Carcinogenicity No oncogenic effects in F rats given 0, 0 or ppm h/day, days/week for years. Ref. Chun JS et al., 1 (summarised in IRIS report Document No. 1). NEL = ppm = x.1. =,0 mg / m =. mg / L For continuous dosisng =. x x x =.1 mg / L 1 1 Daily dose =.1 x 0 0. kg = 0 mg / kg x 0 x x 1 x 1 x 1 = 0 mg / day x 00 = 0,00 ppm Reproductive Toxicity Sprague-Dawley rats given 0, 00, or,00 ppm by inhalation on days -1. No maternal toxicity and no adverse effects on litters. Ref. Conway CC et al., J. Tox. Environ.Health NEL = 00 ppm = 00 x.1. = 01 mg / m =.01 mg / L draft page 1

13 For continuous dosing =.01 x =. mg / L Daily dose =. x 0 0. kg = 1 mg / kg 1 x 0 x x 1 x 1 x 1 = 1 mg / day 1 x 00 = 1,00 ppm 1 CD-1 mice given 0, 00, or,00 ppm by inhalation h/day, days -1. No maternal effects and no adverse effects on litters. Ref. Conway CC et al., J. Tox. Environ.Health As above, continuous exposure =. mg/l. 1 1 Daily dose =. x 0.0 kg = mg / kg 1 1 x 0 1 x x 1 x 1 x 1 = 1 mg / day x 00 = 1,00 ppm No adverse effects on litters when male Sprague-Dawley rats exposed by inhalation to 00, 100 or 00 ppm h/day, day/week for 1 weeks then mated to females dosed for weeks pre-mating and throughout gestation and from days -1 of lactation. Ref. Biles RW et al., Tox Ind. Health 1 () 1-. draft page 1

14 NEL = 00 ppm = 00 x.1. = 1, mg / m = 1. mg / L For continuous dosing = 1. x x x =.1 mg / L Daily dose =.1 x 0 0. kg = 1 mg / kg 1 x 0 x x 1 x 1 x 1 = 1 mg / day 1 x 00 = 1,00 ppm Animal Toxicity F rats exposed by inhalation to 0, 0 or ppm h/day, days/week for years. Chronic progressive nephropathy in males associated with α µ globulin toxicity. This has been shown to be of no relevance for humans since they do not produce that protein In females, which do not produce α µ globulin, chronic progressive nephropathy was also seen. NEL 0 ppm. Ref. Chun JS et al.,1 (summarised in IRIS report Document No., 1) 1 0 NEL = 0 ppm = 0 x.1. = 1 mg / m = 1. mg / L 1 For continuous dosing = 1. x x x = 0. mg / L Daily dose = 0. x 0 0. kg = 1 mg / kg draft page 1

15 1 x 0 x x 1 x 1 x 1 = 1 mg / day 1 x 00 = 1,00 ppm Conclusion The PDE for tert-butylmethyl ether is 1 mg/day. draft page 1

16 1 CUMENE Genotoxicity Negative results in Ames test and in Saccharomyces cerevisiae. Positive in in vitro UDS and in cell transformation assays using mouse embryo cells. Refs. Mut. Res Mut. Res EPA Fiche OTS 001 (1) Carcinogenicity Reproductive Toxicity Animal Toxicity No adverse effects noted in rats exposed to 1 mg/m continuously by inhalation for months. Ref. Jenkins LJ et al., Toxicol. Appl. Pharmacol () mg /m = 0.1 mg / L 1 0 Daily dose = 0.1 x 0 0. =. mg / kg 1. x 0 x x x 1 x 1 = 1. mg / day 1. x 00 = 10 ppm draft page 1

17 Female Wistar rats given 1, and mg/kg by gavage days/week for months. No histopathological changes but slight increases in kidney weights at two higher doses. NEL 1 mg/kg. Ref. Wolf MA et al., Arch. Ind. Health For continuous dosing = 1 x = 1 mg / kg 1 x 0 x x x 1 x 1 = mg / day x 00 = 00 ppm 1 1 Conclusion The 10 study is disregarded since only a single dose was administered and no effect was detected. The PDE for cumene is.0 mg/day. 1 draft page 1

18 DIMETHYL SULFOXIDE Genotoxicity Negative in vitro results in Ames and other bacterial tests, CHO cells, and in host mediated assay. Conflicting results in mouse lymphoma assay. Refs. Brams A et al., Toxicol. Lett Zeiger E et al., Environ. Mol. Mutagen. 1 1 (Suppl 1) - Fluck ER et al., Chem. Biol. Interact Takehisa S and Wolff S. Mut. Res. 1 - Hrelia P et al., Terat. Carcinogen. Mutagen Wangenheim J and Bolcsfoldi G. Mutagen. 1 () 1-0 Amacher DE et al., Mut. Res Carcinogenicity Dermal application of 0 mg times weekly to skin opf ICR/Ha mice for days did not cause skin damage or tumours (only skin examined). Ref. Van Duuren BL et al., J. Ntl. Cancer Inst mg to mice weighting g = 0 x 00 = 1 mg / kg 1 For continuous dosing = 1 x = 10 mg / kg 10 x 0 1 x x 1 x 1 x 1 = mg / day draft page 1

19 x 00 =,00 ppm No tumours in mice dosed with ml/kg orally daily for 0 weeks. (Time of autopsy not stated). Ref. Kanisawa M and Suzuki S. Gann 1-00 ml / kg = x 1.1 =,00 mg / kg,00 x 0 1 x x x 1 x 1 = mg / day x 00 =,00 ppm 1 1 No tumours seen at injection sites after s/c administration of 0.0 ml weekly to ICR/Ha mice for weeks. Ref. Van Duuren BL et al., J. Nell. Cancer Inst ml = 0.0 x 1.1 = mg 1 1 mg to mice weighing g = x 00 = 1 mg / kg 1 1 For continuous dosing = 1 x 1 = 1 mg / kg x 0 1 x x 1 x 1 x 1 = mg / day x 00 =,00 ppm draft page 1

20 Reproductive Toxicity Oral dose of g/kg to Wistar rats for days pre-mating and throughout pregnancy had no effects on mother or offspring. Ref. Caujolle FM et al., C.R. Acad. Sci. Paris 1 (1) x 0 x x 1 x 1 x 1 = 000 mg / day 000 x 00 = 00,000 ppm 1 Swiss mice given -1 g/kg orally days -1 showed no increase in foetal deaths or reduction in foetal weight and no abnormalities were observed although maternal toxicity was seen at all except the lowest level. Ref. Caujolle FM et al., Ann NY Acad. Sci x 0 1 x x 1 x 1 x 1 = 0 mg / day x 00 = 0,00 ppm Hamsters given 0 to 0 mg/kg IV on day. No evidence of maternal toxicity. Increases in foetal deaths at 00 mg/kg and teratogenic effect from,00 mg/kg: exencephaly, cleft lip, and skeletal abnormalities. NEL 00 mg/kg. Ref. Ferm VH J.Embryol. Exp. Morph., 1 1 (1) - 00 x 0 x x 1 x 1 x = 0 mg / day 0 x 00 = 000 ppm draft page 0

21 Animal Toxicity Dogs dosed orally at.,,, 0 and 0 g/kg days/week for weeks showed changes in lens refractiveness making the lens clearer rather than translucent. No changes were detected histologically. LOEL =. g/kg =,00 mg/kg. Ref. Rubin LF and Mattis PA Science For continuous dosing =,00 x = 1 mg / kg 1 x 0 x x x 1 x 1 = mg / day x 00 =,00 ppm , and ml/kg of 0% solution given orally to rhesus monkeys daily for 1 months. Deaths at high dose. NEL ml/kg. Ref. Vogin EE et al., Toxicol. Appl. Pharmacol ml/kg = x 1.1 x 00 x 0% = 0 mg/kg x 0 x x x 1 x 1 = mg / day 1 0 x 00 =,00 ppm 1 and g/kg of 0% solution given orally for days to Wistar rats. High dose caused reduced weight gain and some liver damage. NEL 1 g/kg. Ref. Caujolle FM et al., Ann NY Acad. Sci draft page 1

22 00 x 0 x x x 1 x 1 = 0 mg / day 0 x 00 =,000 ppm Conclusion The PDE for dimethyl sulfoxide is 0 mg/day. draft page

23 ETHANOL Genotoxicity Negative results in Ames tests and in vitro cytogenetic studies with CHO and SHE cells. Refs. Lin YC et al., Mut. Res 1 1 () -. Zeiger E et al., Environ. Mol. Mutagen 1 1 (Suppl 1) -. Murt Res Carcinogenicity A 0% solution administered by gavage twice weekly for weeks to male and female BDVI rats had no oncogenic effects. Volume administered not stated. Ref. Griciute L et al., Cancer Letters Reproductive Toxicity Up to 1,000 ppm by inhalation h/day, days 1-0 had no effects on outcome of pregnancy in Wistar rats. Negative results when males dosed for weeks at same level then mated to untreated females. Ref. Nelson BK et al., Neurobehavr. Toxicol. Teratol NEL = 1000 ppm = 1000 x.0. = 01 mg / m = 0.1 mg / L 1 0 Continuous exposure = 0.1 x =. mg / L 1 Daily dose =. x 0 0. kg = mg / kg x 0 x x 1 x 1 x 1 = mg / day draft page

24 x 00 =,00 ppm Single I/P doses of,,, and g/kg given I/P to CD-1 mice on day. Increased foetal deaths at high dose and reduced foetal weight at and g/kg. Cleft palate noted at foetotoxic levels. Maternal effects not reported. NEL g/kg. Ref. Blakley PM and Scott WJ. Toxicol. Appl. Pharmacol. 1 () x 0 1 x x 1 x x 1 = 1. mg / day 1. x 00 = 1,0 ppm Animal Toxicity Oral LD0 in rats 1. ml/kg. Ref. Verschueren K ed in Handbook of Environmental Data of Organic Chemicals nd Edn. New York 1. Ethanol is a permitted direct food additive. Ref. 1 CFR 1-1 (10) Rat iv LD0 = 0. ml/kg for males, 1.1 ml/kg for females. Dog iv LD0 >0. ml/kg. Ref. Shirai, M., et al., 1, Jpn Pharmacol Ther, week repeat dose in dogs NEL 0.01 ml kg -1 day -1 Ref. Pukutome, A. et al., 1, Jpn Pharmacol Ther, - Human The workplace exposure limit for ethanol (TLV-TWA) is 00 ppm, equal to 10 mg per cubic meter. Assuming inhalation of cubic meters during an -h workday, total daily ethanol intake is 1. g, or mg/kg. The TLV is designed to avoid eye and upper respiratory tract irritation, and does not reflect concern about systemic toxicity. draft page

25 Ref. American Conference of Governmental Industrial Hygienists, Documentation of the Threshold L:imit Values and Biological Exposure Indices,, ACGIH Inc. The maximum recommended social consumption of alcoholic drinks in the UK is 1 units/week for men and 1 units per week for women, where a unit is equivalent to ml of standard beer or lager (% alcohol). Based on units per day, a daily alcohol intake of x x 0.0 = ml/day = 1,0 mg/day is considered to be without significant risk to women. Ref. UK Department of Health Guidelines, latest revision 1. Ethanol is a permitted direct food additive. Ref. 1 CFR 1-1 (10) 1 1 Conclusion The PDE for ethanol is 1. mg/day. draft page

26 1 1 ETHYL ACETATE Genotoxicity Negative results in vitro in Ames tests and in vivo in micronucleus test in Chinese hamsters. Refs. Zeiger E et al., Environ. Mol. Mutagen 1 1 (Suppl 1) - NTP Fiscal Year 1 Annual Plan. NTP Basler A. Mut. Res. 1 1 (1) -1. Carcinogenicity Reproductive Toxicity Animal Toxicity Oral LD0 in rats. ml/kg. Ref. Merck Index th Edn Rats given 000 ppm h/day, days/week for 1 weeks showed no adverse effects on bodyweight or haematological measurements. Ref. Quoted in American Conference of Governmental Industrial Hygienists. Documentation of the TLV and Biological Exposure Indices th Edn ppm = 000 x.. 0 mg / m =. mg / L 1 Continuous exposure =. x x x = 0. mg / L Daily dose = 0. x 0 0. kg = mg / kg draft page

27 x 0 x x x 1 x 1 = mg / day x 00 =,00 ppm Ethyl acetate is a permitted direct food additive. Ref. 1 CFR 1.0. Ethyl acetate is exempt from certification needs for use as a diluent in inks for marking fruit and vegetables under section 0 (c) of the Federal Food, Drug and Cosmetic Act. Ref. 1 CFR.1 (10). 1 Conclusion The PDE for ethyl acetate is mg/day. draft page

28 ETHYL ETHER Genotoxicity Negative results in Ames test. Ref. Waskell L. Mut. Res. 1 - Carcinogenicity Reproductive toxicity CD-1 mice were maintained anaesthetised from day 1. to 1. of gestation. No cleft palate was produced. Actual dosage administered not stated. Ref. Jacobs RM Teratol. 1, Animal toxicity Oral LD0 in rats is approx ml/kg. Ref. Kimura ET et al., Toxicol. Appl. Pharmacol draft page

29 ETHYL FORMATE Genotoxicity Negative in Ames test (Salmonella strains and Saccharomyces cerevisiae) with and without metabolic activation. Ref. Litton Bionetics Project No., Mutagenic Evaluation of Compound Ethyl Formate (FDA -) 1 Carcinogenicity A/He mice given ip injections times/week for weeks (total doses of. or 1.0 g/kg), and examined for primary lung tumours weeks after the first dose, showed no excess over controls. Ref. Stoner GD et al., Cancer Res 'S' strain mice treated dermally with 1 weekly applications of croton oil, and for the first weeks with 0. ml/week ethyl formate (total dose. g), did not have skin cancers when they were killed and examined one week after the last treatment with croton oil. Ref. Roe FJC and Salaman MH British J. Cancer (1) 1-0 Reproductive Toxicity Toxicity Oral LD0 in rats 10 mg/kg. Oral LD0 in guinea pigs mg/kg. Ref. Jenner PM et al., Food Cosmet. Toxicol. 1 () - Oral LD0 in rabbits 0 mg/kg. Ref. Munch JL Ind. Med. Surg. 1 1 () 1 Osborne-Mendel rats given 00, 00 or 000 ppm in the diet for 1 weeks showed no macroscopic effects, or microscopic findings in major organs. NEL 000 ppm. Ref. Hagan EC et al., Food Cosmet. Toxicol. 1-1 Assume rat consumes 0 g/day. draft page

30 Daily dose = 0 x 0. = 0. mg / kg 0. x 0 x x x 1 x 1 =. mg / day Human. x 00 = 1,10 ppm Ethyl formate has GRAS status, and is a permitted food additive. Ref. 1 CFR 1.1 Conclusion The PDE for ethyl formate is. mg/day. draft page 0

31 1 1 FORMIC ACID Genotoxicity Negative in Ames test. Ref. Zeiger E et al., Environ. Mol. Mutagen 1 1 (Suppl 1) - Carcinogenicity No data available Reproductive Toxicity No data available Animal Toxicity Rats given to 0 mg/kg in drinking water for up to weeks showed only reduced weight gain at highest dose. Virtual NEL 0 mg/kg. Ref. Malorny G. Z. Ernaehrungswiss x 0 x x x 1 x 1 = 10 mg / day x 00 = 1,000 ppm F/N rats and BCF1 mice were given, 1,,, or 1 ppm by inhalation h/day, days per week for 1 weeks. Two mice died at the highest dose level and body weight gain in mice was reduced at the and 1 ppm levels. Lesions were generally limited to the highest dose in both species and comprised squamous metaplasia and degeneration of the respiratory and olfactory epithelia. The changes are consistent with the administration of an irritant chemical by the inhalation route. There was no evidence of systemic toxicity. Ref. NTP Tech Report Tox 1, 1. NOAEL for irritancy ppm in both species. ppm = x.0. = 0. mg / m = 0.0 mg / L draft page 1

32 Continuous exposure = 0.0 x x x = 0.0 mg / L Rat daily dose = 0.0 x 0 0. kg =.1 mg / kg.1 x 0 x x x 1 x 1 = 1. mg / day 1. x 00 = 10 ppm Mouse daily dose = 0.0 x 0.0 kg = 1. mg / kg 1 1. x 0 1 x x x 1 x 1 = 1. mg / day x 00 = 10 ppm Formic acid is a permitted direct food additive. Ref. 1 CFR 1.1 (10) Conclusion The inhalation study is disregarded since no systemic toxicity was noted. The PDE for formic acid is 10.0 mg/day. draft page

33 1 HEPTANE Genotoxicity Carcinogenicity Reproductive Toxicity Toxicity Wistar rats given 000 ppm 1 h/day days/week for 1 weeks. Slight effect on weight gain but no effects on motor nerve conduction velocity, mixed nerve conduction velocity or distal latency. NEL 000 ppm. Ref. Takeuchi Y et al., Clin. Tox. 1 (1) ppm = 000 x 0.. = 1 mg / m = 1. mg / L 1 1 For continuous exposure = 1. x 1 =.1 mg / L 1 1 Daily dose =.1 x 0 0. =,1 mg / kg x 0 x x x 1 x 1 = 0 mg / day 1 Limit (ppm) = 0 x 00 =,000 ppm Conclusion The PDE for heptane is 0 mg/day. draft page

34 ISOBUTYL ACETATE Genotoxicity Data not available. Carcinogenicity Data not available. Reproductive Toxicity Data not available. 1 Animal Toxicity Oral LD0 in rats is 1. ml/kg. Ref. Smyth HF et al., Am. Ind. Hyg. Assoc. J Given GRAS status by FEMA Isobutyl acetate is a permitted direct food additive. Ref. 1 CFR 1. 1 (10) draft page

35 ISOPROPYL ACETATE Genotoxicity Negative in Ames test. Ref. Zeiger E et al., Environ. Mol. Mutagen 1 1 (Suppl 1) -. Carcinogenicity Reproductive Toxicity 1 Animal Toxicity Oral LD0 in rats. g/kg. 1 1 Ref. Merck Index th Edn Isopropyl acetate is a permitted direct food additive Ref. 1 CFR 1.1 (10) 1 draft page

36 METHYL ACETATE Genotoxicity Negative in Ames tests. Ref. Zeiger E. et al., Environ. Mol. Mutagen 1 1 (Suppl 1) -. Carcinogenicity Reproductive Toxicity 1 Animal Toxicity Oral LD0 in rats. g/kg. Ref. Reported in Patty s Industrial Hygiene and Toxicology. rd Edn. New York Methyl acetate is a permitted direct food additive. Ref. 1 CFR 1.1 (10). 1 draft page

37 METHYL-1-BUTANOL Genotoxicity Carcinogenicity No suitable data available. Reproductive Toxicity No teratogenic effects were seen when mg was injected into the yolk sac of chick embryos. Higher doses caused the death of the embryos. Ref. McLaughlin J et al., Am. Ind. Hyg. Assoc. J Animal Toxicity No adverse effects when 10, 00 or 00 mg/kg given orally to Ash/LSE rats daily for 1 weeks. Ref. Carpanini FMB et al., Fd. Cosmet. Toxicol NEL = 00 mg / kg x 0 x x x 1 x 1 = 00 mg / day x 00 = 0,000 ppm 1 -methyl-1-butanol is a permitted direct food additive. Ref. 1 CFR 1.1 (10) Conclusion The PDE for -methyl-1-butanol is 00 mg/day. draft page

38 1 1 METHYLETHYL KETONE Genotoxicity Negative results in wide range of in vitro tests and in MNT using mice and hamsters Refs. O Donoghue JL et al., Mut. Res EPA Doc No. 1 Fiche No. 00 (1) Basler A. Mut. Res Carcinogenicity No oral or inhalation carcinogenicity data available. Reproductive Toxicity Rats Exposure to 1, 0 or 00 ppm by inhalation h/day, days -1 caused decreased maternal weight gain and mild developmental retardation at the high dose only. NEL 0 ppm. Ref. Deacon MM et al., Toxicol. Appl. Pharmacol. () ppm = 0 x.1. = mg / m =. mg / L 1 1 For continuous exposure =. x = 0. mg / L 1 1 Daily dose = 0. x 0 0. = mg / kg 0 1 x 0 x x 1 x 1 x 1 = mg / day x 00 =,00 ppm draft page

39 Mice Swiss mice given, or,00 ppm by inhalation h/day, days -1. Slightly decreased foetal weight at high dose only but no materanl effects. NEL ppm. Ref. Schwetz BA et al., Fund. Appl. Toxicol. 1 - ppm = x.1. = mg / m =. mg / L For continuous exposure =. x = 0. mg / L Daily dose = 0. x 0.0 kg = 1 mg / kg 1 1 x 0 1 x x 1 x x 1 = mg / day 1 1 Limit ppm = x 00 =,00 ppm Toxicity F rats exposed to 10,,00 or,000 ppm by inhalation h/day, days/week for 0 days. Decreased weight gain and increased liver weights at high dose only. No neuropathological or histopathological changes. NEL,00 ppm. Ref. Cavender FL et al., Fund. Appl. Toxicol ,00 ppm =,00 x.1. = mg / m =. mg / L For continuous exposure =. x x x = 1.1 mg / L draft page

40 Average wt g = 1.1 x 0 0. = mg / kg x 0 x x x 1 x 1 = 10 mg / day 10 x 00 = 1,000 ppm Cats 10 mg/kg s/c bid days/week for. months did not produce detectable nervous system damage. Ref. Spenser PS and Schaumberg HH. Toxicol. Appl. Pharmacol Dose/day = 00 mg/kg 1 1 For continuous exposure = 00 x = 1 mg / kg x 0 x x x 1 x 1 = mg / day Limit (ppm) = x 00 =,00 ppm No significant behavioural changes in rats in 0 day study dosed by gavage days/week at. m mole/kg. NOAEL. m mole/kg. Ref. Ralston WH et al., Toxicol. Appl. Pharmacol mmole / kg = 10 mg / kg draft page 0

41 For continuous dosing = 10 x = mg / kg x 0 x x x 1 x 1 =. mg / day. x 00 = 0 ppm Human Results There are no relevant data available. 1 1 Conclusion The 1 study in cats and the 1 study in rats are disregarded since they are single dose studies and no toxicity was detected. The PDE for methylethyl ketone is.0 mg/day. draft page 1

42 METHYLISOBUTYL KETONE Genotoxicity Negative is in vitro and in vivo studies. Ref. O Donoghue JL et al., Mut. Res Carcinogenicity Reproductive Toxicity Toxicity F rats exposed to 0, 0 or 00 ppm by inhalation h/day, days/week for 1 weeks. Slight increase in liver weight at high dose but no histopathological change. Slight increase in incidence and extent of hyaline droplets in proximal kidney tubule cells at 0 and 00 ppm. This is a rat-specific finding related to the occurrence of α µ globulin in that species. Virtual NEL =00 ppm. Ref. Phillips RD et al., Fund. Appl. Toxicol ppm = 00 x 0.1. = 0 mg / m =.1 mg / L 1 1 For continuous exposure =.1 x x x = 0. mg / L 0 1 Daily dose = 0. x 0 0. = mg / kg x 0 x x x 1 x 1 =. mg / day. x 00 =,0 ppm draft page

43 10 mg/kg S/C bid days/week for. months did not produce nervous system damage to cats. Ref. Spenser PS and Schaumburg HH. Toxicol. Appl. Pharmacol For continuous exposure = 00 x = 1 mg / kg 1 x 0 x x x 1 x 1 =. mg / day. x 00 =,0 ppm 1 1 Conclusion The 1 study in cats is disregarded since it is a single dose study and no toxicity was detected. The The PDE for methylisobutyl ketone is 0 mg/day. 1 draft page

44 -METHYL-1-PROPANOL Genotoxicity Negative results in Ames test. Ref. Shimizu H et al., Jpn. J. Ind. Health Carcinogenicity No suitable data available. Reproductive Toxicity 1 Animal Toxicity Acute oral LD0 in rats. g/kg. Ref. Merck Index th Edn Molar solution given as sole drinking fluid to rats for months did not produce any adverse reactions on liver. Ref. Hilbbom ME et al., Res. Commun. Chem. Path. Pharmacol. 1 (1) M = g/l = mg/ml 1 0 Rat consumes 0 ml/day 1 Daily dose = x 0 0. = mg / kg x 0 x x x 1 x 1 =. mg / day draft page

45 . x 00 =,0 ppm -methyl-1-propanol is a permitted direct food additive Ref. 1 CFR 1.1 (10) Conclusion The PDE for -methyl-1-propanol is. mg/day. draft page

46 1 PENTANE Genotoxicity Negative in Ames test. Ref. Kirwin CJ et al., J. Soc. Cosmet. Chem Carcinogenicity Reproductive Toxicity Animal Toxicity Rats exposed to 000 ppm by inhalation 1 h/day for 1 weeks did not develop peripheral nerve damage. Ref. Takeuchi Y et al., Br. J. Ind. Med. 10 () NEL 000 ppm = 000 x.1. = mg / m =. mg / L 1 1 Continuous exposure =. x 1 =. mg / L 1 1 Daily dose =. x 0 0. kg = 0 mg / kg x 0 x x x 1 x 1 = 0. mg / day 1 0. x 00 = 0,0 ppm Conclusion The PDE for pentane is 0. mg/kg. draft page

47 1-PENTANOL Genotoxicity Carcinogenicity Reproductive toxicity 1,000 mg/m by inhalation h/day, days 1-1 had no adverse effects on the foetuses of Sprague-Dawley rats. Ref. Nelson BK et al., J. Amer. Coll. Tox. 1 () 0-. 1, 000 mg / m = 1 mg/l 1 1 For continuous dosing = 1 x =.0 mg / L 1 1 Daily dose =.0 x 0 0. = mg / kg 1 1 x 0 x x 1 x 1 x 1 = mg / day 1 1 x 00 =,00 ppm 0 1 Animal toxicity 0, 10 and 00 mg/kg administered by gavage daily to ASH/CSE rats for 1 weeks produced no adverse effects. NEL 00 mg/kg. Ref. Butterworth KR et al., Fd. Cosmet. Toxicol. 1 1 () 0- draft page

48 00 x 0 x x x 1 x 1 = 00 mg / day 00 x 00 = 0,000 ppm 1-Pentanol is a permitted direct food additive. Ref. 1 CFR 1.1 (10). Conclusion The PDE for 1-pentanol is 00 mg/day. draft page

49 1 1 1-PROPANOL Genotoxicity Negative in vitro results in Ames test. Mouse lymphoma assay, SCE. Refs. Short Term Programs NCI 1 Mut Res. 1-. Carcinogenicity No suitable data available. Reproductive Toxicity Animal Toxicity Oral LD0 in rats 1. g/kg. Ref. Smyth HF et al., Arch. Ind. Hyg. Occup. Med Propanol is a permitted direct food additive Ref. 1 CFR 1.1 (10) draft page

50 -PROPANOL Genotoxicity Negative in vitro results in Ames tests and in transformation assay in SHE cells. Refs. Shimizu H et al., Ipn. J. Ind Health Zeiger E et al., Environ. Mol. Mutagen 1 1 (suppl1) - Mut Res 1-1 Carcinogenicity Mice exposed to 000ppm. hr/day days/week for months by inhalation. No tumourigenic activity when examined at 1 months of age. Ref. Neil CS et al., Arch. Ind. Hygien. Assoc. J Reproductive Toxicity A 1.% solution in drinking ware was administered to rats for generations. Other than a slight early growth retardation in the first generation, no adverse effects were seen. NOEL 1.%. Ref. Lehman A J et al., Pharmacul;. Exp. Therap % = 1.mL/0mL = 1. x 0.0 = 1.1 g/0 ml. Rat consumes 0 ml/day 1 0 Daily dose = 0 x 0 0 x 0. = mg / kg 1 x 0 x x 1 x 1 x 1 = mg / day x 00 =,00 ppm draft page 0

51 00, 00 or 100 mg/kg were administered by gavage to D rats daily from day -1. Deaths were noted in the dams at the intermediate and high levels. Foetal weights were reduced at the intermediate and high levels but no tertogenic on embryocellular effects were noted. NOEL 00mg/kg. Ref. 10 FDA Internal report Ref. SBJ x 0 x x 1 x 1 x 1 = 00 mg / day 00 x 00 = 0,000 ppm , 0 or 0 mg/kg were administered by gavage to NZW rabbits on days -1. Deaths and reduced maternal weight gain were noted in dams at the high dose level only. No adverse effects were noted in any of the foetuses. NOEL 0 mg/kg. Ref. 10 FDA Internalreport Ref. SBJ00001 : x 0. x x 1 x 1 x 1 = 0 mg / day x 00 =,000 ppm Animal Toxicity Male rats were given 0. or.% and females 1% or % in drinking water for months. Deaths, not thought to be associated with treatment, were noted in animals from the 0.% and.% groups. Decreased weight gain was noted in the female animals but there were no gross or microscopic changes at any dose level. Ref. Lehman AJ and Chase HF J. Lat. Med NOEL = 0.% = 0. ml/0 ml = 0. x 0.0 = 0. g/0 ml Daily dose = 0 x 0 0 x 0. = mg / kg draft page 1

52 x 0 x x x 1 x 1 = 1 mg / day 1 x 00 = 1,00 ppm Rhesus monkeys were given or 0 mg/kg by gavage for months. No adverse effects were noted. NOEL is 0 mg/kg. Ref. 1 FDA Internal Report Ref. SBJ00001 :-0. 0 x 0 x x x 1 x 1 = 1 mg / day 1 x 00 = 0 ppm 1 - Propanol is a permitted direct food additive. Ref. 1 CFR 1.1 (10) Conclusion The 1 study by the FDA in monkeys is disregarded since no toxicity was detected. The PDE for -propanol is 1 mg/day. draft page

53 PROPYL ACETATE Genotoxicity Carcinogenicity Reproductive Toxicity Animal Toxicity Oral LD0 in rats. g/kg. Ref. Merck Index th Edn 1 1 Propyl acetate is a permitted direct food additive. 1 CFR 1.1 (10) 1 draft page

54 1 1 TETRAHYDROFURAN Genotoxicity Negative in Ames test and SCE assay. Ref. Florin I. Et al., Toxicol Mortelmans K et al., Environ. Mut. 1 (Suppl ) 1- Galloway SM et al., Environ. Mol. Mutagen 1 (Suppl ) 1-1 Carcinogenicity Reproductive Toxicity 00, 00, or,000 ppm given by inhalation to SC rats h/day, days -1 of gestation. Reduced maternal weight gain and foetal weight at high dose level only but no abnormalities. NOEL 100 ppm. Ref Mast TJ et al., Fund. Appl. Toxicol NEL = 100 ppm = 100 x.. = 0 mg / m =.1 mg / L 1 1 For continuous dosing =.1 x = 1. mg / L 1 1 Daily dose = 1. x 0 0. = mg / kg 0 1 x 0 x x 1 x 1 x 1 = mg / day x 00 =,00 ppm draft page

55 CD-1 mice were given 00, 100, or 000 ppm by inhalation h/day on days -1. Deaths at high dose and sedation at intermediate and high levels. Reduced weight gain at 000 ppm. Increased incidence of intrauterine deaths at intermediate and high levels. No teratogenic effects. NOEL 00 ppm. Ref Mast TJ et al., Fund. Appl. Toxicol NEL = 00 ppm = 00 x.. = 1 mg / m = 1. mg / L For continuous dosing = 1. x = 0. mg / L Daily dose = 0. x 0.0 =. mg / kg 1. x 0 1 x x 1 x 1 x 1 = mg / day 1 1 x 00 = 1,00 ppm Toxicity Reported that 1,000 ppm by inhalation h/day, days/week for weeks produced no evidence of liver or kidney damage in rabbits. Ref. Oettel H - Personal communication to ACIG TLV committee 0 1 1,000 ppm = 1,000 x.. = 0 mg / m = 0 mg / L For continuous exposure = 0 x x x =. mg / L draft page

56 Daily dose =. x 10 = 0 mg / kg 0 x 0. x x x 1 x 1 = 1 mg / day 1 x 00 =,0 ppm F rats given, 00, 00, 100 or 000 ppm by inhalation h/day, days/week for 1 weeks. High dose level animals were ataxic and had slightly increased liver weights. Acanthosis and inflammation of the fore stomach were noted at the high dose only. NOEL 100 ppm. Ref. Chhabra RS et al., Fund. Appl. Toxicol NEL = 100 ppm = 100 x.. = 0 mg / m =.1 mg / L 1 1 For continuous dosing =.1 x x x = 0. mg / L 1 1 Daily dose = 0. x 0 0. =. mg / kg 1 1. x 0 x x x 1 x 1 = 1 mg / day x 00 = 1,00 ppm 1 BCF1 mice exposed to, 00, 00, 100, or 000 ppm by inhalation h/day, days/week for 1 weeks. Reduced weight gain, narcosis, and deaths at high dose level. Decreased thymic and spleen weights and increased liver weights at high dose. Mild draft page

57 centrilobular hepatocytomegaly in high dose level animals of both sexes and atrophy of uterus and degeneration of inner cortex of adrenal cortex in females. NOEL 100 ppm. Ref. Chhabra RS et al., Fund. Appl. Toxicol As above, 100 ppm = 0. mg/l continuous exposure Daily dose = 0. x 0..0 = 1 mg / kg 1 x 0 1 x x x 1 x 1 = mg / day x 00 = 1,0 ppm Human Results Conclusion The PDE for tetrahydrofuran is mg/day. draft page