1
2 APPENDIX 6.  TOXICOLOGICAL DATA FOR CLASS 3 SOLVENTS
draft 7 page 1 1
2 ACETIC ACID
3 Genotoxicity
4 Negative results in Ames tests.
5 Refs.  Zeiger E et al.,  Environ. Mol. Mutagen.  1992 19 (suppl21) 2-41
6 Mut.  Res  1986  168  69-240.
7
8 Carcinogenicity
9 No relevant data available
10
11 Reproductive Toxicity
12 Doses up to 1.6 g/kg administered by gavage to rabbits from days 6-18.  No material toxicity
13 and no adverse effects on the offspring NOEL 1.6g/kg..
14 Ref. 1974 FDA Internal report Ref. GRM000080 14:2702
15
1600 x 50
PDE  =   =  3200 mg/day
2.5 x 10 x 1 x 1 x 1
16
3200 x 1000
Limit  =     =  320,000 ppm
10
17
18 Animal Toxicity
19 Oral LD50 in rats is 3.53 g/kg.  Ref. Merck Index 10th Edn 1983
20 Acetic acid is a permitted direct food additive.  Ref. 21CFR 184.1005 (1990)
21
22 Conclusion
23 The PDE for acetic acid is 3200 mg/day.
draft 7 page 2 1 ACETONE
2 Genotoxicity
3 Negative in vitro results in Ames test, sister chromatid exchange assay, SHE cell
4 transformation assay and in DNA repair-deficient bacterial tests.  Also negative in vivo in
5 micronucleus test.
6 Refs. De Flora S et al.,  Mut. Res. 1984 133 (3) 161-78.
7 Zeiger E et al.,  Environ. Mol. Mutagen. 1992 19 (Suppl 21) 1-141.
8 Mut. Res. 1981 87 17.
9 Mut. Res. 1983 114 283-385.
10 Mut. Res. 1981 87 211-97.
11 Mut. Res. 1990 239 29-80.
12 Carcinogenicity
13 No increase in tumour incidence when 0.2 ml applied weekly to skin of CF1 mice for 2 years.
14 Ref. Zakova N et al.,  Fd. Chem. Toxicol. 1985 23 1081-9
15
16 0.2 ml  =  0.2 x 0.79  =  158 mg
17
158 x 1
18 For continuous dosing  =     =  22.6 mg
7
19
22.6 x 1000
20 Daily dose  =     =  807 mg / kg
28
21
807 x 50
22 PDE  =     =  336 mg/day
12 x 10 x 1 x 1 x 1
23
336 x 1000
24 Limit  =     =  33,600 ppm
10
25
draft 7 page 3 1 Reproductive toxicity
2 No suitable data available.
3
4 Animal toxicity
5 Oral LD50 in rats is 10.7 ml/kg.
6 Ref. Smyth HF et al.,  Ind. Hyg. J. 1965 23 95.
7
8 Rats given 19,000 ppm by inhalation 3 h/day, 5 days/week for 8 weeks showed no evidence
9 of toxicity.  Ref. Bruckner JV and Peterson RG.  Toxicol. Appl. Pharmacol. 1978 45 359.
10
19,000 x 58
11 19000 ppm  =     =  45,072 mg/ m3  =  45.1 mg/L
24.45 
12
45.1 x 3 x 5
13 For continuous dosing  =     =  4.03 mg/ L
24 x 7
14
4.03 x 290
15 Daily dose  =     =  2750 mg / kg
0.425
16
2750 x 50
17 PDE  =     =  275 mg/day
5 x 10 x 10 x 1 x 1
18
275 x 1000
19 Limit  =     =  27,500 ppm
10
20
21 F344 rats given 2,500;  5,000;  10,000, 20,000 and 50,000 ppm in drinking water for 13
22 weeks.  Weight gain was depressed and kidney changes were noted at the two highest
23 concentrations and at 50,000 ppm hypogonadism occurred in the testes.  NEL 10,000 ppm
24 (equivalent to 1050 mg/kg - time weighted average).
25 Ref. Dietz DD et al.,  Fund. Appl. Toxicol. 1991 17 347-60.
26
draft 7 page 4 1050 x 50
1 PDE  =     =  210 mg/day
5 x 10 x 5 x 1 x 1
2
210 x 1000
3 Limit  =     =  21,000 ppm
10
4
5 Conclusion
6 The PDE for acetone is 210.0  mg/day.
draft 7 page 5 1 ANISOLE
2
3 Genotoxicity
4 No data available.
5
6 Carcinogenicity
7 No data available.
8
9 Reproductive Toxicity
10 No data available.
11
12 Toxicity
13 Oral LD50 in rats reported as 3.7 g/kg and 4.29 g/kg.
14 Refs. Jenner PM et al., Food Cosmet. Toxicol. 1964 2 (3) 327-343
15 Smyth HF et al., Arch. Ind. Hyg. Occup. Med. 1954 10 61-68
16 Oral LD50 in mice 2.8 g/kg.
17 Ref. J. Pharmacol. Exp. Ther. 1946 88 400
18
19 Human
20 Anisole has GRAS status and is permitted for food use as an artificial flavouring substance.
21 Ref. 21 CFR 172.515
22
draft 7 page 6 1
2 1-BUTANOL
3 Genotoxicity
4 Negative results in Ames and SCE assays.
5 Refs. Jung R et al.,  Mut. Res. 1992 278 (4) 265-70
6 Conners T H et al.,  Toxicol. Lett. 1985 25 (1) 33-40
7 Mut. Res. 1986 168 69-240
8 Mut. Res. 1981 87 17-62
9 Carcinogenicity
10 No data available.
11 Reproductive toxicity
12 Teratogenic when administered into yolk sac of chick embryos.
13 Ref. McLaughlin J et al.,   Am. Ind. Hygien. Assoc. J. 1964 25 (3) 282-4.
14
15 Animal toxicity
16 Oral LD50 is 4.36 g/kg.
17 Ref. Smyth HF et al.,   Am. Ind. Hygien Occup. Med. J. 1951 4 119.
18
19 1-Butanol is a permitted direct food additive.
20 Ref. 21 CFR 172.515 (1988).
draft 7 page 7 1
2 2-BUTANOL
3 Genotoxicity
4 Negative in Ames and CHO assays.  Ref. Brook TM et al.,  Mutagen.  1988 3 227-232
5
6 Carcinogenicity
7 No data available
8
9 Reproductive Toxicity
10 Wistar rats given 0.3, 1.0 or 2.0% in drinking water, equivalent to 500.  1500 or 3000mg/kg,
11 for 8 weeks then mated.  The Fia generation was used for a toxicity study (see below).  The
12 foetuses of the Flb generation were examined at the end of pregnancy. (Dosing of generation
13 continues throughout.)  No maternal effects were noted but foetal weight was slightly
14 reduced at the high dose level only and there was evidence of retarded skeletal development.
15 NOEL is 1500mg/kg.  Ref. 1975 Internal FDA document. ASP 000145
16
1500 x 50
17 PDE  =     =  300 mg/day
5 x 10 x 5 x 1 x 1
18
300 x 1000
19 Limit  =     =  30,000 ppm
10
20
21 Animal Toxicity
22 A parent generation of Wistar rats was given 0.3, 1.0 or 2.0% in drinking water, equivalent to
23 500, 1500 or 3000 mg/kg, for 8 weeks then mated.  Dosing continued throughout pregnancy
24 and weaning.  The F1 generation was treated for 9 weeks then mated.  Daily continued
25 throughout pregnancy at the end of which the F1 generation was killed and examined (routine
26 laboratory examinations were performed and tissues were examined microscopically).  Kidney
27 changed comprising tubular degeneration and microcysts in the papilla were noted at the high
draft 7 page 8 1 dose level only.  NOEL 1%, equivalent to 1500 mg/kg.  Ref. 1975 internal FDA document
2 000145.
3
1500 x 50
4 PDE  =     =  300 mg/day
5 x 10 x 5 x 1 x 1
5
300 x 1000
6 Limit  =     =  30,000 ppm
10
7
8 Oral LD50 in rats is 6.5g/kg.  Ref. Merck index 10th Edn (1983)
9 2- Butanol is a permitted direct food additive.  Ref. 21CFR 172.515 (1990)
10
11 CONCLUSION
12 The PDE for 2-butanol is 300 mg/day.
draft 7 page 9 1
2 BUTYL ACETATE
3
4 Genotoxicity
5 Negative in Ames tests.  Ref. shimizu H et al.,  Sangyo lgaku 1985 27 400-419
6
7 Carcinogenicity
8 No data available
9
10 Reproductive Toxicity
11 No data available
12
13 Animal Toxicity
14 CD-1 mice were given 300, 1000 or 3000mg/kg in the diet daily for 90 days.  Reduced motor
15 activity, prostration, and laboured breathing were noted at the high dose level only and serum
16 cholesterol was reduced in this group .  Not microscopic changes were noted at any dose
17 level.  NOEL 1000mg/kg.  Ref. 1977 Internal FDA report Ref. FAP 8A3360 2:261
18
1000 x 50
19 PDE  =     =  83.3 mg/day
12 x 10 x 5 x 1 x 1
20
83.3 x 1000
21 Limit  =     =  8,300 ppm
10
22
23 Sprague-Dawley rats were given 600, 2000 or 6000 mg/kg daily by gavage for 90 days.  All
24 rats salivated after dosing but this was considered a response to the test of the material rather
25 than toxicity.  Reduced motor activity was seen at the intermediate and high levels with
26 lachrymation and prostration in a few high dose animals only.  High dose level animals
draft 7 page 10 1 showed reduced weight gain.  Stomach lesions were noted in the inter and high dose level
2 animals.  NOEL 600 mg/kg.  Ref. 1978  Internal FDA report  Ref. FAP 8A3360 5:1197
3
600 x 50
4 PDE  =     =  120 mg/day
5 x 10 x 5 x 1 x 1
5
120 x 1000
6 Limit  =     =  12,000 ppm
10
7
8 Oral LD50 in rats is 14.13g/kg.  Ref. Merck index 10th Edn 1983
9 Butyl acetate is a permitted direct food additive.  Ref. 21 CFR 172.515 (1990)
10
11 Conclusion
12 The PDE for butyl acetate is 83.3 mg/day.
draft 7 page 11 1
2 TERT-BUTYLMETHYL ETHER
3 Genotoxity
4 No data available.
5 Carcinogenicity
6 No oncogenic effects in F344 rats given 403, 3023 or 7977 ppm 6 h/day, 5 days/week for 2
7 years.  Ref. Chun JS et al., 1992 (summarised in IRIS report Document No. 537 1993).
8
7977 x 88.15
9 NEL  =  7977 ppm  =     =  28,760 mg/ m3  =  28.76 mg/ L
24.45
10
28.76 x 6 x 5
11 For continuous dosisng  =     =  5.14 mg/ L
24 x 7
12
5.14 x 290
13 Daily dose  =     =  3507 mg/ kg
0.425 kg
14
3507 x 50
15 PDE  =     =  3507 mg/day
5 x 10 x 1 x 1 x 1
16
3507 x 1000
17 Limit  =     =  350,700 ppm
10
18
19 Reproductive Toxicity
20 Sprague-Dawley rats given 250, 1000, or 2,500 ppm by inhalation on days 6-15.  No maternal
21 toxicity and no adverse effects on litters. Ref. Conway CC et al.,  J. Tox. Environ.Health
22 1985 16 797-809
23
2500 x 88.15
24 NEL  =  2500 ppm  =     =  9013 mg/ m3  =  9.01 mg/L
24.45
draft 7 page 12 1
9.01 x 6
2 For continuous dosing  =     =  2.25 mg/ L
24
3
2.25 x 290
4 Daily dose  =     =  1977 mg/ kg
0.33 kg
5
1977 x 50
6 PDE  =     =  1977 mg/day 
5 x 10 x 1 x 1 x 1
7
1977 x 1000
8 Limit  =     =  197,700 ppm
10
9
10 CD-1 mice given 250, 1000, or 2,500 ppm by inhalation 6h/day, days 6-15.  No maternal
11 effects and no adverse effects on litters. Ref. Conway CC et al.,  J. Tox. Environ.Health 1985
12 16 797-809.  As above, continuous exposure = 2.25 mg/L.
13
2.25 x 43
14 Daily dose  =     =  3225 mg/ kg
0.03 kg
15
3225 x 50
16 PDE  =     =  1344 mg/day 
12 x 10 x 1 x 1 x 1
17
1344 x 1000
18 Limit  =     =  134,400 ppm
10
19
20 No adverse effects on litters when male Sprague-Dawley rats exposed by inhalation to 300,
21 1300 or 3400 ppm 6h/day, 5 day/week for 12 weeks then mated to females dosed for 3 weeks
22 pre-mating and throughout gestation and from days 5-21 of lactation.
23 Ref. Biles RW et al.,  Tox Ind. Health 1987 3 (4) 519-34.
24
draft 7 page 13 3400 x 88.15
1 NEL  =  3400 ppm  =     =  12,258 mg/ m3  =  12.26 mg/ L
24.45
2
12.26 x 6 x 5
3 For continuous dosing  =     =  2.19 mg/ L
24 x 7
4
2.19 x 290
5 Daily dose  =     =  1925 mg / kg
0.33 kg
6
1925 x 50
7 PDE  =     =  1925 mg/day 
5 x 10 x 1 x 1 x 1
8
1925 x 1000
9 Limit  =     =  192,500 ppm
10
10
11 Animal Toxicity
12 F344 rats exposed by inhalation to 403, 3023 or 7977 ppm 6 h/day, 5 days/week for 2 years.
13 Chronic progressive nephropathy in males associated with a 2  globulin toxicity.  This has
14 been shown to be of no relevance for humans since they do not produce that protein.
15
16 In females, which do not produce a 2  globulin, chronic progressive nephropathy was also
17 seen.  NEL 403 ppm.
18 Ref. Chun JS et al.,1992 (summarised in IRIS report Document No. 537, 1993)
19
403 x 88.15
20 NEL  =  403 ppm  =     =  1453 mg/ m3  =  1.45 mg/ L
24.45
21
1.45 x 6 x 5
22 For continuous dosing  =     =  0.26 mg/ L
24 x 7
23
0.26 x 290
24 Daily dose  =     =  177 mg / kg
0.425 kg
draft 7 page 14 1
177 x 50
2 PDE  =     =  177 mg/day
5 x 10 x 1 x 1 x 1
3
177 x 1000
4  Limit  =     =  17,700 ppm
10 
5
6 Conclusion
7 The PDE for tert-butylmethyl ether is 177 mg/day.
draft 7 page 15 1
2 CUMENE
3 Genotoxicity
4 Negative results in Ames test and in Saccharomyces cerevisiae.  Positive in in vitro UDS and
5 in cell transformation assays using mouse embryo cells.
6 Refs. Mut. Res. 1986 168 69-240.
7 Mut. Res. 1984 133 199-244.
8 EPA Fiche OTS 0509712 (1984)
9 Carcinogenicity
10 No data available.
11 Reproductive Toxicity
12 No data available.
13
14 Animal Toxicity
15 No adverse effects noted in rats exposed to 146 mg/m3 continuously by inhalation for 4
16 months.  Ref. Jenkins LJ et al.,  Toxicol. Appl. Pharmacol. 1970 16 (3) 818-23.
17
18 146 mg/m3  =  0.146 mg/ L
19
0.146 x 290
20 Daily dose  =     =  99.6 mg/ kg
0.425
21
99.6 x 50
22 PDE  =     =  19.9 mg/day
5 x 10 x 5 x 1 x 1
23
19.9 x 1000
24 Limit  =     =  1990 ppm
10
25
draft 7 page 16 1 Female Wistar rats given 154, 462 and 769 mg/kg by gavage 5 days/week for 6 months.  No
2 histopathological changes but slight increases in kidney weights at two higher doses.  NEL
3 154 mg/kg.  Ref. Wolf MA et al.,  Arch. Ind. Health 1956 14 387-98.
4
154 x 5
5 For continuous dosing  =     =  110 mg/ kg
7
6
110 x 50
7 PDE  =     =  55 mg/day
5 x 10 x 2 x 1 x 1
8
55 x 1000
9 Limit  =     =  5500 ppm
10
10
11 Conclusion
12 The 1970 study is disregarded since only a single dose was administered and no effect was
13 detected.  The PDE for cumene is 55.0 mg/day.
14
draft 7 page 17 1
2 DIMETHYL SULFOXIDE
3
4 Genotoxicity
5 Negative in vitro results in Ames and other bacterial tests, CHO cells, and in host mediated
6 assay.
7 Conflicting results in mouse lymphoma assay.
8 Refs. Brams A et al.,  Toxicol. Lett. 1987 38 123-33
9 Zeiger E et al., Environ. Mol. Mutagen. 1992 19 (Suppl 21) 2-141
10 Fluck ER et al., Chem. Biol. Interact. 1976 15 219-31
11 Takehisa S and Wolff S.  Mut. Res. 1978 58 103-6
12 Hrelia P et al.,  Terat. Carcinogen. Mutagen. 1990 10 263-71
13 Wangenheim J and Bolcsfoldi G.  Mutagen. 1988 3 (3) 193-205
14 Amacher DE et al.,  Mut. Res. 1980 72 447-74.
15 Carcinogenicity
16 Dermal application of 100 mg 3 times weekly to skin opf ICR/Ha mice for 663 days did not
17 cause skin damage or tumours (only skin examined).
18 Ref. Van Duuren BL et al.,  J. Ntl. Cancer Inst. 1967 39 1217-28
19
100 x 1000
20 100 mg to mice weighting 28g  =     =  3571 mg/ kg
28
21
3571 x 3
22 For continuous dosing  =     =  1530 mg / kg
7
23
1530 x 50
24 PDE  =     =  6375 mg/day
12 x 10 x 1 x 1 x 1
25
draft 7 page 18 6375 x 1000
1 Limit  =     =  637,500 ppm
10
2
3 No tumours in mice dosed with 5 ml/kg orally daily for 50 weeks.  (Time of autopsy not
4 stated).  Ref. Kanisawa M and Suzuki S.  Gann 1978 69 599-600
5
6 5 ml/ kg  =   5 x 1.1  =  5,500 mg/ kg
7
5,500 x 50
8 PDE  =     =  229 mg/day
12 x 10 x 10 x 1 x 1
9
229 x 1000
10 Limit  =     =  22,900 ppm
10
11
12 No tumours seen at injection sites after s/c administration of 0.05 ml weekly to ICR/Ha mice
13 for 76 weeks.  Ref. Van Duuren BL et al.,  J. Nell. Cancer Inst. 1971 46 143-49
14
15 0.05 ml  =  0.05 x 1.1  =  55 mg
16
55 x 1000
17 55 mg to mice weighing 28 g  =     =  1964 mg/ kg
28
18
1964 x 1
19 For continuous dosing  =     =  281 mg/ kg
7
20
281 x 50
21 PDE  =     =  117 mg/day
12 x 10 x 1 x 1 x 1
22
117 x 1000
23 Limit  =     =  11,700 ppm
10
24
draft 7 page 19 1 Reproductive Toxicity
2 Oral dose of 5 g/kg to Wistar rats for 4 days pre-mating and throughout pregnancy had no
3 effects on mother or offspring.
4 Ref. Caujolle FM et al.,  C.R. Acad. Sci. Paris 1964 258 (13) 2224-6
5
5000 x 50
6 PDE  =     =  5000 mg/day
5 x 10 x 1 x 1 x 1
7
5000 x 1000
8 Limit  =     =  500,000 ppm
10
9
10 Swiss mice given 5-12 g/kg orally days 6-12 showed no increase in foetal deaths or reduction
11 in foetal weight and no abnormalities were observed although maternal toxicity was seen at all
12 except the lowest level.  Ref. Caujolle FM et al.,  Ann NY Acad. Sci. 1967 141 110-25
13
5000 x 50
14 PDE  =     =  2083 mg/day
12 x 10 x 1 x 1 x 1
15
2083 x 1000
16 Limit  =     =  208,300 ppm
10
17
18 Hamsters given 50 to 8250 mg/kg IV on day 8.  No evidence of maternal toxicity.  Increases
19 in foetal deaths at 5500 mg/kg and teratogenic effect from 2,500 mg/kg: exencephaly, cleft
20 lip, and skeletal abnormalities.  NEL 1000 mg/kg.  Ref. Ferm VH  J.Embryol. Exp. Morph.,
21 1966 16 (1) 49-54
1000 x 50
22 PDE  =     =  50 mg/day
10 x 10 x 1 x 1 x 10
23
50 x 1000
24 Limit  =     =  5000 ppm
10
25
draft 7 page 20 1 Animal Toxicity
2 Dogs dosed orally at 2.5, 5, 10, 20 and 40 g/kg 5 days/week for 23 weeks showed changes in
3 lens refractiveness making the lens clearer rather than translucent.  No changes were detected
4 histologically. LOEL = 2.5 g/kg = 2,500 mg/kg.
5 Ref. Rubin LF and Mattis PA  Science 1966 153 83-4
6
2,500 x 5
7 For continuous dosing   =     =  1786 mg / kg
7
8
1786 x 50
9 PDE  =     =  2233 mg/day
2 x 10 x 2 x 1 x 1
10
2233 x 1000
11 Limit  =     =  223,300 ppm
10
12
13 1, 3 and 9 ml/kg of 90% solution given orally to rhesus monkeys daily for 18 months.
14 Deaths at high dose. NEL 3 ml/kg.  Ref. Vogin EE et al.,  Toxicol. Appl. Pharmacol. 1970 16
15 606-12.
16 3 mL/kg = 3 x 1.1 x 1000 x 90% = 2970 mg/kg
17
2970 x 50
18 PDE  =     =  297 mg/day
10 x 10 x 5  x 1 x 1
19
297 x 1000
20 Limit  =     =  29,700 ppm
10
21
22 2 and 5 g/kg of 50% solution given orally for 45 days to Wistar rats.  High dose caused
23 reduced weight gain and some liver damage.  NEL 1 g/kg.
24 Ref. Caujolle FM et al.,  Ann NY Acad. Sci. 1967 141 110-25
25
draft 7 page 21 1000 x 50
1 PDE  =     =  50 mg/day
10 x 10 x 10 x 1 x 1
2
50 x 1000
3 Limit  =     =  5,000 ppm
10
4
5 Conclusion
6 The PDE for dimethyl sulfoxide is 50 mg/day.
draft 7 page 22 1
2 ETHANOL
3 Genotoxicity
4 Negative results in Ames tests and in vitro cytogenetic studies with CHO and SHE cells.
5 Refs. Lin YC et al.,  Mut. Res 1989 216 (2) 93-9.
6 Zeiger E et al.,  Environ. Mol. Mutagen 1992 19 (Suppl 21) 2-141.
7 Murt Res 1983 14 283-385.
8 Carcinogenicity
9 A 40% solution administered by gavage twice weekly for 78 weeks to male and female BDVI
10 rats had no oncogenic effects. Volume administered not stated.  Ref. Griciute L et al., Cancer
11 Letters 1986 31 267-75.
12 Reproductive Toxicity
13 Up to 16,000 ppm by inhalation 7 h/day, days 1-20 had no effects on outcome of pregnancy
14 in Wistar rats.
15 Negative results when males dosed for 6 weeks at same level then mated to untreated
16 females. Ref. Nelson BK et al., Neurobehavr. Toxicol. Teratol. 1985 7 779-83.
17
16000 x 46.07
18 NEL  =  16000 ppm  =     =  30148 mg/ m3  =  30.1 mg/ L
24.45
19
30.1 x 7
20 Continuous exposure  =     =  8.8 mg/ L
24 
21
8.8 x 290
22 Daily dose  =     =  7733 mg / kg
0.33 kg
23
7733 x 50
24 PDE  =     =  7733 mg/day
5 x 10 x 1 x 1 x 1
25
draft 7 page 23 7733 x 1000
1 Limit  =     =  773,300 ppm
10
2
3 Single I/P doses of  2, 4, 6, and 7g/kg given I/P to CD-1 mice on day 10.  Increased foetal
4 deaths at high dose and reduced foetal weight at 6 and 7 g/kg.  Cleft palate noted at
5 foetotoxic levels.  Maternal effects not reported.  NEL 4 g/kg.
6 Ref. Blakley PM and Scott WJ.  Toxicol. Appl. Pharmacol. 1984 72 (2) 355-63.
7
4000 x 50
8 PDE  =     =  166.7 mg/day
12 x 10 x 1 x 10 x 1
9
166.7 x 1000
10 Limit  =     =  16,670 ppm
10
11
12 Animal Toxicity
13 Oral LD50 in rats 13.7 ml/kg.
14 Ref. Verschueren K ed in Handbook of Environmental Data of Organic Chemicals 2nd Edn.
15 New York 1983.  Ethanol is a permitted direct food additive. Ref. 21 CFR 184 - 1293 (1990)
16
17 Rat iv LD50 = 0.96 mL/kg for males, 1.15 mL/kg for females.
18 Dog iv LD0 >0.52 mL/kg.  Ref.  Shirai, M., et al., 1996, Jpn Pharmacol Ther 24, 309-322
19
-1  -1
20 4-week repeat dose in dogs NEL 0.01 mL kg day
21 Ref. Pukutome, A. et al., 1996, Jpn Pharmacol Ther 24, 323-348
22
23 Human
24 The workplace exposure limit for ethanol (TLV-TWA) is 1000 ppm, equal to 1880 mg per
25 cubic meter.  Assuming inhalation of 10 cubic meters during an 8-h workday, total daily
26 ethanol intake is 18.8 g, or 376 mg/kg.  The TLV is designed to avoid eye and upper
27 respiratory tract irritation, and does not reflect concern about systemic toxicity.
draft 7 page 24 1 Ref. American Conference of Governmental Industrial Hygienists, Documentation of the
2 Threshold L:imit Values and Biological Exposure Indices, 1991, ACGIH Inc.
3
4 The maximum recommended social consumption of alcoholic drinks in the UK is 21
5 units/week for men and 14 units per week for women, where a unit is equivalent to 275 mL of
6 standard beer or lager (4% alcohol).  Based on 2 units per day, a daily alcohol intake of 275 x
7 2 x 0.04 = 22 mL/day = 17,360 mg/day  is considered to be without significant risk to
8 women.  Ref. UK Department of Health Guidelines, latest revision 1995.
9
10 Ethanol is a permitted direct food additive.  Ref. 21 CFR 184-1293 (1990)
11
12 Conclusion
13 The PDE for ethanol is 166.7 mg/day.
draft 7 page 25 1 ETHYL ACETATE
2 Genotoxicity
3 Negative results in vitro in Ames tests and in vivo in micronucleus test in Chinese hamsters.
4 Refs. Zeiger E et al., Environ. Mol. Mutagen 1992 19 (Suppl 21) 2-141
5 NTP Fiscal Year 1987 Annual Plan. NTP - 87-001
6 Basler A. Mut. Res. 1986 174 (1) 11-13.
7 Carcinogenicity
8 No data available.
9 Reproductive Toxicity
10 No data available.
11 Animal Toxicity
12 Oral LD50 in rats 11.3 ml/kg.
13 Ref. Merck Index 10th Edn. 1983.
14
15 Rats given 2000 ppm 4 h/day, 5 days/week for 13 weeks showed no adverse effects on
16 bodyweight or haematological measurements.
17 Ref. Quoted in American Conference of Governmental Industrial Hygienists.  Documentation
18 of the TLV and Biological Exposure Indices 5th Edn. 1986.
19
2000 x 88.10
20 2000 ppm  =   7207 mg/ m3  =  7.2 mg/ L
24.45
21
7.2 x 4 x 5
22 Continuous exposure  =     =  0.86 mg/ L
24 x 7
23
0.86 x 290
24 Daily dose  =     =  587 mg / kg
0.425 kg
25
draft 7 page 26 587 x 50
1 PDE  =     =  117 mg/day
5 x 10 x 5 x 1 x 1
2
117 x 1000
3 Limit  =     =  11,700 ppm
10
4
5 Ethyl acetate is a permitted direct food additive.  Ref. 21 CFR 182.60.
6
7 Ethyl acetate is exempt from certification needs for use as a diluent in inks for marking fruit
8 and vegetables under section 706 (c) of the Federal Food, Drug and Cosmetic Act.
9 Ref. 21 CFR 73.1 (1990).
10
11 Conclusion
12 The PDE for ethyl acetate is 117 mg/day.
draft 7 page 27 1
2 ETHYL ETHER
3 Genotoxicity
4 Negative results in Ames test.
5 Ref. Waskell L.  Mut. Res. 1978 57 141-53
6 Carcinogenicity
7 No data available.
8 Reproductive toxicity
9 CD-1 mice were maintained anaesthetised from day 13.5 to 15.5 of gestation.  No cleft palate
10 was produced.  Actual dosage administered not stated.  Ref. Jacobs RM Teratol. 19 4, 699-
11 74
12
13 Animal toxicity
14 Oral LD50 in rats is approx 2 mL/kg.
15 Ref. Kimura ET et al.,  Toxicol. Appl. Pharmacol. 1971 19 699-74.
draft 7 page 28 1
2 ETHYL FORMATE
3
4 Genotoxicity
5 Negative in Ames test (Salmonella strains and Saccharomyces cerevisiae) with and without
6 metabolic activation.
7 Ref. Litton Bionetics Project No. 2468, Mutagenic Evaluation of Compound Ethyl Formate
8 (FDA 75-49) 1976
9
10 Carcinogenicity
11 A/He mice given ip injections 3 times/week for 8 weeks (total doses of 2.4 or 12.0 g/kg), and
12 examined for primary lung tumours 24 weeks after the first dose, showed no excess over
13 controls.
14 Ref. Stoner GD et al., Cancer Res. 1973 33 3069-3085
15
16 'S' strain mice treated dermally with 18 weekly applications of croton oil, and for the first 10
17 weeks with 0.3 mL/week ethyl formate (total dose 2.76 g), did not have skin cancers when
18 they were killed and examined one week after the last treatment with croton oil.
19 Ref. Roe FJC and Salaman MH British J. Cancer (1955) 9 177-203
20
21 Reproductive Toxicity
22 No data available.
23
24 Toxicity
25 Oral LD50 in rats 1850 mg/kg.
26 Oral LD50 in guinea pigs 1110 mg/kg.
27 Ref. Jenner PM et al., Food Cosmet. Toxicol. 1964 2 (3) 327-343
28 Oral LD50 in rabbits 2075 mg/kg.  Ref. Munch JL Ind. Med. Surg. 1972 41 (4) 31
29
30 Osborne-Mendel rats given 1000, 2500 or 10000 ppm in the diet for 17 weeks showed no
31 macroscopic effects, or microscopic findings in major organs. NEL 10000 ppm.
32 Ref. Hagan EC et al., Food Cosmet. Toxicol. 1967 5 141-157
33 Assume rat consumes 30 g/day.
draft 7 page 29 1
30 x 10
Daily dose  =     =  705.9 mg/kg
0.425
705.9 x 50
2 PDE  =     =  141.2 mg/day
5 x 10 x 5 x 1 x 1
141.2 x 1000
Limit  =     =14,120 ppm
10
3
4 Human
5 Ethyl formate has GRAS status, and is a permitted food additive.  Ref. 21 CFR 172.515
6
7 Conclusion
8 The PDE for ethyl formate is 141.2 mg/day.
9
draft 7 page 30 1
2 FORMIC ACID
3 Genotoxicity
4 Negative in Ames test.
5 Ref. Zeiger E et al., Environ. Mol. Mutagen 1992 19 (Suppl 21) 2-141
6 Carcinogenicity
7 No data available
8 Reproductive Toxicity
9 No data available
10 Animal Toxicity
11 Rats given 8 to 360 mg/kg in drinking water for up to 27 weeks showed only reduced weight
12 gain at highest dose.  Virtual NEL   360 mg/kg.
13 Ref. Malorny G. Z. Ernaehrungswiss 1969 9 332-9
14
360 x 50
15 PDE  =     =  180 mg/day
5 x 10 x 2 x 1 x 1 
16
180 x 1000
17 Limit  =     =  18,000 ppm
10
18
19 F344/N rats and B6C3F1 mice were given 8, 16, 32, 64, or 128 ppm by inhalation 6 h/day, 5
20 days per week for 13 weeks.  Two mice died at the highest dose level and body weight gain in
21 mice was reduced at the 64 and 128 ppm levels.  Lesions were generally limited to the highest
22 dose in both species and comprised squamous metaplasia and degeneration of the respiratory
23 and olfactory epithelia.  The changes are consistent with the administration of an irritant
24 chemical by the inhalation route.  There was no evidence of systemic toxicity.
25 Ref . NTP Tech Report Tox 19, 1992.  NOAEL for irritancy 32 ppm in both species.
26
32 x 46.02
27 32 ppm  =     =  60.2 mg/ m3  =  0.06 mg/ L
24.45
draft 7 page 31 1
0.06 x 6 x 5
2 Continuous exposure  =     =  0.011 mg/ L
24 x 7
3
0.011 x 290
4 Rat daily dose  =     =  7.51 mg/ kg
0.425 kg
5
7.51 x 50
6 PDE  =     =  1.5 mg/day
5 x 10 x 5 x 1 x 1
7
1.5 x 1000
8 Limit  =     =  150 ppm
10
9
0.011 x 43
10 Mouse daily dose  =     =  16.9 mg/ kg
0.028 kg
11
16.9 x 50
12 PDE  =     =  1.4 mg/day
12 x 10 x 5 x 1 x 1
13
1.4 x 1000
14 Limit  =     =  140 ppm
10
15
16
17 Formic acid is a permitted direct food additive. Ref. 21 CFR 172.515 (1990)
18
19 Conclusion
20 The inhalation study is disregarded since no systemic toxicity was noted.  The PDE for formic
21 acid is 180.0 mg/day.
draft 7 page 32 1
2 HEPTANE
3 Genotoxicity
4 No data available.
5 Carcinogenicity
6 No data available.
7 Reproductive Toxicity
8 No data available.
9 Toxicity
10 Wistar rats given 3000 ppm 12 h/day 7 days/week for 16 weeks.   Slight effect on weight gain
11 but no effects on motor nerve conduction velocity, mixed nerve conduction velocity or distal
12 latency.   NEL 3000 ppm. Ref. Takeuchi Y et al.,  Clin. Tox. 1981 18 (12) 1395-1402
13
3000 x 100.2
14 3000 ppm  =     =  12294 mg/ m3  =  12.3 mg/ L
24.45
15
12.3 x 12
16 For continuous exposure  =     =  6.15 mg/ L
24
17
6.15 x 290
18 Daily dose  =     =  4,196 mg/ kg
0.425
19
4196 x 50
20 PDE  =     =  840 mg/day
5 x 10 x 5 x 1 x 1
21
840 x 1000
22 Limit (ppm)  =     =  84,000 ppm
10
23 Conclusion
24 The PDE for heptane is 840 mg/day.
draft 7 page 33 1
2 ISOBUTYL ACETATE
3 Genotoxicity
4 Data not available.
5 Carcinogenicity
6 Data not available.
7 Reproductive Toxicity
8 Data not available.
9
10 Animal Toxicity
11 Oral LD50 in rats is 15.4 ml/kg.
12 Ref. Smyth HF et al.,  Am. Ind. Hyg. Assoc. J. 1962 23 95.
13
14 Given GRAS status by FEMA 1965.
15
16 Isobutyl acetate is a permitted direct food additive.
17 Ref. 21 CFR 172. 515 (1990)
draft 7 page 34 1
2 ISOPROPYL ACETATE
3 Genotoxicity
4 Negative in Ames test.
5 Ref. Zeiger E et al.,  Environ. Mol. Mutagen 1992 19 (Suppl 21) 2-141.
6 Carcinogenicity
7 No data available.
8 Reproductive Toxicity
9 No data available.
10
11 Animal Toxicity
12 Oral LD50 in rats 6.75 g/kg.
13
14 Ref. Merck Index 10th Edn. 1983.
15
16 Isopropyl acetate is a permitted direct food additive
17 Ref. 21 CFR 172.515 (1990)
18
draft 7 page 35 1 METHYL ACETATE
2 Genotoxicity
3 Negative in Ames tests.
4 Ref. Zeiger E. et al.,  Environ. Mol. Mutagen 1992 19 (Suppl 21) 2-141.
5 Carcinogenicity
6 No data available.
7 Reproductive Toxicity
8 No data available.
9
10 Animal Toxicity
11 Oral LD50 in rats 3.7 g/kg.
12 Ref. Reported in Pattys Industrial Hygiene and Toxicology. 3rd Edn. New York 1982.
13
14 Methyl acetate is a permitted direct food additive.
15 Ref. 21 CFR 172.515 (1990).
16
draft 7 page 36 1
2 3-METHYL-1-BUTANOL
3 Genotoxicity
4 No data available.
5 Carcinogenicity
6 No suitable data available.
7 Reproductive Toxicity
8 No teratogenic effects were seen when 8 mg was injected into the yolk sac of chick embryos.
9 Higher doses caused the death of the embryos.
10 Ref. McLaughlin J et al.,  Am. Ind. Hyg. Assoc. J. 1964 25 282-4.
11 Animal Toxicity
12 No adverse effects when 150, 500 or 1000 mg/kg given orally to Ash/LSE rats daily for 17
13 weeks.
14 Ref. Carpanini FMB et al.,  Fd. Cosmet. Toxicol. 1973 11 713-24.
15
16 NEL  =  1000 mg/ kg
17
1000 x 50
18 PDE  =   =  200 mg/day
5 x 10 x 5 x 1 x 1
19
200 x 1000
20 Limit  =      =  20,000 ppm
10
21
22 3-methyl-1-butanol is a permitted direct food additive.  Ref. 21 CFR 172.515 (1990)
23
24 Conclusion
25 The PDE for 3-methyl-1-butanol is 200 mg/day.
draft 7 page 37 1
2 METHYLETHYL KETONE
3 Genotoxicity
4 Negative results in wide range of in vitro tests and in MNT using mice and hamsters
5 Refs. ODonoghue JL et al., Mut. Res. 1988 206 149-61
6 EPA Doc No. 878210125 Fiche No. 206206 (1982)
7 Basler A. Mut. Res. 1986 174 11-13
8 Carcinogenicity
9 No oral or inhalation carcinogenicity data available.
10 Reproductive Toxicity
11 Rats Exposure to 412, 1002 or 3005 ppm by inhalation 7 h/day, days 6-15 caused decreased
12 maternal weight gain and mild developmental retardation at the high dose only.  NEL 1002
13 ppm.  Ref. Deacon MM et al., Toxicol. Appl. Pharmacol. 1981 59 (3) 620-22
14
1002 x 72.1
15 1002 ppm  =     =  2955 mg/ m3  =  2.96 mg/ L
24.45
16
2.96 x 7
17 For continuous exposure  =     =  0.86 mg/ L
24
18
0.86 x 290
19 Daily dose  =     =  756 mg/kg
0.33
20
756 x 50
21 PDE  =     =  756 mg/day
5 x 10 x 1 x 1 x 1
22
756 x 1000
23 Limit  =     =  75,600 ppm
10
24
draft 7 page 38 1 Mice
2 Swiss mice given 398, 1010 or 3,020 ppm by inhalation 7 h/day, days 6-15.  Slightly
3 decreased foetal weight at high dose only but no materanl effects.  NEL 1010 ppm.
4 Ref. Schwetz BA et al., Fund. Appl. Toxicol. 1991 16 742-48
5
1010 x 72.1
6 1010 ppm  =     =  2978 mg/ m3  =  2.98 mg/ L
24.45
7
2.98 x 7
8 For continuous exposure  =     =  0.869 mg/ L
24
9
0.869 x 43
10 Daily dose  =     =  1246 mg/ kg
0.03 kg 
11
1246 x 50
12 PDE  =     =  104 mg/day
12 x 10 x 1 x 5 x 1
13
104 x 1000
14 Limit ppm  =     =  10,400 ppm
10
15
16 Toxicity
17 F344 rats exposed to 1250, 2,500 or 5,000 ppm by inhalation 6 h/day, 5 days/week for 90
18 days.  Decreased weight gain and increased liver weights at high dose only.  No
19 neuropathological or histopathological changes.  NEL 2,500 ppm.
20 Ref. Cavender FL et al., Fund. Appl. Toxicol. 1983 3 264-70
21
2,500 x 72.1
22 2,500 ppm  =     =  7372 mg/ m3  =  7.37 mg/ L
24.45
23
7.37 x 6 x 5
24 For continuous exposure  =     =  1.316 mg/ L
24 x 7
draft 7 page 39 1
1.316 x 290
2 Average wt 425 g  =     =  898 mg / kg
0.425
3
898 x 50
4 PDE  =     =  180 mg/day
5 x 10 x 5 x 1 x 1
5
180 x 1000
6 Limit  =     =  18,000 ppm
10
7
8 Cats
9 150 mg/kg s/c bid 5 days/week for 8.5 months did not produce detectable nervous system
10 damage.  Ref. Spenser PS and Schaumberg HH. Toxicol. Appl. Pharmacol. 1976 37 301-11
11 Dose/day = 300 mg/kg
12
300 x 5
13 For continuous exposure  =   =  214 mg / kg
7 
14
214 x 50
15 PDE  =     =  54 mg/day
10 x 10 x 2 x 1 x 1
16
54 x 1000
17 Limit (ppm)  =   =  5,400 ppm
10
18
19 No significant behavioural changes in rats in 90 day study dosed by gavage 5 days/week at
20 2.2 m mole/kg. NOAEL 2.2 m mole/kg.
21 Ref. Ralston WH et al.,  Toxicol. Appl. Pharmacol. 1985 81 319-27.
22
23
24 2.2 mmole/kg  =  160 mg/ kg
draft 7 page 40 1
160 x 5
2 For continuous dosing  =     =  114 mg/ kg
7
3
114 x 50
4 PDE  =     =  22.8 mg/day
5 x 10 x 5 x 1 x 1
5
22.8 x 1000
6 Limit  =     =  2280 ppm
10 
7
8 Human Results
9 There are no relevant data available.
10
11 Conclusion
12 The 1976 study in cats and the 1985 study in rats are disregarded since they are single dose
13 studies and no toxicity was detected.  The PDE for methylethyl ketone is 104.0 mg/day.
draft 7 page 41 1
2 METHYLISOBUTYL KETONE
3 Genotoxicity
4 Negative is in vitro and in vivo studies.
5 Ref.  ODonoghue JL et al.,  Mut. Res. 1988 206 149-61
6 Carcinogenicity
7 No data available.
8 Reproductive Toxicity
9 No data available.
10 Toxicity
11 F344 rats exposed to 50, 250 or 1000 ppm by inhalation 6 h/day, 5 days/week for 14 weeks.
12 Slight increase in liver weight at high dose but no histopathological change.  Slight increase in
13 incidence and extent of hyaline droplets in proximal kidney tubule cells at 250 and 1000 ppm.
14 This is a rat-specific finding related to the occurrence of 2-a  m globulin in that species. Virtual
15 NEL =1000 ppm. Ref. Phillips RD et al., Fund. Appl. Toxicol.1987 9 380-88
16
1000 x 100.16
17 1000 ppm  =     =  4097 mg/ m3  =  4.1 mg/ L
24.45
18
4.1 x 6 x 5
19 For continuous exposure  =     =  0.73 mg/L
24 x 7
20
0.73 x 290
21 Daily dose  =     =  498 mg/kg
0.425
22
498 x 50
23 PDE  =     =  99.6 mg/day
5 x 10 x 5 x 1 x 1
24
99.6 x 1000
25 Limit  =     =  9,960 ppm
10
draft 7 page 42 1
2 150 mg/kg S/C bid 5 days/week for 8.5 months did not produce nervous system damage to
3 cats. Ref.  Spenser PS and Schaumburg HH.  Toxicol. Appl. Pharmacol. 1976 37 301-11
4
300 x 5
5 For continuous exposure  =     =  214 mg/ kg
7
6
214 x 50
7 PDE  =     =  53.5 mg/day
10 x 10 x 2 x 1 x 1
8
53.5 x 1000
9 Limit  =     =  5,350 ppm
10
10
11 Conclusion
12 The 1976 study in cats is disregarded since it is a single dose study and no toxicity was
13 detected. The The PDE for methylisobutyl ketone is 100 mg/day.
14
draft 7 page 43 1
2 2-METHYL-1-PROPANOL
3 Genotoxicity
4 Negative results in Ames test.
5 Ref. Shimizu H et al.,  Jpn. J. Ind. Health 1985 27 400-19
6 Carcinogenicity
7 No suitable data available.
8 Reproductive Toxicity
9 No data available.
10
11 Animal Toxicity
12 Acute oral LD50 in rats 2.46 g/kg.  Ref. Merck Index 10th Edn. 1983
13
14 1-Molar solution given as sole drinking fluid to rats for 4 months did not produce any adverse
15 reactions on liver.
16 Ref. Hilbbom ME et al., Res. Commun. Chem. Path. Pharmacol. 1974 9 (1) 177-80.
17
18 1 M = 74 g/L = 74 mg/mL
19
20 Rat consumes 30 mL/day
21
74 x 30
22 Daily dose  =     =  5224 mg/ kg
0.425
23
5224 x 50
24 PDE  =     =  1044.8 mg/day
5 x 10 x 5 x 1 x 1
25
draft 7 page 44 1044.8 x 1000
1 Limit  =     =  104,480 ppm
10
2
3 2-methyl-1-propanol is a permitted direct food additive  Ref. 21 CFR 172.515 (1990)
4
5 Conclusion
6 The PDE for 2-methyl-1-propanol is 1044.8 mg/day.
draft 7 page 45 1
2 PENTANE
3 Genotoxicity
4 Negative in Ames test.
5 Ref. Kirwin CJ et al.,  J. Soc. Cosmet. Chem. 1980 31 367-70.
6 Carcinogenicity
7 No data available.
8 Reproductive Toxicity
9 No data available.
10 Animal Toxicity
11 Rats exposed to 3000 ppm by inhalation 12 h/day for 16 weeks did not develop peripheral
12 nerve damage.  Ref. Takeuchi Y et al.,  Br. J. Ind. Med. 1980 37 (3) 241-7.
13
3000 x 72.15
14 NEL 3000 ppm  =     =  8853 mg/ m3  =  8.85 mg/ L
24.45
15
8.85 x 12
16 Continuous exposure  =     =  4.43 mg/ L
24
17
4.43 x 290 
18 Daily dose  =     =  3023 mg/ kg
0.425 kg
19
3023 x 50
20 PDE  =   =  604.6 mg/day
5 x 10 x 5 x 1 x 1
21
604.6 x 1000
22 Limit  =     =  60,460 ppm
10
23 Conclusion
24 The PDE for pentane is 604.6 mg/kg.
draft 7 page 46 1
2 1-PENTANOL
3 Genotoxicity
4 No data available.
5 Carcinogenicity
6 No data available.
7 Reproductive toxicity
8 14,000 mg/m3 by inhalation 7 h/day, days 1-19 had no adverse effects on the foetuses of
9 Sprague-Dawley rats.  Ref.  Nelson BK et al.,  J. Amer. Coll. Tox. 1989 8 (2) 405-10.
10
11 14,000 mg/ m3 = 14 mg/L
12
14 x 7
13 For continuous dosing  =     =  4.08 mg/ L
24
14
4.08 x 290
15 Daily dose  =     =  3585 mg / kg
0.33
16
3585 x 50
17 PDE  =     =  3585 mg/day
5 x 10 x 1 x 1 x 1
18
3585 x 1000
19 Limit  =     =  358,500 ppm
10 
20
21 Animal toxicity
22 50, 150 and 1000 mg/kg administered by gavage daily to ASH/CSE rats for 13 weeks
23 produced no adverse effects.   NEL 1000 mg/kg.
24 Ref. Butterworth KR et al.,  Fd. Cosmet. Toxicol. 1978 16 (3) 203-8
25
draft 7 page 47 1000 x 50
1 PDE  =     =  200 mg/day
5 x 10 x 5 x 1 x 1
2
200 x 1000
3 Limit  =   =  20,000 ppm
10
4
5 1-Pentanol is a permitted direct food additive.  Ref. 21 CFR 172.515 (1990).
6
7 Conclusion
8 The PDE for 1-pentanol is 200 mg/day.
draft 7 page 48 1
2 1-PROPANOL
3 Genotoxicity
4 Negative in vitro results in Ames test.  Mouse lymphoma assay, SCE.
5 Refs. Short Term Programs NCI 1984
6 Mut Res. 1981 87 17-62.
7 Carcinogenicity
8 No suitable data available.
9 Reproductive Toxicity
10 No data available.
11 Animal Toxicity
12 Oral LD50 in rats 1.9 g/kg.
13 Ref. Smyth HF et al.,  Arch. Ind. Hyg. Occup. Med. 1954 10 1
14
15 1-Propanol is a permitted direct food additive
16 Ref. 21 CFR 172.515 (1990)
draft 7 page 49 1
2 2-PROPANOL
3 Genotoxicity
4 Negative in vitro results in Ames tests and in transformation assay in SHE cells.
5 Refs. Shimizu H et al.,  Ipn. J. Ind Health 1985 27 400-419
6 Zeiger E et al.,  Environ. Mol. Mutagen 1992 19 (suppl21) 2-141
7 Mut Res 1983 114 283-385
8
9 Carcinogenicity
10 Mice exposed to 3000ppm. 7hr/day 5 days/week for 8 months by inhalation.  No
11 tumourigenic activity when examined at 12 months of age.
12 Ref. Neil CS et al.,  Arch. Ind. Hygien. Assoc. J  1952 5 535-547.
13
14 Reproductive Toxicity
15 A 1.5% solution in drinking ware was administered to rats for 2 generations.  Other than a
16 slight early growth retardation in the first generation, no adverse effects were seen.  NOEL
17 1.5%.  Ref. Lehman A J et al.,  Pharmacul;. Exp. Therap.  1945 85 61
18 1.5% = 1.5mL/100mL = 1.5 x 0.78505 = 1.18 g/100 mL.  Rat consumes 30 mL/day
19
1180 x 30
20 Daily dose  =     =  833 mg/ kg
100 x 0.425
21
833 x 50
22 PDE  =     =  833 mg/day
5 x 10 x 1 x 1 x 1
23
833 x 1000
24 Limit  =     =  83,300 ppm
10 
25
draft 7 page 50 1 400, 800 or 1200 mg/kg were administered by gavage to 5D rats daily from day 6-15.  Deaths
2 were noted in the dams at the intermediate and high levels.  Foetal weights were reduced at
3 the intermediate and high levels but no tertogenic on embryocellular effects were noted.
4 NOEL 400mg/kg.  Ref. 1990 FDA Internal report Ref. SBJ000051 3 681-973
5
400 x 50
6 PDE  =     =  400 mg/day
5 x 10 x 1 x 1 x 1
7
400 x 1000
8 Limit  =     =  40,000 ppm
10 
9
10 120, 240 or 480 mg/kg were administered by gavage to NZW rabbits on days 6-18.  Deaths
11 and reduced maternal weight gain were noted in dams at the high dose level only.  No adverse
12 effects were noted in any of the foetuses.  NOEL 240 mg/kg.
13 Ref. 1990 FDA Internalreport Ref. SBJ000051 3:447-680
14
240 x 50
15 PDE  =     =  480 mg/day
2.5 x 10 x 1 x 1 x 1
16
480 x 1000
17 Limit  =     =  48,000 ppm
10 
18
19 Animal Toxicity
20 Male rats were given 0.5 or 2.5% and females 1% or 5% in drinking water for 6 months.
21 Deaths, not thought to be associated with treatment, were noted in animals from the 0.5%
22 and 2.5% groups.  Decreased weight gain was noted in the female animals but there were no
23 gross or microscopic changes at any dose level.  Ref.  Lehman AJ and Chase HF J. Lat.
24 Med. 1944 29 561.  NOEL = 0.5% = 0.5 mL/100 mL = 0.5 x 0.78505 = 0.39 g/100 mL
25
390 x 30
26 Daily dose  =     =  275 mg/ kg
100 x 0.425
27
draft 7 page 51 275 x 50
1 PDE  =     =  138 mg/day
5 x 10 x 2 x 1 x 1
2
138 x 1000
3 Limit  =     =  13,800 ppm
10 
4
5 Rhesus monkeys were given 2 or 20 mg/kg by gavage for 9 months.  No adverse effects were
6 noted.  NOEL is 20 mg/kg.  Ref. 1968 FDA Internal Report Ref. SBJ000051 2:339-405.
7
20 x 50
8 PDE  =     =  1 mg/day
10 x 10 x 10 x 1 x 1
9
1 x 1000
10 Limit  =     =  100 ppm
10 
11
12 2- Propanol is a permitted direct food additive.  Ref. 21 CFR 172.515 (1990)
13
14 Conclusion
15 The 1968 study by the FDA in monkeys is disregarded since no toxicity was detected.   The
16 PDE for 2-propanol is 138 mg/day.
draft 7 page 52 1 PROPYL ACETATE
2 Genotoxicity
3 No data available.
4 Carcinogenicity
5 No data available.
6 Reproductive Toxicity
7  No data available.
8
9 Animal Toxicity
10 Oral LD50 in rats 9.4 g/kg.  Ref. Merck Index 10th Edn 1983
11
12 Propyl acetate is a permitted direct food additive.  21 CFR 172.515 (1990)
13
draft 7 page 53 1
2 TETRAHYDROFURAN
3 Genotoxicity
4 Negative in Ames test and SCE assay.
5 Ref.  Florin I. Et al.,  Toxicol. 1980 15 219-32.
6 Mortelmans K et al.,  Environ. Mut. 1986 8 (Suppl 7) 1-119
7 Galloway SM et al., Environ. Mol. Mutagen 1987 10 (Suppl 10) 1-175
8 Carcinogenicity
9 No data available.
10 Reproductive Toxicity
11 600, 800, or 5,000 ppm given by inhalation to SC rats 6 h/day, days 6-19 of gestation.
12 Reduced maternal weight gain and foetal weight at high dose level only but no abnormalities.
13 NOEL 1800 ppm.  Ref  Mast TJ et al., Fund. Appl. Toxicol 1992 18 255-265
14
1800 x 72.10
15 NEL  =  1800 ppm  =     =  5308 mg/ m3  =  5.31 mg/ L
24.45
16
5.31 x 6
17 For continuous dosing  =     =  1.33 mg/ L
24
18
1.33 x 290
19 Daily dose  =     =  1166 mg/ kg
0.33
20
1166 x 50
21 PDE  =     =  1166 mg/day
5 x 10 x 1 x 1 x 1
22
1166 x 1000
23 Limit  =     =  116,600 ppm
10
24
draft 7 page 54 1 CD-1 mice were given 600, 1800, or 5000 ppm by inhalation 6 h/day on days 6-17.  Deaths at
2 high dose and sedation at intermediate and high levels.  Reduced weight gain at 5000 ppm.
3 Increased incidence of intrauterine deaths at intermediate and high levels. No teratogenic
4 effects.  NOEL 600 ppm. Ref  Mast TJ et al., Fund. Appl. Toxicol 1992 18 255-265
5
600 x 72.10
6 NEL  =  600 ppm  =     =  1769 mg/ m3  =  1.77 mg/ L
24.45
7
1.77 x 6
8 For continuous dosing  =     =  0.44 mg/ L
24
9
0.44 x 43
10 Daily dose  =     =  633.5 mg/ kg
0.03
11
633.5 x 50
12 PDE  =     =  264 mg/day
12 x 10 x 1 x 1 x 1
13
264 x 1000
14 Limit  =     =  31,800 ppm
10
15
16 Toxicity
17 Reported that 17,000 ppm by inhalation 6 h/day, 5 days/week for 6 weeks produced no
18 evidence of liver or kidney damage in rabbits.
19 Ref. Oettel H - Personal communication to ACIG TLV committee
20
17,000 x 72.10
21 17,000 ppm  =     =  50131 mg / m3  =  50 mg/ L
24.45
22
50 x 6 x 5
23 For continuous exposure  =     =  8.9 mg/ L
24 x 7
24
draft 7 page 55 8.9 x 1440
1 Daily dose  =     =  3204 mg/ kg
4
2
3204 x 50
3 PDE  =     =  641 mg/day
2.5 x 10 x 10 x 1 x 1
4
641 x 1000
5 Limit  =     =  64,100 ppm
10
6
7 F344 rats given 66, 200, 600, 1800 or 5000 ppm by inhalation 6 h/day, 5 days/week for 13
8 weeks.  High dose level animals were ataxic and had slightly increased liver weights.
9 Acanthosis and inflammation of the fore stomach were noted at the high dose only. NOEL
10 1800 ppm.  Ref. Chhabra RS et al., Fund. Appl. Toxicol. 1990 14 338-345
11
1800 x 72.10
12 NEL  =  1800 ppm  =     =  5308 mg/ m3  =  5.31 mg/ L
24.45
13
5.31 x 6 x 5
14 For continuous dosing  =     =  0.95 mg/ L
24 x 7
15
0.95 x 290
16 Daily dose  =     =  646.9 mg/ kg
0.425
17
646.9 x 50
18 PDE  =     =  129 mg/day
5 x 10 x 5 x 1 x 1
19
129 x 1000
20 Limit  =     =  12,900 ppm
10
21
22 B6C3F1 mice exposed to 66, 200, 600, 1800, or 5000 ppm by inhalation 6 h/day, 5
23 days/week for 13 weeks.  Reduced weight gain, narcosis, and deaths at high dose level.
24 Decreased thymic and spleen weights and increased liver weights at high dose.  Mild
draft 7 page 56 1 centrilobular hepatocytomegaly in high dose level animals of both sexes and atrophy of uterus
2 and degeneration of inner cortex of adrenal cortex in females.  NOEL 1800 ppm.    Ref.
3 Chhabra RS et al., Fund. Appl. Toxicol. 1990 14 338-345
4
5 As above, 1800 ppm = 0.95 mg/L continuous exposure
6
0.95 x 43
7 Daily dose  =     =  1456 mg/ kg
0..028
8
1456 x 50
9 PDE  =     =  121 mg/day
12 x 10 x 5 x 1 x 1
10
121 x 1000
11 Limit  =     =  12,100 ppm
10
12
13 Human Results
14 No data available.
15
16 Conclusion
17 The PDE for tetrahydrofuran is 121 mg/day.
draft 7 page 57