Appendix 5 Toxiclogical Data for Class 2 Solvents
Page 1
draft 7 page
1
APPENDIX 5. TOXICOLOGICAL DATA FOR CLASS 2 SOLVENTS
1
Page 2
draft 7 page
2
1
ACETONITRILE
2
Genotoxicity
3
Negative in most studies.
4
Ref. Schlegelmilch R et al., J. Appl. Toxicol. 1988 8 (3) 201-9
5
EPA Doc No. 40-8446070 Fiche No. OTS 0507279 (1984)
6
NTP Tech Report 447; NIH Pub. No. 96 - 3363 (1996)
7
Carcinogenicity
8
F344 rats were given 100, 200 or 400 ppm by inhalation 6 h/day, 5 days/week for 2 years.
9
Slight increase in incidence of hepatocellular adenoma or carcinoma (combined) in the high
10
dose males which was slightly higher than the historic control range. NOEL 200 ppm.
11
Ref. NTP Tech Report 447, NIH Pub. No. 96 - 3363 (1996)
12
13
200 ppm =
200 x 41.05
24.45
= 335.8 mg / m
mg / L
3
= 0 336
.
14
15
For continuous exposure =
0.336 x 6 x 5
24 x 7
= 0.06 mg / L
16
17
Daily dose =
0.06 x 290
0.425
= 40.9 mg / kg
18
19
PDE =
40.9 x 50
5 x 10 x 1 x 10 x 1
= 4.1 mg / day
20
21
Limit =
4.1 x 1000
10
= 410 ppm
22
23
B6C3F1 mice were given 50, 100 or 200 ppm by inhalation, 6 h/day, 5 days/week for 2 years.
24
No treatment related oncongenic changes were noted.
25
Page 3
draft 7 page
3
NOEL 200 ppm. Ref. NTP Tech Report 447, NIH Pub. No. 96 - 3363 (1996)
1
As above 200 ppm = 0.336 mg/L
2
3
For continuous exposure =
0.336 x 6 x 5
24 x 7
= 0.06 mg / L
4
5
Daily dose =
0.06 x 43
0.028
= 92.1 mg / kg
6
7
PDE =
92.1 x 50
12 x 10 x 1 x 1 x 1
= 38 mg / day
8
9
Limit =
38 x 1000
10
= 3800 ppm
10
11
Reproductive Toxicity
12
125, 190 and 275 mg/kg given by gavage to Sprague-Dawley rats, days 6-19. Some
13
mortality, reduced maternal weight gain and increased foetal loss at high dose only. No
14
teratogenic effects but reduced ossification associated with the maternal toxicity. NEL 190
15
mg/kg. Ref. Johannsen FR et al., Fund. Appl. Toxicol. 1986 7 33-40
16
17
PDE =
190 x 50
5 x 10 x 1 x 1 x 1
= 190 mg / day
18
19
Limit (ppm) =
190 x 1000
10
= 19,000 ppm
20
21
100, 400 or 1200 ppm by inhalation 6 h/day to rats on days 6-19. One death at 400 and 2 at
22
1200 ppm but no other maternal signs of toxicity. No adverse effects on foetuses. NOEL
23
1200 ppm for teratogenicity. Ref. NTP Tech Report 447, NIH Pub. No. 94 - 3363 (1994)
24
25
Page 4
draft 7 page
4
1200 ppm =
1200 x 41.05
24.45
= 2015 mg / m
mg / L
3
= 2 015
.
1
2
For continuous exposure =
2.015 x 6
24
= 0.504 mg / L
3
4
Daily dose =
0.504 x 290
0.33
= 443 mg / kg
5
6
PDE =
443 x 50
5 x 10 x 1 x 1 x 1
= 443 mg / day
7
8
Limit =
443 x 1000
10
= 44,300 ppm
9
10
2, 15, 30 mg/kg by gavage to NZW rabbits days 6-18. Deaths and abortions in dams at high
11
dose and reduced weight gain at 15 and 30 mg/kg. Reduction in numbers of live foetuses at
12
high dose level but survivors unaffected. Virtual NEL 15 mg/kg.
13
Ref. EPA Doc No. 40-8446070 Fiche No. OTS 0507279 (1984)
14
15
PDE
15 x 50
2.5 x 10 x 1 x 1 x 1
30 mg / day
=
=
16
17
Limit (ppm)
30 x 1000
10
3,000 ppm
=
=
18
19
Toxicity
20
Rats exposed to 25, 50, 100, 200 and 400 ppm by inhalation 6.5 h/day, 5 days/week for 13
21
weeks caused cytoplasmic vacuolisation of hepatocytes at 400 ppm only. NEL 200 ppm.
22
Ref. Hazleton Labs Reports for NTP 1983 (referenced in Am.Conf. of Governmental Ind.
23
Hyg. Doc of TLU and Biological Exposure Indices 1986)
24
Page 5
draft 7 page
5
1
200 ppm
200 x 41.05
24.45
336 mg / m = 0.34 mg / L
3
=
=
2
3
For continuous exposure
0.34 x 6.5 x 5
24 x 7
= 0.066 mg / L
=
4
5
Daily dose
0.066 x 290
0.425
= 45 mg / kg
=
6
7
PDE
45 x 50
5 x 10 x 5 x 1 x 1
= 9.0 mg / day
=
8
9
Limit (ppm)
9.0 x 1000
10
= 900 ppm
=
10
11
Mice exposed to 50, 100, 200, 400 ppm by inhalation 6.5 h/day, 5 days/week for 13 weeks.
12
No effects at 50 ppm. 100 ppm caused only slightly increased liver weight in females and at
13
higher levels changes in liver seen and RBC and WBC reduced. Virtual NEL 100 ppm
14
Ref. Hazleton Labs Report for NTP 1983 (referenced in ACIG Document as above)
15
16
100 ppm
100 x 41.05
24.45
= 168 mg / m = 0.168 mg / L
3
=
17
18
For continuous exposure
0.168 x 6.5 x 5
24 x 7
= 0.033 mg / L
=
19
20
Daily dose =
0.033 x 43
0.028
50.7 mg / kg
=
21
22
PDE =
50.7 x 50
12 x 10 x 5 x 1 x 1
4.22 mg / day
=
23
Page 6
draft 7 page
6
1
Limit (ppm)
4.22 x 1000
10
422 ppm
=
=
2
3
Human
4
No chronic data available. Acute death at high unknown exposure probably due to
5
thiocyanate.
6
Ref. Amdur ML J. Occup. Med. 1959 1 627
7
Metabolism
8
Acetonitrile slowly metabolised to cyanide but blood cyanide and urinary thiocyanate
9
measurements not good indicators of low level exposure.
10
11
Conclusion
12
The PDE for acetonitrile is 4.1 mg/day.
13
Page 7
draft 7 page
7
1
CHLOROBENZENE
2
3
Genotoxicity
4
Negative results in a range of studies comprising Ames test, against Aspergillus nidulans
5
chinese hamster ovary cell chromosome aberration assay, in vitro rat liver UDS assay and a
6
sex linked recessive lethal assay in Drosophila
7
Refs. NTP Tech. Report Series No. 261 NIH Pub.No. 86-2517 (1985)
8
Prasad I and Pramer D. Genetics 1968 60 212-213
9
EPA Doc. No. 40-8320545. Fiche No. OTS 0511274 (1982)
10
EPA Doc. No. FYI-0284-0291. Fiche No. OTS 0000291-0 (1984)
11
12
Carcinogenicity
13
Rats Fischer 344 rats given 60 or 120 mg/kg by gavage 5 days/week for 2 years. Weight
14
gain unaffected by treatment but reduced survival in high dose males. Increased incidence of
15
hyperplastic nodules in livers of high dose male rats only. After 2 years, not considered
16
carcinogenic response.
17
Ref. NTP Tech Report Series No. 261. NIH Pub.No. 86-2517 (1985)
18
NEL 60 mg/kg
19
20
Continuous exposure =
60 x 5
7
= 43 mg / kg
PDE =
43 x 50
5 x 10 x 1 x 1 x 1
= 43.0 mg / day
Limit =
43.0 x 1000
10
= 4300 ppm
21
22
Page 8
draft 7 page
8
Mice Female B6C3F1 mice given 60 or 120 mg/kg and male mice given 30 or 60 mg/kg by
1
gavage 5 days/week for 2 years. No effects on survival or tumour incidence were noted.
2
Ref. NTP Tech Report Series No. 261 NIH Pub.No. 86-2517 (1985)
3
NEL is 60 mg/kg as above.
4
5
Continuous exposure =
60 x 5
7
= 43 mg / kg
PDE =
43 x 50
12 x 10 x 1 x 1 x 1
= 17.9 mg / day
Limit =
17.9 x 1000
10
= 1790 ppm
6
7
Reproductive Toxicity
8
Rats Fischer 344 rats given 75, 210 or 590 ppm by inhalation 6 h/day during days 6-15 of
9
gestation. There was decreased maternal weight gain and food consumption at the high
10
dose level but no embryotoxic or teratogenic effects. Ossification was slightly delayed at the
11
maternally toxic level.
12
Ref. John JA et al., Toxicol. Appl. Pharmacol. 1984 76 365-7
13
NEL 590 ppm
14
15
Page 9
draft 7 page
9
590 x 112.56
24.45
= 2716 mg / m = 2.72 mg / L
Continuous exposure =
2.72 x 6
24
= 0.68 mg / L
Daily dose =
0.68 x 290
0.33
= 598 mg / kg
PDE =
598 x 50
5 x 10 x 1 x 1 x 1
= 598 mg / day
Limit =
599 x 1000
10
= 59,800 ppm
3
1
2
Sprague-Dawley rats received 50, 150 or 450 ppm by inhalation 6 h/day through a 10 week
3
premating period and then throughout 2 successive generations. No effects on fertility or
4
reproductive performance were noted. Ref. Nair RS et al., Fund. Appl. Toxicol. 1987 9
5
678-86
6
NEL is 450 ppm
7
8
450 x 112.56
24.45
= 2072 mg / m = 2.07 mg / L
3
9
10
Continuous dosing =
2.07 x 6
24
= 0.52 mg / L
Daily dose =
0.52 x 290
0.33
= 457 mg / kg
PDE =
457 x 50
5 x 10 x 1 x 1 x 1
= 457 mg / day
Limit =
457 x 1000
10
= 45,700 ppm
11
12
Page 10
draft 7 page
10
Rabbits NZW rabbits were given 75, 210 or 590 ppm by inhalation 6 h/day, days 6-18.
1
Slight maternal toxicity at intermediate and high levels. No effects on litter size or mean
2
foetal weight. Slight increase in malformations in all treatment groups but with no dose-
3
related trends in frequency or nature of the defects. The study was repeated using levels of
4
10, 30, 75 or 590 ppm. Higher incidence of resorptions at the highest level but no
5
embryotoxic or teratogenic effects. The increased level of resorptions was within the
6
historical range and was not considered to be a drug induced effect.
7
Ref. John JA et al., Toxicol. Appl. Pharmacol. 1984 76 365-73. NEL 590 ppm
8
9
As above for continuous exposure = 0.68 mg / L
Daily dose =
0.68 x 1440
4
= 245 mg / kg
PDE =
245 x 50
2.5 x 10 x 1 x 1 x 1
= 490 mg / day
Limit =
490 x 1000
10
= 49,000 ppm
10
11
Animal Toxiocity
12
Dogs Given 27.25, 54.5 or 272.5 mg/kg by gavage 5 days/week for 3 months. Deaths
13
occurred at the high dose level with damage to liver, kidneys, GI tract and haemopoeitic
14
system. No changes were observed at lower levels. NEL 54.5 mg/kg
15
Ref. Knapp WK et al., Toxicol. Appl. Pharmacol. 1971 19 393
16
17
Continuous dosing =
54.5 x 5
7
= 38.9 mg / kg
18
19
PDE =
38.9 x 50
2 x 10 x 5 x 1 x 1
= 19.5 mg / day
Limit =
19.5 x 1000
10
= 1950 ppm
20
Page 11
draft 7 page
11
1
Rats Given 12.5, 50 or 250 mg/kg in diet daily for 3 months. Reduced weight gain in males
2
at high dose level. Liver and kidney weights increased at intermediate and high levels but no
3
pathology.
4
Ref. Knapp WK et al., Toxicol. Appl. Pharmacol. 1971 19 393. NEL 50 mg/kg
5
6
PDE =
50 x 50
5 x 10 x 5 x 1 x 1
= 10.0 mg / day
Limit =
5.0 x 1000
10
= 1,000 ppm
7
8
Fischer 344 rats given 60, 125, 250, 500 or 750 mg/kg by gavage 5 days/week for 13 weeks.
9
The 500 and 750 mg/kg levels were lethal. Weight gain in males was depressed in those
10
animals receiving 250 mg/kg or more and for females that received 500 mg/kg or more.
11
Relative liver weights were increased at doses of 250 mg/kg and above in both sexes and in
12
the 125 mg/kg females. Relative kidney weights were increased at 500 mg/kg and above.
13
Absolute kidney weights were only increased in the high dose female group and absolute liver
14
weights were increased in all except the low dose group.
15
Centrilobular hepatocellular necrosis was noted at 250 mg/kg and above with increasing
16
severity. Renal tubular degeneration was seen in male and female rats at 750 mg/kg and in
17
male rats at 500 mg/kg. Lymphoid depletion of the thymus occurred in both sexes at the
18
high dose and myeloid depletion of the marrow was seen at the 500 and 750 mg/kg levels in
19
both sexes.
20
Ref. NTP Tech Report Series No. 261 NIH Pub.No. 86-2517 (1985). NOEL 125 mg/kg
21
22
Continuous dosing =
125 x 5
7
= 89 mg / kg
PDE =
89 x 50
5 x 10 x 5 x 1 x 1
= 17.8 mg / day
Limit =
17.8 x 1000
10
= 1780 ppm
23
Page 12
draft 7 page
12
1
Mice B6C3F1 mice given 60, 125, 250, 500 or 750 mg/kg by gavage 5 days/week for 13
2
weeks. All animals receiving the two highest dosages died by week 9 and deaths were also
3
noted at 125 and 250 mg/kg. Absolute and relative liver weights were increased in surviving
4
males at 125 and 250 mg/kg and in surviving females at 250 and 500 mg/kg. Hepatic necrosis
5
was seen in one male at 60 mg/kg, one at 125 mg/kg and more generally at higher levels.
6
Necrosis of the renal tubular epithelium was observed in male mice at 250 mg/kg and above
7
but only at 250 mg/kg in females. Myeloid depletion of the bone marrow and lymphoid
8
depletion or necrosis of the thymus occurred in both sexes at 250 mg/kg and above. NOEL
9
60 mg/kg (apart from one instance of hepatic necrosis)
10
Ref. NTP Tech Report Series No. 261 NIH Pub. No. 86-2517 (1985)
11
12
Continuous dosing =
60 x 5
7
= 43 mg / kg
PDE =
43 x 50
12 x 10 x 5 x 1 x 1
= 3.58 mg / day
Limit =
3.58 x 1000
10
= 358 ppm
13
14
Conclusion
15
The PDE for chlorobenzene is 3.6 mg/day.
16
Page 13
draft 7 page
13
1
CHLOROFORM
2
Genotoxicity
3
Chloroform has been widely examined in in vitro studies, the bulk of which give negative
4
results. Some more equivocal results have been obtained in in vivo studies but many of the
5
studies are of questionable quality and the weight of in vivo evidence is convincingly negative.
6
Refs. Ashby J in Prog. In Mut Res. 1981 1 111-171
7
Reitz RH et al., Environ. Health Perspect. 1982 46 163-68
8
IARC Monograph 1987 Suppl. 6
9
Carcinogenicity
10
As per Pharm. Forum 1990 P543-549
11
Mouse Roe FC et al., J. Environ. Path Toxicol. 1979 2 799-819
12
Liver and renal tumours in male mice at 60 mg/kg 6 days/week
13
NOEL 17 mg/kg corrected to 14.6 mg/kg for 7 days/week treatment
14
15
PDE =
14.6 x 50
12 x 10 x 1 x 10 x 1
= 0.61 mg / day
16
17
Limit ppm =
0.61 x 1000
10
= 61 ppm
18
19
Rat Jorgenson TA et al., Fund.Appl. Toxicol. 1985 5 760-69
20
Kidney tumours at 400 mg/L in drinking water for 2 years
21
(TWA 38 mg/kg) NEL 200 mg/L (19 mg/kg)
22
23
PDE =
19 x 50
5 x 10 x 1 x 10 x 1
= 1.9 mg / day
24
25
Page 14
draft 7 page
14
Limit (ppm) =
1.9 x 1000
10
= 190 ppm
1
2
Reproductive Toxicity
3
Ref. Thompson D et al., Toxicol. Appl. Pharmacol. 1974 29 348-57
4
Rats given 20, 50, or 126 mg/kg by gavage, days 6-15. Maternal and foetal toxicity at high
5
dose but no teratogenic effects. NOEL 50 mg/kg.
6
7
PDE =
50 x 50
5 x 10 x 1 x 1 x 1
= 50 mg / day
8
9
Limit (ppm) =
50 x 1000
10
= 5,000 ppm
10
11
Rabbits given 20, 35, or 50 mg/kg by gavage, days 6-18. Hepatotoxicity and death in some
12
high dose level animals. Reduced foetal weight at high dose only but no teratogenic effects.
13
NOEL 35 mg/kg.
14
15
PDE =
35 x 50
2.5 x 10 x 1 x 1 x 1
= 70 mg / day
16
17
Limit =
70 x 1000
10
= 7000 ppm
18
19
Toxicity
20
25 ppm given by inhalation 7 h/day, 5 days/week for 6 months to rats was NEL. Higher doses
21
caused liver and kidney damage.
22
Ref. Torkelson T et al., Am.Ind.Hyg.J. 1976 37 697-705
23
24
25 ppm =
25 x 119.38
24.45
= 122 mg / m = 0.12 mg / L
3
25
Page 15
draft 7 page
15
1
For continuous dosing =
0.12 x 7 x 5
24 x 7
= 0.025 mg / L
2
3
Daily dose =
0.025 x 290
0.425 kg
= 17.1 mg / kg
4
5
PDE =
17.1 x 50
5 x 10 x 2 x 1 x 1
= 8.6 mg / day
6
7
Limit =
8.6 x 1000
10
= 860 ppm
8
9
15 and 30 mg/kg given by gavage, 6 days/week for 7.5 years to beagle dogs. Fatty cysts in
10
kidneys and nodular liver changes with increased enzyme activities at both levels. LOAEL
11
15 mg/kg. Ref. Heywood R et al., J. Environ. Path. Tox. 1979 2 835-51
12
13
For continuous dosing =
15 x 6
7
= 12.9 mg / kg
14
15
PDE =
12.9 x 50
2 x 10 x 1 x 1 x 10
= 3.2 mg / day
16
17
Limit =
3.2 x 1000
10
= 320 ppm
18
19
Human
20
No epidemiological data available.
21
22
Conclusion
23
The PDE for chloroform is 0.6 mg/day.
24
Page 16
draft 7 page
16
1
CYCLOHEXANE
2
Genotoxicity
3
Negative in in vitro studies.
4
Refs. McCann JE et al., Proc. Ntl. Acad. Sci. USA. 1975 72 5135-39
5
Perocco P et a.. Toxicol Lett. 1983 16 69-75
6
Carcinogenicity
7
No data available.
8
Reproductive Toxicity
9
No data available.
10
Toxicity
11
Exposure of rabbits to 434 and 786 ppm by inhalation 6 h/day, 5 days/week for 10 weeks had
12
no adverse effects. 786 ppm caused slight changes in liver and kidneys. NEL 434 ppm.
13
Ref. Treon JE et al., J. Ind. Hyg. 1943 25 199
14
15
434 ppm
434 x 84.16
24.45
1494 mg / m = 1.5 mg / L
3
=
=
16
17
For continuous exposure
1.5 x 6 x 5
24 x 7
= 0.27 mg / L
=
18
19
Daily dose
0.27 x 1440
4
97.2 mg / kg
=
=
20
21
PDE
97.2 x 50
2.5 x 10 x 5 x 1 x 1
= 38.8 mg / day
=
22
23
Limit
38.8 x 1000
10
3880 ppm
=
=
24
Page 17
draft 7 page
17
1
Human
2
No relevant Data.
3
4
Conclusion
5
The PDE for cyclohexane is 38.8 mg/day.
6
Page 18
draft 7 page
18
1
1,2-DICHLOROETHENE
2
Genotoxicity
3
Negative in Ames test and in Saccharomyces cerevisiae. Only the cis isomer showed some
4
activity in the host-mediated assay.
5
Refs. Martelmans K et al., Environ. Mutagen. 1986 8 1-119.
6
Bronzetti G et al., Teratogen. Carcinogen. Mutagen. 1984 4 (4) 365-75.
7
Carcinogenicity
8
No data available.
9
Reproductive toxicity
10
No data available.
11
Animal toxicity
12
Rats exposed to 500 to 1000 ppm by inhalation 7 h/day, 5 days/week for 6 months showed no
13
adverse effects. NOEL 1000 ppm.
14
Ref. Reported in American Conference of Governmental Industrial Hygienists.
15
Documentation of TLV and Biological Exposure Indices 6th Edn. 1991 P430.
16
17
1000 ppm =
1000 x 96.95
24.45
= 3965 mg / m
3.97 mg / L
3
=
18
19
Continuous exposure =
3.97 x 7 x 5
24 x 7
= 0.83 mg / L
20
21
Daily dose =
0.83 x 290
0.425
= 566 mg / kg
22
23
PDE =
566 x 50
5 x 10 x 2 x 1 x 1
= 284 mg / day
24
25
Page 19
draft 7 page
19
Limit =
284 x 1000
10
= 28,400 ppm
1
2
CD-1 mice were dosed in the drinking water for 90 days at levels giving time-weighted
3
average of 17, 175 and 387 mg/kg (males), and 23, 224 and 452 mg/kg (females). Minimal
4
changes were observed. Thymus weights were reduced in females only at high dose level.
5
No histopathological examination undertaken. NEL 224 mg/kg.
6
Ref. Barnes DW et al., Drug. Chem. Toxicol. 1985 8 (5) 373-392.
7
8
PDE =
224 x 50
12 x 10 x 5 x 1 x 1
= 18.7 mg / day
9
10
Limit =
18.7 x 1000
10
1870 ppm
=
11
12
Conclusion
13
The PDE for 1,2-dichloroethene is 18.7 mg/day.
14
Page 20
draft 7 page
20
1
DICHLOROMETHANE
2
Genotoxicity
3
Methylene chloride gives some positive results in vitro but not in vivo.
4
Refs. Sivak A Food Solvent Workshop No. 1. Washington 1984
5
Jongen WMF et al., Mut. Res. 1981 81 203-13
6
Carcinogenicity
7
Rats F344 rats given inhaled doses of 1000, 2000, 4000 ppm 6 h/day, 5 days/week for 2 years
8
had increased incidence of benign mammary tumours at all levels but no increase in malignant
9
tumours. Ref. NTP Tech Report No. 306 NIH Pub No. 86 - 2562 (1986)
10
11
1000 ppm =
1000 x 84.94
24.45
= 3479 mg / m = 3.5 mg / L
3
12
13
For continuous exposure =
3.5 x 6 x 5
24 x 7
= 0.625 mg / L
14
15
Assuming average rat wt = 0.425 kg
Daily dose =
0.625 x 290
0.425 kg
= 426 mg / kg
16
17
PDE =
426 x 50
5 x 10 x 1 x 5 x 10
= 8.5 mg / day
18
19
Limit
8.5 x 1000
10
= 850 ppm
=
20
21
22
Page 21
draft 7 page
21
Mice B6C3F1 mice exposed 6 h/day, 5 day/week to 2,000 or 4,000 ppm by inhalation for 2
1
years. Lung and hepatocellular carcinomas at both levels
2
Ref. NTP Tech Report No. 306 NIH Pub. No. 86 - 2562 (1986)
3
4
2,000 ppm = 7 mg / L
For continuous exposure = 1.25 mg / L
Assuming average mouse wt 28g
Daily dose =
1.25 x 43
0.028
= 1920 mg / kg
5
6
PDE =
1920 x 50
12 x 10 x 1 x 10 x 10
= 8.0 mg / day
7
8
Limit =
8.0 x 1000
10
= 800 ppm
9
10
Reproductive Toxicity
11
Rats given 4,500 ppm by inhalation 6 h/day 7 days/week for 2 weeks before mating and until
12
day 17 of pregnancy. No teratogenic effects.
13
Ref. Hardin BD and Manson JM Toxicol. Appl. Pharmacol. 1980 52 22-28
14
4,500 ppm = 15633 mg/m
3
= 15.6mg/L
15
16
For continuous exposure =
15.6 x 6
24
= 3.9 mg / L
17
18
Assuming average wt of 330 g
Daily dose =
3.9 x 290
0.33
= 3427 mg / kg
19
Page 22
draft 7 page
22
1
PDE =
3427 x 50
5 x 10 x 1 x 1 x 1
= 3427 mg / day
2
3
Limit =
3427 x 1000
10
= 342,700 ppm
4
5
Toxicity
6
Rats 6, 50, 125 or 250 mg/kg given to Fischer 344 rats in drinking water daily for 2 years.
7
Reduced weight gain, fatty liver changes and areas of foci. No increase in neoplastic changes
8
in liver or any other tissue. NOEL 6 mg/kg
9
Ref. Serota DG et al., Toxicol. Appl. Pharmacol. 1986 24 (9) 951-58
10
11
PDE =
6 x 50
5 x 10 x 1 x 1 x 1
= 6.0 mg / day
12
13
Limit =
6.0 x 1000
10
= 600 ppm
14
15
Human Results
16
No changes in mortality or tumour incidence following inhalation exposures up to 350 ppm
17
for several years or TWA of 26 ppm for 22 years.
18
Refs. Friedlander BR et al., J. Occup. Med. 1978 20 (10) 657-66
19
Hearne FT et al., J. Occup. Med. 1987 29 (3) 217-28
20
Metabolism
21
Methylene chloride is metabolised to carbon monoxide and carbon dioxide by mixed function
22
oxidase systems. When these systems become saturated a disproportionate amount is
23
metabolised via the glutathione-s-transferase system producing reactive intermediate. Mice
24
have much greater glutathione activity than rats or humans therefore more metabolism by this
25
pathway.
26
Page 23
draft 7 page
23
An I/P dose of 412 mg/kg to rats results in >90% being excreted unchanged in expired air
1
whereas in mice at 100 mg/kg only 40% is expired unchanged.
2
Ref. Yesair DW et al., Fdn. Proc. Fdn. Am. Soc. Exp.Biol. 1977 36 988
3
4
Conclusion
5
No carcinogenic risk.
6
The PDE for dichloromethane is 6.0 mg/day.
7
Page 24
draft 7 page
24
1
1,2-DIMETHOXYETHANE
2
3
Genotoxicity
4
No data available.
5
6
Carcinogenicity
7
No data available.
8
9
Reproductive Toxicity
10
Mice given 250, 350 or 490 mg/kg daily on days 7-10 of gestation. No effects on maternal
11
weight gain. Increased foetal deaths at all dose levels. Teratogenic effects - neural tube
12
closure defects, cleft palate and skeletal defects.
13
Ref. Uemura K. Acta Obstet. Gynaec. Japan 1980 32 (1) 113-121. LOEL 250 mg/kg
14
15
PDE =
250 x 50
12 x 10 x 1 x 10 x 10
= 1.04 mg / day
Limit =
1.04 x 1000
10
= 104 ppm
16
17
Animal Toxicity
18
Female rats exposed to 1000, 2000, 4000 or 8000 ppm by inhalation 4 h/day 5 days/week for
19
2 weeks. Reduced growth rate in each group and mortalities at 4,000 and 8,000 ppm.
20
Gross autopsy revealed massive haemorrhage to lungs and GI tract. (Surviving animals were
21
not autopsied.)
22
Ref. Goldberg ME et al., Am. Ind. Hygien. Assoc. J. 1964 25 369-375. LOEL = 1000 ppm
23
24
Page 25
draft 7 page
25
1000 ppm =
1000 x 90.12
24.45
= 3686 mg / m = 3.69 mg / L
Continuous dosing =
3.69 x 4 x 5
24 x 7
= 0.44 mg / L
Daily dose =
0.44 x 290
0.425
= 300 mg / kg
PDE =
300 x 50
5 x 10 x 10 x 1 x 5
= 6.00 mg / day
Limit =
6.00 x 1000
10
= 600 ppm
3
1
2
Conclusion
3
The PDE for 1,2-dimethoxyethane is 1.0 mg/day.
4
Page 26
draft 7 page
26
1
N,N-DIMETHYLACETAMIDE
2
Genotoxicity
3
Negative results reported in Ames test, in vitro UDS in rat hepatocytes, dominant lethal test
4
in rats and in rat micronucleus test.
5
Ref. McGregor DB NIOSH report. Government Report Announcements No. 27 PB83 -
6
14973 - 2 1980. Zeiger E et al., Environ. Mol. Mutagen. 1988 11 (Suppl 12) 1-158.
7
8
Carcinogenicity
9
Rats
25, 100, or 350 ppm administered by inhalation to Sprague-Dawley rats 6 h/day, 5
10
days/week for 2 years had no effect on survival and no oncogenic effects were observed.
11
NEL 350 ppm.
12
Ref. Malley, L. A., et al., Fund. Appl. Toxicol., 1995, 28, 80-93.
13
14
350 ppm =
350 x 87.12
24.45
= 1247 mg / m = 1.25 mg / L
For continuous dosing =
1.25 x 6 x 5
24 x 7
= 0.223 mg / L
Daily dose =
0.223 x 290
0.425
= 152 mg / kg
PDE =
152 x 50
5 x 10 x 1 x 1 x1
= 152 mg / day
Limit =
152 x 1000
10
= 15,200 ppm
3
15
16
Mice 25, 100, or 350 ppm administered by inhalation to CD-1 mice 6 h/day, 5 days/week for
17
18 months had no effect on survival and no oncogenic effects were observed.
18
Ref. Malley, L. A., et al., Fund. Appl. Toxicol., 1995, 28, 80-93.
19
Page 27
draft 7 page
27
1
As above for continuous dosing at 350 ppm = 0.223 mg / L
Daily dose =
0.223 x 43
0.028
= 343 mg / kg
PDE =
343 x 50
12 x 10 x 1 x 1 x 1
= 142.9 mg / day
Limit =
142.9 x 1000
10
= 14,290 ppm
2
3
Reproductive Toxicity
4
Rats dosed up to 300 ppm by inhalation 6h/day, 5 days/week for 10 weeks pre-mating and
5
during mating, pregnancy and lactation. Treatment had no adverse effects on mating or on
6
the outcome of pregnancy.
7
Ref. Ferenz RL and Kennedy G.L. Fund. Appl. Toxicol. 1986 7 132-7
8
9
NEL = 300 ppm =
300 x 87.12
24.45
= 1069 mg / m = 1.07 mg / L
3
10
11
For continuous dosing =
1.07 x 6 x 5
24 x 7
= 0.19 mg / L
12
13
Daily dose =
0.19 x 290
0.33
= 167 mg / kg
14
15
PDE =
167 x 50
5 x 10 x 1 x 1 x 1
= 167 mg / day
16
17
Limit =
167 x 1000
10
= 16,700 ppm
18
19
Page 28
draft 7 page
28
Complete resorption in rabbits dosed orally at 500microL/kg during days 6 to 18 of gestation
1
and increased resorptions and decreased foetal weight at 300 microL/kg. Maternal weight
2
gain reduced at both levels. No effects at the non-maternally toxic dose of 100 microL/kg.
3
Ref. Merkle J. and Zeller H. Arzneimittel Forsch 1980 30 (9) 1557-62.
4
5
NEL 100 L / kg = 100 x 0.9429 = 94 mg / kg
µ
6
7
PDE =
94 x 50
2.5 x 10 x 1 x 1 x 1
= 188 mg / day
8
9
Limit =
188 x 1000
10
= 18,800 ppm
10
11
Sprague-Dawley rats given 65, 160 and 400 mg/kg by gavage days 6-19. Reduced maternal
12
body weight at high dose with increased foetal loss, decreased foetal weight; heart and c/v
13
defects.
14
NEL 160 mg/kg. Ref. Johannsen FR et al., Fund. Appl. Toxicol. 1987 9 550-56.
15
16
PDE =
160 x 50
5 x 10 x 1 x 5 x 1
= 32 mg / day
17
18
Limit =
32 x 1000
10
= 3200 ppm
19
20
Animal Toxicity
21
25, 100, or 350 ppm administered by inhalation 6 h/day, 5 days/week for 2 years to Sprague-
22
Dawley rats. Increased liver weights, hepatic focal cystic degeneration, hepatic peliosis and
23
haemosiderin accumulation in Kupffer cells. NEL 25 ppm. Ref. Malley LA et al., Fund.
24
Appl. Toxicol. 1995 28 80-93.
25
26
Page 29
draft 7 page
29
25 ppm =
25 87.12
24.45
= 89 mg / m = 0.089 mg / L
For continuous dosing =
0.089 6 5
24 7
= 0.016 mg / L
Daily dose =
0.016 290
0.425
= 10.9 mg / kg
PDE =
10.9 50
5 x 10 x 1 x 1 x 1
= 10.9 mg / day
Limit =
10.9 1000
10
= 1,090 ppm
3
×
× ×
×
×
×
×
1
Conclusion
2
The PDE for N,N-dimethylacetamide is 10.9 mg/day.
3
Page 30
draft 7 page
30
1
N,N-DIMETHYLFORMAMIDE
2
Genotoxicity
3
Negative in most studies reported.
4
Refs. Brams A et al., Tox. Lett 1987 38 123-33
5
Mayer VW and Goin GJ Mut. Res. 1987 187 21-30
6
Williams GM Cancer Res. 1977 37 1845-51
7
Topham JC Mut. Res. 1980 74 379-87
8
Mitchell AD et al., Environ. Mol. Mutagen. 1988 12 (Suppl 13) 37-101
9
Carcinogenicity
10
Daily oral doses of 75 - 150 mg/kg to rats for 250-500 days did not produce tumours. NEL
11
150 mg/kg. Ref. Druckrey H et al., Z. Krebforsch 1967 69 103-201
12
13
PDE =
150 x 50
5 x 10 x 5 x 1 x 1
= 30 mg / day
14
15
Limit =
30 x 1000
10
= 3,000 ppm
16
17
Reproductive Toxicity
18
Russian rabbits given 46.4, 68.1 or 200 microL/kg. Some abortions at high dose. No
19
increase in uterine deaths but decreased foetal weight at 200 microL/kg. Hydrocephalus at
20
68.1 and 200 microL/kg, also umbilical hernia at high dose. No maternal effects at 68.1
21
microL/kg. NEL 46.4 microL/kg.
22
Ref. Merkle J and Zeller H. Arzneimittel Forsch. 1980 30 (9) 1557-62
23
24
46 / 4 l / kg = 46.4 x 0.9445 = 43.8 mg / kg
µ
25
26
Page 31
draft 7 page
31
PDE =
43.8 x 50
2.5 x 10 x 1 x 10 x 1
= 8.76 mg / kg
1
2
Limit =
8.76 x 1000
10
= 876 ppm
3
4
However no adverse effects were reported when 200 mg/kg, 1/17 of lethal dose, was applied
5
dermally to NZW rabbits days 8 -16.
6
Ref. Stula EF and Krauss WC. Toxicol. Appl. Pharmacol. 1977 41 (1) 35-56
7
8
PDE =
200 x 50
2.5 x 10 x 1 x 1 x 1
= 400 mg / day
9
10
Limit (ppm) =
400 x 1000
10
40,000 ppm
=
11
12
Rats given 600, 1200 or 2,400 mg/kg, 1/4 of lethal dose, dermally at varying times.
13
Increased foetal loss and decreased foetal weight associated with maternal toxicity at high
14
dose only. NEL 1200 mg/kg.
15
Ref. Stula EF and Drauss WC. Toxicol.Appl. Pharmacol. 1977 41 (1) 35-56
16
17
PDE =
1200 x 50
5 x 10 x 1 x 1 x 1
= 1200 mg / day
18
19
Limit =
1200 x 1000
10
= 120,000 ppm
20
21
Toxicity
22
Slightly increased liver weight, regarded as adaptive change, when 1000 ppm diet fed to rats
23
in 90 day study. No microscopic changes. Higher doses caused minimal hepatocellular
24
enlargement and increased mitotic figures. Virtual NOAEL 1000 ppm diet.
25
Page 32
draft 7 page
32
Ref. Kennedy GL and Sherman H. Drug Chem. Toxicol. 1986 9 147-70.
1
Rat eats 30 g/day
2
3
Daily dose =
30 x 1000
1000 x 0.425
= 70.6 mg / kg
4
5
PDE =
70.6 x 50
5 x 10 x 5 x 1 x 1
= 14.1 mg / day
6
7
Limit =
14.1 x 1000
10
= 1,410 ppm
8
9
Single I/P doses of 0.6, 0.9 and 1.2 ml/kg given to Wistar rats. Inflammatory changes at 0.6
10
ml/kg with necrosis at higher doses. LOEL 0.6 ml/kg.
11
Ref. Mathew T et al., Lab. Invest. 1980 42 (2) 257-62
12
13
0.6 ml / kg = 0.6 x 0.9445 = 567 mg / kg
14
15
PDE =
567 x 50
5 x 10 x 10 x 1 x 1
= 56.7 mg / day
16
17
Limit =
56.7 x 1000
10
5,670 ppm
=
18
Page 33
draft 7 page
33
Human
1
Possible risk of testicular germ cell cancer in humans. (Exposure not specified and other
2
causes not excluded)
3
Ref. IARC Monograph 47 186
4
Levin SM et al., Lancet 1987 II 1153
5
6
Conclusion
7
The PDE for N,N-dimethylformamide is 8.8 mg/day.
8
Page 34
draft 7 page
34
1
1,4-DIOXANE
2
Genotoxicity
3
Consistently negative results in in vitro studies.
4
Refs. McGregor DB et al., Environ. Mol. Mutagen. 1991 17 196-218
5
Zimmermann FK et al., Mut. Res. 1985 149 339-51
6
Stott WT et al., Toxicol. Appl. Pharmacol. 1981 60 (2) 287-300
7
8
Limited in vivo data also negative
9
Ref. Stott WT et al., Toxicol. Appl. Pharmacol. 1981 60 (2) 287-300
10
1,4 - Dioxane is not genotoxic.
11
12
Carcinogenicity
13
Mice Hepatocellular tumours in B6C3F1 mice given 0.5% or 1%
v
/v in drinking water for 90
14
weeks. Ref. NCI Tech Repeat No. 80. NIH Pub No. 78-1330 (1978)
15
Assuming mice drink 5 ml/day
16
17
Daily dose =
500 x 5 x 1.00329
100 x 0.028
= 922 mg / kg
18
19
PDE =
922 x 50
12 x 10 x 1 x 10 x 10
= 3.84 mg / day
20
21
Limit (ppm) =
3.84 x 1000
10
= 384 ppm
22
23
Rats 0.01, 0.1 or 1.0% v/v in drinking water for 23 months. Severe liver and renal toxicity at
24
1.0% with hepatocellular and nasal carcinoma (equivalent to 1015 mg/kg males; 1599 mg/kg
25
females). Renal and liver degenerative changes at 0.1% (equivalent to 94 and 148 mg/kg to
26
Page 35
draft 7 page
35
males and females) but no neoplastic changes. No changes at 0.01% (equivalent to 9.6 and
1
19 mg/kg to male and female rats).
2
Ref. Kociba RJ et al., Toxicol. Appl. Pharmacol. 1974 30 275-86
3
4
PDE =
94 mg / kg x 50
5 x 10 x 1 x 10 x 1
= 9.4 mg / day
5
6
Limit ppm =
9.4 x 1000
10
= 940 ppm
7
8
Reproductive Toxicity
9
No teratogenicity in rats at 0.25, 0.5, and 1 mL/kg when administered by gavage during days
10
6-15 of pregnancy. Slightly reduced foetal weights associated with maternal toxicity at high
11
dose level. NEL = 1 mL/kg = 1.03 g/kg. Ref. Giavini E et al., Toxicol. Lett. 1985 26 (1) 85-
12
8
13
PDE =
1030 x 50
5 x 10 x 1 x 1 x 1
= 1030 mg / day
14
15
Limit =
1030 x 1000
10
= 103,000 ppm
16
Toxicity
17
Rats Ref. Kociba RJ et al., Toxicol. Appl. Pharmacol. 1974 30 275-86
18
As above NEL 9.6 mg/kg (males) and 19 mg/kg (females)
19
20
PDE =
9.6 x 50
5 x 10 x 1 x 1 x 1
= 9.6 mg / day
21
22
Limit =
9.6 x 1000
10
= 960 ppm
23
Page 36
draft 7 page
36
1
Human Results
2
Fatalities have been reported following varying exposures to very high levels by inhalation.
3
Refs. Barber H Guys Hosp. Rep. 1934 84 267-80
4
A follow-up study indicated no increase in cancer-induced deaths above the expected in
5
workers exposed to low levels (approx 2 ppm) for several years.
6
Ref. Buffler PA et al., J. Occup. Med. 1978 20 (4) 255-59.
7
Metabolism
8
In rats oral doses up to 10 mg/kg or inhaled doses of 50 ppm for 6 hours are eliminated
9
within about one hour. At higher doses metabolism to β hydroxyethoxy-acetic acid is
10
saturated and dioxane is excreted in the breath. Toxicity only occurs at these levels. In man
11
50 ppm for 6 hours is eliminated in urine within one hour and no toxicity is seen.
12
13
Conclusion
14
The PDE for 1,4-dioxane is 3.8 mg/day.
15
Page 37
draft 7 page
37
1
2-ETHOXYETHANOL
2
Genotoxicity
3
Negative in Ames test.
4
Ref. Shimazu H et al., Jpn. J. Ind. Health 1985 27 400-19
5
Carcinogenicity
6
No data available.
7
Reproductive Toxicity
8
1 to 4.2 g/kg by gavage to CD-1 mice days 8-14. Reduced weight gain and increased
9
resorptions and abnormalities from 1.8 g/kg, syndactyly, exencephaly, open eyes, cleft palate.
10
Reduced foetal weight at 1g/kg. LOEL 1g/kg.
11
Ref. Wier PJ et al., Terat.Carc. Mutagen. 1987 7 55-64
12
13
PDE =
1000 x 50
12 x 10 x 1 x 5 x 10
= 8.3 mg / day
14
15
Limit =
8.3 x 1000
10
= 830 ppm
16
17
200 or 765 ppm by inhalation to rats 6 h/day, days 1-19. Maternal toxicity and total litter
18
loss at high dose. Reduced foetal weight, increased skeletal and C/V defect at low dose.
19
Ref. Hardin BD et al., Scand. J. Work Environ. Health 1981 7 (suppl 4) 66-75
20
21
200 ppm =
200 x 90.12
24.45
= 737 mg / m = 0.74 mg / L
3
22
23
For continuous exposure =
0.74 x 6
24
= 0.185 mg / L
24
25
Page 38
draft 7 page
38
Daily dose =
0.185 x 290
0.33 kg
= 163 mg / kg
1
2
PDE =
163 x 50
5 x 10 x 1 x 10 x 10
= 1.63 mg / day
3
4
Limit =
1.63 x 1000
10
= 163 ppm
5
6
NZW rabbits given 160 or 615 ppm by inhalation 6 h/day, days 1-18. Maternal deaths and
7
weight loss at high dose with complete litter loss. Increased foetal deaths and renal, C/V and
8
ventral body wall anomalies at low dose with slight maternal toxicity.
9
Ref. Hardin BD et al., Scand. J. Work. Environ. Health 1981 7 (Suppl 4) 66-75
10
11
160 ppm =
160 x 90.12
24.45
= 590 mg / m = 0.59 mg / L
3
12
13
For continuous exposure =
0.59 x 6
24
= 0.148 mg / L
14
15
Daily dose =
0.148 x 1440
4
= 53.3 mg / kg
16
17
PDE =
53.3 x 50
2.5 x 10 x 1 x 5 x 10
= 2.13 mg / day
18
19
Limit =
2.13 x 1000
10
= 213 ppm
20
Page 39
draft 7 page
39
Toxicity
1
Rats fed 1.45% in diet for 2 years showed testicular oedema and atrophy.
2
Ref. Morris HJ et al., J. Pharmacol. Exp. Therap. 1942 74 266-73
3
Assume rat consumes 30 g/day
4
1.45% of 30,000 mg = 435 mg
5
Average weight = 0.425 kg
6
Daily consumption =
435
0.425
= 1024 mg / kg
7
8
PDE =
1024 x 50
5 x 10 x 1 x 1 x 10
= 102.4 mg / day
9
10
Limit =
102.4 x 1000
= 10,240 ppm
10
11
12
Oral doses of 500 and 1000 mg/kg to Sprague-Dawley rats for 11 days caused damage to
13
primary spermatocytes and spermatogonia. NEL 250 mg/kg.
14
Ref. Foster PMD et al., Toxicol.Appl.Pharmacol. 1983 69 385-99
15
16
PDE =
250 x 50
5 x 10 x 10 x 1 x 1
= 25 mg / day
17
18
Limit =
25 x 1000
10
= 2,500 ppm
19
20
Oral dose of 150 mg/kg by gavage to Long-Evans rats 5 days/week for 6 weeks caused
21
changes in sperm counts and morphology. Benchmark dose (BMD) at 10% incidence was
22
calculated with 95% confidence limits to be 31 mg/kg per day.
23
Ref. Hurtt, ME and Zenick H Fund. Appl. Toxicol., 1986, 7, 348-53.
24
25
Page 40
draft 7 page
40
PDE =
31 x 50
5 x 10 x 5 x 1 x 1
= 6.2 mg / day
1
2
Limit =
3.1 x 1000
10
= 310 ppm
3
4
Human Results
5
Reduced sperm counts in workers exposed to varying unknown concentrations of 2-
6
ethoxyethanol and other solvents.
7
Refs. Ratcliffe JM et al., Br. J. Occup.Med. 1989 46 399
8
Welch LS et al., Am. J. Ind. Med. 1988 14 509-36
9
Metabolism
10
Metabolic product, 2-ethoxyacetic acid, but not 2-ethoxyethanol, caused degeneration of
11
pachytene and dividing spermatocytes when added to primary mixed cultures of germ cells
12
and Sertoli cells.
13
Ref. Grey TJB et al., Toxicol. Appl. Pharmacol. 1985 79 490-501
14
15
Conclusion
16
The PDE for 2-ethoxyethanol is 1.6 mg/day.
17
Page 41
draft 7 page
41
1
ETHYLENEGLYCOL
2
3
Genotoxicity
4
Negative results in microbial mutagenicity assays, mouse lymphoma assay and in vivo in a
5
dominant lethal assay.
6
Refs. Clark CR et al., Toxicol. Appl. Pharmacol. 1979 51 529-35
7
McGregor DB et al., Environ. Mol. Mutagen. 1991 17 (3) 196-219
8
DePass LR et al., Fund. Appl. Toxicol. 1986 7 566-72.
9
10
Carcinogenicity
11
Negative results have been obtained in all the studies reported.
12
Rats Fischer 344 rats were given 40, 200 or 1000 mg/kg daily in the diet for 2 years.
13
All the high dose male rats died within 475 days. No oncogenic effects were observed.
14
Ref. DePass LR et al., Fund. Appl. Toxicol. 1986 7 547-65.
15
NOEL 200 mg/kg
16
17
PDE =
200 x 50
5 x 10 x 1 x 1 x 1
= 200 mg / day
Limit =
200 x 1000
10
= 20,000 ppm
18
19
Fischer 344 rats given 30, 100, 300 or 1000 mg/kg by S/L injection twice weekly for 1 year
20
then retained until 18 months. No increase in tumour incidence was observed.
21
Ref. Mason MM et al., Clin Toxicol 1971 4 (2) 185-204
22
23
Page 42
draft 7 page
42
Continuous dosing =
1000 x 2
7
= 286 mg / kg
PDE =
286 x 50
5 x 10 x 10 x 1 x 1
= 28.6 mg / day
Limit =
28.6 x 1000
10
= 2860 ppm
1
2
Mice
3
CD-1 mice given 40, 200 or 1000 mg/kg/day in diet for 2 years. No evidence of
4
oncogenicity was seen.
5
Ref. DePass LR et al., Fund. Appl. Toxicol. 1986 7 547-65. NOEL is 1000 mg/kg
6
7
PDE =
1000 x 50
12 x 10 x 1 x 1 x 1
= 416.7 mg / day
Limit =
416.7 x 1000
10
= 41,670 ppm
8
9
Reproductive Toxicity
10
Rats Fischer 344 rats given 40, 200 or 1000 mg/kg in diet daily from days 6-15 of gestation.
11
No maternal or embryotoxicity was noted and there was no increase in malformations.
12
Ref. Maronpot RR et al., Drug Chem. Tox. 1983 6 (6) 579-94. NEL 1000 mg/kg
13
14
PDE =
1000 x 50
5 x 10 x 1 x 1 x 1
= 1000 mg / day
Limit =
1000 x 1000
10
= 100,000 ppm
15
16
17
Page 43
draft 7 page
43
Sprague-Dawley rats were given 1250, 2500 or 5,000 mg/kg by gavage daily from day 6-15
1
of gestation. There was a dose-related reduction in maternal weight gain at all levels; the
2
number of live foetuses and mean foetal weights were reduced at the intermediate and high
3
levels, and malformations were noted at all levels including cleft palate, neural tube closure
4
defects and axial skeletal dysplasia.
5
Ref. Price CJ et al., Toxicol. Appl. Pharmacol. 1985 81 113-127. LOEL is 1250 mg/kg.
6
7
PDE =
1250 x 50
5 x 10 x 1 x 5 x 10
= 25 mg / day
Limit =
25 x 1000
10
= 2500 ppm
8
9
Mice CD-1 mice were given 750, 1500 or 3000 mg/kg by gavage daily from day 6-15 of
10
gestation. Maternal weight gain was reduced at the intermediate and high dose levels and the
11
number of live foetuses was reduced at the high dose level. Mean foetal weights were
12
reduced and malformations were noted at all dose levels including craniofacial, neural tube
13
closure defects and axial skeletal dysplasia.
14
Ref. Price CJ et al., Toxicol. Appl. Pharmacol. 1985 81 113-127. LOEL is 750 mg/kg
15
16
PDE =
750 x 50
12 x 10 x 1 x 10 x 10
= 3.12 mg / day
Limit =
3.12 x 1000
10
= 312 ppm
17
18
Animal Toxicity
19
Rats were given 0.05, 0.1, 0.25 and 1% in diet for 16 weeks. Oxalate crystals and damage
20
were seen in the kidneys of the male animals given 0.25 and 1% and similar but lesser effects
21
were seen in the high dose females. NOEL was 0.1% (equivalent to approx 80 mg/kg).
22
Ref. Gaunt IF et al., BIBRA Bull 1975 14 109-11
23
24
Page 44
draft 7 page
44
PDE =
80 x 50
5 x 10 x 5 x 1 x 1
= 16 mg / day
Limit =
16 x 1000
10
= 1600 ppm
1
2
Sprague-Dawley rats fed 0.1, 0.2, 0.5, 1 or 4% in diet for 2 years. Increased mortality in
3
males at 1 and 4%. Calcification of kidney tubules and oxalate - containing calculi in males
4
at 0.5, 1 and 4%. In females tubular calcification noted at 1 and 4% and oxalate calculi only
5
at 4%. Ref. Blood FR Fd. Cosmet. Toxicol. 1965 3 229-34. NEL 0.2%
6
7
Assume rat consumes 30 g/day
8
0.2% of 20,000 = 60 mg
9
Av Wt 0.425 kg
10
Daily consumption =
60
0.425
= 141 mg / kg
PDE =
141 x 50
5 x 10 x 1 x 1 x 1
= 141 mg / day
Limit =
141 x 1000
10
= 14,100 ppm
11
12
Fischer 344 rats fed 40, 200 or 1000 mg/kg in diet daily for 2 years. The high dose level was
13
lethal to the male rats. Urinary calcium oxalate and uric acid crystals and increased kidney
14
weights were noted in the high dose female animals and fatty changes were seen in the livers
15
of the intermediate and high dose females.
16
Renal tubular hyperplasia and dilation was noted in high dose males killed after 6 months.
17
Ref. DePass LR et al., Fund. Appl. Toxicol. 1986 7 547-65. NOEL is 40 mg/kg
18
19
Page 45
draft 7 page
45
PDE =
40 x 50
5 x 10 x 1 x 1 x 1
= 40 mg / day
Limit =
40 x 1000
10
= 4000 ppm
1
2
Human Results
3
Single oral lethal dose estimated at 1.4 ml/kg
4
Ref. Lang EP et al., J. Ind. Hygien. Toxicol. 1939 21 173
5
6
Volunteers maintained in atmosphere of 3 or 67 mg/m
3
22 h/day for 30 days. Little evidence
7
of absorption and no serious signs of toxicity.
8
Ref. Wills JH et al., Clin. Toxicol. 1974 7 (5) 463-76. NEL 67 mg/m
3
= 0.067 mg/L
9
10
Continuous exposure =
0.067 x 22
24
= 0.061 mg / L
Daily dose =
0.061 x 28,800
50
= 35 mg / kg
11
12
Conclusion
13
The PDE for ethyleneglycol is 3.1 mg/day.
14
Page 46
draft 7 page
46
1
FORMAMIDE
2
Genotoxicity
3
Negative in Ames test.
4
Ref. Mortelmans K et al., Environ Mutagen 1986 8 1-119
5
Carcinogenicity
6
No data available
7
Reproductive toxicity
8
1 ml I/P to rats days 11-16 increased resorptions, decreased foetal weight and caused cleft
9
palate and digital defects.
10
Ref. Thiersch JB in Tuchmann-Duplessis H Ed.
11
Malformations Congenitals des Mammiferes, Paris, 1971
12
13
20, 70 and 200µl/kg dosed orally to Russian rabbits days 6-18.
14
200 µl/kg was lethal to litters and 70 µl/kg caused decreased foetal weight, increased
15
resorption and cleft lip/palate and anasarca. NEL was 20 µl/kg.
16
Ref. Merckle J and Keller H. Arzneimittel Forsch. 1980 30 (a) 1557-62.
17
18
NEL = 20 l / kg = 20 x 1.1334 = 22.7 mg / kg
µ
19
20
PDE =
22.7 x 50
2.5 x 10 x 1 x 10 x 1
= 4.54 mg / day
21
22
Limit =
4.54 x 1000
10
= 454 ppm
23
24
Page 47
draft 7 page
47
Animal toxicity
1
Oral LD
50
in rats is 6 g/kg
2
Ref. Thiersch JB J Reprod. Fert 1962 4 219
3
100, 500 or 1500 ppm given 6 h/day, 5 day/week for 2 weeks to rats.
4
Decreased weight gain and necrosis of renal tubulular epithelium at high dose. Decreases in
5
platelets and/or lymphocytes at 500 and 1500 ppm. NEL 100 ppm
6
Ref. Warheit DB et al., Fund. Appl. Toxicol. 1989 13 702-13
7
8
NEL = 100 ppm =
100 x 45.04
24.45
= 184 mg / m = 0.184 mg / L
3
9
10
For continuous dosing =
0.184 x 6 x 5
24 x 7
= 0.033 mg / L
11
12
Daily dose =
0.033 x 290
0.425 kg
= 22.4 mg / kg
13
14
PDE =
22.4 x 50
5 x 10 x 10 x 1 x 1
= 2.2 mg / day
15
16
Limit =
2.2 x 1000
10
= 220 ppm
17
18
Conclusion
19
The PDE for formamide is 2.2 mg/day.
20
Page 48
draft 7 page
48
1
HEXANE
2
Genotoxicity
3
No data available.
4
Carcinogenicity
5
No data available.
6
Reproductive Toxicity
7
F344 rats given 1000 ppm by inhalation 6 h/day, day 8-16. No adverse effects on dams or
8
litters. NOEL 1000 ppm. Ref. Bus JS et al., Toxicol. Appl. Pharmacol. 1979 51 295-302
9
10
1000 ppm =
1000 x 86.17
24.45
= 3524 mg / m = 3.5 mg / L
3
11
12
For continuous dosing =
3.5 x 6
24
= 0.875 mg / L
13
14
Daily dose =
0.875 x 290
0.33 kg
= 769 mg / kg
15
16
PDE =
769 x 50
5 x 10 x 1 x 1 x 1
= 769 mg / day
17
18
Limit (ppm) =
769 x 1000
10
= 76,900 ppm
19
20
Toxicity
21
100 ppm 12 h/day for 24 weeks to Wistar rats by inhalation did not effect motor nerve
22
conduction velocity, mixed nerve conduction velocity or distal latency. Higher doses cause
23
severe effects with giant axonal swelling and fibre degeneration in both CNS and PNS.
24
Refs. Takeuchi Y et al., Br. J. Ind. Med. 1983 40 199-203
25
Page 49
draft 7 page
49
Schmidt R et al., Respiration 1984 46 362-69.
1
2
100 ppm =
100 x 86.17
24.45
= 352 mg / m = 0.35 mg / L
3
3
4
Continuous exposure =
0.35 x 12
24
= 0.175 mg / L
5
6
Daily dose =
0.175 x 290
0.425
= 119 mg / kg
7
8
PDE =
119 x 50
5 x 10 x 10 x 1 x 2
= 5.95 mg / day
9
10
Limit =
5.95 x 1000
10
= 595 ppm
11
12
200 and 570 mg/kg administered to rats by gavage 5 days/week for 13 weeks.
13
Severe hindlimb weakness or paralysis with tibial nerve lesions and atrophy of testicular
14
germinal epithelium at 570 mg/kg. Liver and kidney weights increased at 200 mg/kg.
15
NOEL 200 mg/kg. Ref. Til HP, et al., Final report, Zeist. The Netherlands, TNO-CIVO
16
Institutes (Project No. B/88-0541, Report No. V/89.089) 1989 166 pp.
17
18
For continuous dosing =
200 x 5
7
= 143 mg / kg
19
20
PDE =
143 x 50
5 x 10 x 10 x 5 x 1
= 2.86 mg / day
21
22
Limit =
2.86 x 1000
10
= 286 ppm
23
Page 50
draft 7 page
50
1
Human Results
2
Several reports of polyneuropathy in workers exposed to n-hexane by inhalation. Dose range
3
is 500 - 2,500 ppm.
4
Refs. Iida M et al., Electromyogr. 1969 9 247-61
5
Sobue I et al., Int. J. Neurol. 1978 11 317-30
6
Rizzuto N et al., Eur. Neurol. 1980 19 308-15
7
Metabolism
8
In guinea pigs n-hexane metabolised to 2,5-hexanedione and 5-hydroxy-2-hexanone. Both
9
are also metabolites of methyl butyl ketone which is also neurotoxic.
10
Refs. DiVincenzo GD et al., Toxicol. Appl. Pharmacol. 1976 36 511
11
Schaumburg HH and Spenser PS. Brain 1976 99 183
12
13
Conclusion
14
The PDE for hexane is 2.9 mg/day.
15
Page 51
draft 7 page
51
1
METHANOL
2
Genotoxicity
3
Negative results in vitro in Ames test and SCE assays.
4
Refs. Shimizu H et al., Jpn. J. Ind. Health 1985 27 400 - 19.
5
Latt SA et al., Mut. Res. 1981 87 (1) 17-62.
6
Campbell JA Mut. Res. 1991 260 257-64
7
Carcinogenicity
8
No data available.
9
Reproductive Toxicity
10
Rats given 5000, 10,000, and 20,000 ppm by inhalation 7 h/day throughout gestation. Slight
11
maternal toxicity and increases in defects in skeletal, cardiac and urinary systems at high dose
12
and reduced foetal weights at intermediate level with small increase in abnormalities.
13
NEL 5,000 ppm. Ref. Nelson BK et al., Fund. Appl. Toxicol. 1985 5 727-36.
14
15
NEL = 5,000 ppm =
5,000 x 32.04
24.45
= 6552 mg / m = 6.55 mg / L
3
16
17
For continuous dosing =
6.55 x 7
24
= 1.91 mg / L
18
19
Daily dose =
1.91 x 290
0.33 kg
= 1678 mg / kg
20
21
PDE =
1678 x 50
5 x 10 x 1 x 10 x 1
= 167.8 mg / day
22
23
Limit =
167.8 x 1000
10
= 16,780 ppm
24
Page 52
draft 7 page
52
1
Animal Toxicity
2
Oral LD50 in rats 3.56 g/kg.
3
Ref. Reported in Patty’s Industrial Hygiene and Toxicology, 3rd Edn. New York 1982.
4
5
6 g/kg given by gavage to rhesus monkeys for 3 days causes lethal acidosis but if this is
6
treated with sodium bicarbonate survivors show characteristic retinal oedema as seen in
7
humans. Ref. Potts A.M. Am J. Ophthalmol. 1955 39 86-92.
8
9
PDE =
6000 x 50
10 x 10 x 10 x 1 x 10
= 30 mg / day
10
11
Limit =
30 x 1000
10
= 3,000 ppm
12
13
Metabolism
14
Characteristic methanol toxicity is seen in monkeys and humans but not in rats and mice.
15
There is a strong correlation with low hepatic tetrahydrofolate levels and decreased hepatic
16
10 - formyltetrahydrofolate dehydrogenase activity in susceptible species.
17
Ref. Johlin FC et al., Mol. Pharmacol. 1987 31 (5) 557-61.
18
19
Conclusion
20
The PDE for methanol is 30 mg/day.
21
22
Page 53
draft 7 page
53
1
2-METHOXYETHANOL
2
Genotoxicity
3
Negative in in vitro studies. Negative in vivo SCE in rat bone marrow. Positive in dominant
4
lethal in rats and mice. Effect on spermatids and spermatogonia (not genotoxic - effect on
5
fertility). Refs. McGreger BD et al., Toxicol.Appl. Pharmacol. 1983 70 303-16
6
Chapin RE et al., Fund.Appl.Toxicol. 1985 5 182-9
7
Rao KS et al., Fund.Appl.Toxicol. 1983 33 80-85
8
Carcinogenicity
9
Data not available.
10
Reproductive Toxicity
11
New Zealand white rabbits exposed to 3, 10, or 50 ppm by inhalation 6h/day on days 6-18.
12
Decreased weight gain at high dose during exposure period with partial recovery later.
13
Decreased foetal weight at high dose with high incidence of abnormalities to skeletal and c/v
14
systems. NEL 10 ppm. Ref. Hanley TR et al., Toxicol. Appl. Pharmacol. 1984 75 409-22
15
16
10 ppm =
10 x 76.09
24.45
= 31.1 mg / m = 0.031 mg / L
3
17
18
For continuous exposure =
0.031 x 6
24
= 0.008 mg / L
19
20
Daily dose =
0.008 x 1440
4
= 2.88 mg / kg
21
22
PDE =
2.88 x 50
2.5 x 10 x 1 x 1 x 5
= 1.15 mg / day
23
24
Limit =
1.15 x 1000
10
= 115 ppm
25
Page 54
draft 7 page
54
1
Toxicity
2
Oral doses of 50, 100, 250 and 500 mg/kg orally for 11 days to Sprague-Dawley rats caused
3
testicular damage affecting spermatocytes and spermatogonia. NEL 50 mg/kg.
4
Ref. Foster PMD et al., Toxicol.Appl.Pharmacol. 1983 69 385-99
5
6
PDE =
50 x 50
5 x 10 x 10 x 1 x 1
= 5 mg / day
7
8
Limit =
5 x 1000
10
= 250 ppm
9
10
Sprague-Dawley rats given 30, 100 or 300 ppm by inhalation 6 h/day, 5 days/week for 13
11
weeks. Bodyweight, thymus and testicular weight reduced at high dose with degeneration of
12
germinal epithelium. NEL 100 ppm. Ref. Miller RP et al., Fund. Appl.Toxicol 1983 3 49-54
13
14
100 ppm =
100 x 76.09
24.45
= 311 mg / m = 0.311 mg / L
3
15
16
For continuous dosing =
0.311 x 6 x 5
24 x 7
= 0.056 mg / L
17
18
Daily dose =
0.056 x 290
0.425
= 38.2 mg / kg
19
20
PDE =
38.2 x 50
5 x 10 x 5 x 1 x 1
= 7.64 mg / day
21
22
Limit =
7.64 x 1000
10
= 764 ppm
23
24
Page 55
draft 7 page
55
NZW rabbits given 30, 100, 300 ppm by inhalation 6 h/day, 5 days/week for 13 weeks.
1
Deaths in rabbits. Decreased testicular size at all levels, degeneration of germinal epithelium
2
at all levels (minimal change at 30 ppm). LOEL 30 ppm.
3
Ref. Miller RP et al., Fund.Appl.Pharmacol. 1983 3 49-54
4
5
30 ppm =
30 x 76.09
24.45
= 93.36 mg / m = 0.093 mg / L
3
6
7
For continuous dosing =
0.093 x 6 x 5
24 x 7
= 0.017 mg / L
8
9
Daily dose =
0.017 x 1440
4
= 6.1 mg / kg
10
11
PDE =
6.1 x 50
2.5 x 10 x 5 x 1 x 5
= 0.49 mg / day
12
13
Limit =
0.49 x 1000
10
= 49 ppm
14
15
Human Results
16
Groups of shipyard workers exposed to 2-methoxyethanol and other materials at varying
17
concentrations had anaemia and reduced sperm counts.
18
Ref. Welch LS et al., Am. J. Ind. Med. 1988 14 509-36
19
20
Conclusion
21
The PDE for 2-methoxyethanol is 0.5 mg/day.
22
Page 56
draft 7 page
56
1
METHYLBUTYL KETONE
2
Genotoxicity
3
No data available
4
Carcinogenicity
5
No data available
6
Reproductive toxicity
7
F344 rats were exposed to 500, 1000 and 2000 ppm by inhalation 6 h/day throughout
8
gestation. Maternal weight gain reduced at 1000 and 2000 ppm with reduced litter size and
9
pup weights at high dose. No abnormalities but pups were hyperactive at 1000 and 2000
10
ppm. Postnatal results at 500 ppm not available. NOEL 1000 ppm for foetal toxicity. Post
11
natal results uninterpretable.
12
Ref. Peters MA et al., Ecotox and Environ. Safety 1981 5 291-306.
13
14
1000 ppm =
1000 x 100.16
24.45
= 4097 mg / m
4.1 mg / L
3
=
15
16
For continuous dosing =
4.1 x 6
24
= 1.03 mg / L
17
18
Daily dose =
1.03 x 290
0.33
= 905 mg / kg
19
20
PDE =
905 x 50
5 x 10 x 1 x 1 x 1
= 905 mg / day
21
22
Limit =
905 x 1000
10
= 90,500 ppm
23
Page 57
draft 7 page
57
Animal toxicity
1
Several papers report peripheral neuropathy after oral administration or by inhalation.
2
Axonal swelling, beading and degeneration with demyelination are usually noted.
3
Wistar rats given 50 ppm by inhalation 8 h/day, 5 days/week for 13 weeks showed evidence
4
of demyelination but nothing was seen at 40 ppm.
5
Ref. Duckett S et al., Experientia 1979 35 (10) 1365-7.
6
7
40 ppm =
40 x 100.16
24.45
= 164 mg / m = 0.164 mg / L
3
8
9
For continuous dosing =
0.164 x 8 x 5
24 x 7
= 0.039 mg / L
10
11
Daily dose =
0.039 x 290
0.425
= 26.6 mg / kg
12
13
PDE =
26.6 x 50
5 x 10 x 10 x 1 x 5
= 0.53 mg / day
14
15
Limit =
0.53 x 1000
10
= 53 ppm
16
17
Male rats were given 0.25, 0.5 and 1% in drinking water for 13 months. Reduced weight gain
18
at all levels. Clinical signs of neuropathy at intermediate and high levels but morphological
19
changes seen at all dosages. LOEL = 0.25%
20
Ref. Krasavage WJ et al., Toxicol. Appl. Pharmacol. 1979 48 A205
21
22
0.25% = 250 mg /100 ml
Rat drinks 30 ml / day
23
24
Page 58
draft 7 page
58
i.e. consumes
250 x 30
100
= 75 mg / day
1
2
Daily dose =
75 x 1000
425
= 176 mg / kg
3
4
PDE =
176 x 50
5 x 10 x 1 x 10 x 10
= 1.76 mg / day
5
6
Limit =
1.76 x 1000
10
= 176 ppm
7
8
Human Results
9
Several reports of peripheral polyneuropathy. Similar pathology seen to animal studies.
10
Refs. Davenport JG et al., Neurol. 1976 26 912-23
11
Billmaier D et al., J. Occup. Med. 1974 16 (10) 665-71
12
Wickersham CW and Fredericks EJ Conn. Med. 1976 40 311-12
13
Allen N et al., Arch. Neurol. 1975 32 209-18
14
Mallov JS. J. Am. Med. Assoc. 1976 235 1455-57.
15
16
Conclusion
17
The PDE for methylbutyl ketone is 0.5 mg/day.
18
Page 59
draft 7 page
59
1
METHYLCYCLOHEXANE
2
3
Genotoxicity
4
No data available.
5
Carcinogenicity
6
No data available.
7
Reproductive Toxicity
8
No data available.
9
Toxicity
10
Oral LD50 in mice 2.25 g/kg. Oral LDLo in rabbits 4 g/kg.
11
Ref. Nikunen E Environmental Properties of Chemicals 1990 VAPK Publishing, Helsinki
12
Inhalation LC50 (2h) in mice 41,500 mg/m
3
.
13
Ref. Izmerov NF et al., Toxicometric Parameters of Industrial Toxic Chemicals under Single
14
Exposure 1982 CIP, Moscow
15
16
The tissues of rabbits exposed to 0.948 or 4.57 mg/L (241 or 1162 ppm), 6h/day, 5
17
days/week for 10 weeks showed no evidence of toxicity when examined microscopically 2
18
months after exposure ceased. NEL 4.57 mg/L.
19
Ref. Treon JF J. Indust. Hyg. Toxicol. 1943 25 (6) 323-347
20
21
Continuous exposure =
4.57 x 6 x 5
24 x 7
= 0.82 mg / L
Daily dose =
0.82 x 1440
4
= 295 mg / kg
PDE=
295 x 50
2.5 x 10 x 10 x 5 x 1
= 11.8 mg / day
22
23
Limit =
11.8 x 1000
10
= 1180
24
25
Page 60
draft 7 page
60
Human
1
No relevant data.
2
3
Conclusion
4
The PDE for methylcyclohexane is 11.8 mg/day.
5
Page 61
draft 7 page
61
1
N-METHYLPYRROLIDONE
2
Genotoxicity
3
Negative in Ames test, caused aneuploidy in Saccharomyces cerevisiae.
4
Refs. Wells DA et al., J. Appl. Toxicol. 1988 8 (2) 135-9
5
Mayer VW et al., Environ. Mol. Mutagen 1988 11 (1) 31-40
6
Carcinogenicity
7
0.04 and 0.4 mg/L given by inhalation 6 h/day, 5 days/week to Sprague-Dawley rats for 2
8
years.
9
No toxic or carcinogenic effects. Ref. Lee KP et al., Fund. Appl. Toxicol. 1987 9 222-35.
10
NEL = 0.4 mg/L
11
12
For continuous dosing =
0.4 x 6 x 5
24 x 7
= 0071 mg / L
13
14
Daily dose =
0.071 x 290
0.425
= 48.4 mg / kg
15
16
PDE =
48.4 x 50
5 x 10 x 1 x 1 x 1
= 48.4 mg / day
17
18
Limit =
48.4 x 1000
10
= 4840 ppm
19
20
Reproductive Toxicity
21
Single I/P dose of 166 mg/kg to mice on day 7 caused increased resorptions. The same dose
22
on day 9 caused malformations. Ref. Schmidt R. Biol. Rundsch. 1976 14 (1) 38.
23
0.1 and 0.36 mg/L 6 h/day days 6-15 had no adverse effects on pregnancy in Sprague-Dawley
24
rats.
25
Page 62
draft 7 page
62
Ref. Lee KP et al., Fund. Appl. Toxicol. 1987 9 222-35. NEL 0.36 mg/L
1
2
For continuous dosing =
0.36 x 6
24
= 0.09 mg / L
3
4
Daily dose =
0.09 x 290
0.33 kg
= 79 mg / kg
5
6
PDE =
79 x 50
5 x 10 x 1 x 1 x 1
= 79 mg / day
7
8
Limit =
79 x 1000
10
= 7900 ppm
9
10
Animal Toxicity
11
As in ‘carcinogenicity’ above, no adverse effects seen after 0.4 mg/L administered 6 h/day, 5
12
days/week for 2 years to Sprague-Dawley rats.
13
Ref. Lee KP et al., Fund. Appl. Toxicol. 1987 9 222-35.
14
15
Conclusion
16
The PDE for N-methylpyrrolidone is 48.4 mg/day.
17
18
Page 63
draft 7 page
63
1
NITROMETHANE
2
3
Genotoxicity
4
Negative in up to 5 strains of Salmonella typhimurium in several Ames tests, at
5
concentrations of up to 10000 ug/plate, and in the presence or absence of metabolic activating
6
systems from rat and hamster liver. Negative in a sex-linked recessive lethal assay in
7
Drosophila. Negative in micronucleus tests in mouse bone marrow at intraperitoneal doses of
8
up to 1830 mg/kg in vivo.
9
Refs. Mortelmans K et al., Environmental Mutagenesis 1986 8 (suppl. 7) 1-119
10
Gocke E et al., Mutation Research 1981 90 (2) 91-109
11
Chiu CW et al., Mutation Research 1978 58 11-22
12
Lofroth G et al., Environmental Mutagenesis 1981 3 (3) 336
13
Dellarco VL and Prival MJ Env. Mol. Mutagenesis 1989 13 (2) 116-127
14
15
Carcinogenicity
16
F344 rats given 94, 188, or 375 ppm by inhalation 6h/day, 5 days/week for 2 years. Mammary
17
gland fibroadenoma, or fibroadenoma/adenoma combined with fibroadenoma, adenoma, or
18
carcinoma (combined) in females, in intermediate and high groups increased. Also incidences
19
of mammary gland carcinoma and of adenoma or carcinoma (combined) in the high dose
20
group was increased. Ref NTP Tech Report 461 NIH Pub No. 95-3377 (1995)
21
22
94 ppm =
94 x 61.04
24.45
= 234.6 mg / m = 0.235 mg / L
3
23
24
For continuous dosing =
0.235 x 6 x 5
24 x 7
= 0.042 mg / L
25
26
Daily dose =
0.042 x 290
0.425
= 28.7 mg / kg
27
Page 64
draft 7 page
64
1
PDE =
28.7 x 50
5 x 10 x 1 x 10 x 1
= 2.87 mg / day
2
3
Limit =
2.87 x 1000
10
= 287 ppm
4
5
B6C3F1 mice given 188, 375, or 750 ppm by inhalation 6h/day, 5 days/week for 2 years.
6
Harderian gland adenoma and adenoma or carcinoma (combined) increased at intermediate
7
and high levels. Incidence of Harderian gland carcinoma also increased at intermediate and
8
high levels. Incidence of alveolar/broncheolar carcinoma in males at high level and females at
9
intermediate level also increased. Female low and high level mice had increased hepatocellular
10
adenoma and adenoma or carcinoma combined. Eosinophilic liver foci increased at
11
intermediate and high levels. Degeneration and metaplasia of olefactory epithelium increased
12
in all groups. Ref NTP Tech Report 461 NIH Pub No. 95-3377 (1995)
13
14
188 ppm =
188 x 61.04
24.45
= 469 mg / m = 0.469 mg / L
3
15
16
For continuous dosing =
0.469 x 6 x 5
24 x 7
= 0.08 mg / L
17
18
Daily dose =
0.08 x 43
0.028
= 123 mg / kg
19
20
PDE =
123 x 50
12 x 10 x 1 x 10 x 10
= 0.51 mg / day
21
22
Limit =
0.51 x 1000
10
= 51 ppm
23
24
Reproductive Toxicity
25
Page 65
draft 7 page
65
No data on teratogenicity available. Female rats were given 0.5 mL of 1.5 M nitromethane in
1
NaCl every third day from one week before mating, and at least throughout gestation (unclear
2
whether dosing continued through lactation). No effects on fertility, litter parameters or pup
3
behaviour were found. There was a suggestion of impaired maze-learning when pups were
4
tested at 2.5 months old.
5
Ref. Whitman RD et al., J. Abnorm. Psychol. 1977 86 662-664
6
7
Virtual NEL =
0.5 x 1.5 x 61.04
0.330
= 138.8 mg / kg
Continuous exposure =
138.8
3
= 46.3 mg / kg
PDE =
46.3 x 50
5 x 10 x 1 x 1 x 1
= 46.3 mg / day
8
9
Limit =
46.3 x 1000
10
= 4630 ppm
10
11
Toxicity
12
Oral LD50 in mice 1440 mg/kg.
13
Ref. Weatherby JH Arch. Ind. Hyg. Occup. Med. 1955 11 102-106
14
Oral LD50 in rats 1210 mg/kg.
15
Ref. Martin JL and Baker PJ in Kirk-Othmer Encyclopedia of Chemical Technology (ed.
16
Standen A), 2nd ed. 1967 13 864-888, Wiley, New York
17
Oral LDLo in dogs 125 mg/kg. Pathologic lesions generally confined to liver, and appeared to
18
be dose-related.
19
Oral LDLo in rabbits 750 mg/kg.
20
Intravenous LDLo in dogs and rabbits 750-800 mg/kg.
21
Ref. Weatherby JH Arch. Ind. Hyg. Occup. Med. 1955 11 102-106
22
23
Page 66
draft 7 page
66
Rats given 0.25 or 0.1% in drinking water for 15 weeks; daily doses estimated as 150 and 80
1
mg/kg/day. 3/10 and 4/10 rats died at 0.25 and 0.1%, respectively. Reduced weight gain in
2
survivors and evidence of liver damage. LOEL = 80 mg/kg
3
Ref. Weatherby JH Arch. Ind. Hyg. Occup. Med. 1955 11 102-106
4
5
PDE =
80 x 50
5 x 10 x 5 x 1 x 10
= 1.6 mg / day
Limit =
1.6 x 1000
10
= 160 ppm
6
7
B6C3F1 mice exposed by inhalation to 0, 94, 188, 375, 750, 1500 ppm for 6 h/day, 5
8
days/week for 13 weeks. Dose-related changes in olfactory and respiratory epithelium in both
9
sexes at ≥ 375 ppm, and in females at 188 ppm. Hyaline droplets in females at 94 and 188
10
ppm. LOEL 94 ppm.
11
Ref. Battelle Pacific Northwest Laboratories, 13-Week Subchronic Inhalation Toxicity Study
12
Report on Nitromethane in Mice, NTP Contract No. N01-ES-75189, 12122, 1989, Battelle,
13
Richland, WA
14
15
94 ppm =
94 x 61.04
24.45
= 234.7 mg / m = 0.235 mg / L
Continuous exposure =
0.235 x 6 x 5
24 x 7
= 0.042 mg / L
Daily dose =
0.042 x 43
0.028
= 64.5 mg / kg
PDE =
64.5 x 50
12 x 10 x 5 x 1 x 5
= 1.08 mg / day
Limit =
1.08 x 1000
10
= 108 ppm
3
16
17
Page 67
draft 7 page
67
Fischer 344 rats exposed by inhalation to 0, 94, 188, 375, 750, 1500 ppm for 6 h/day, 5
1
days/week for 13 weeks. Reductions in body weight gain,erythrocyte values, grip strength,
2
and cellularity of bone marrow were found, with degeneration of olfactory epithelium and
3
respiratory epithelial hyaline droplet formation. Sciatic nerve and spinal cord degeneration
4
was evident at ≥ 375 ppm. NEL 94 ppm.
5
Ref. Battelle Pacific Northwest Laboratories, 13-Week Subchronic Inhalation Toxicity Study
6
Report on Nitromethane in Rats, NTP Contract No. N01-ES-75189, 12122, 1989, Battelle,
7
Richland, WA
8
9
94 ppm =
94 x 61.04
24.45
= 234.7 mg / m = 0.235 mg / L
Continuous exposure =
0.235 x 6 x 5
24 x 7
= 0.042 mg / L
Daily dose =
0.042 x 290
0.425
= 28.7 mg / kg
PDE =
28.7 x 50
5 x 10 x 5 x 10 x 1
= 0.57 mg / day
Limit =
0.57 x 1000
10
= 57 ppm
3
10
11
Sprague-Dawley rats exposed by inhalation to 0, 98 or 745 ppm, 7 h/day, 5 days/week for 6
12
months. Ten rats from treated and control groups killed after 2 days, 10 days, 1, 3 and 6
13
months. Effects on haematocrit and Hb, decreased weight gain at 745 ppm; small increases in
14
thyroid weight at 98 and 745 ppm. LOEL 98 ppm.
15
Ref. Lewis TR et al., J. Environ. Pathol. Toxicol. 1979 2 233-249
16
17
Page 68
draft 7 page
68
98 ppm =
98 x 61.04
24.45
= 244.7 mg / m = 0.245 mg / L
Continuous exposure =
0.245 x 7 x 5
24 x 7
= 0.05 mg / L
Daily dose =
0.05 x 290
0.425
= 34.1 mg / kg
PDE =
34.1 x 50
5 x 10 x 2 x 1 x 5
= 3.41 mg / day
Limit =
3.41 x 1000
10
= 341 ppm
3
1
2
New Zealand White rabbits exposed by inhalation to 0, 98 or 745 ppm, 7h/day, 5 days/week
3
for 6 months. Five rabbits from treated and control groups killed after 2 days, 10 days, 1, 3
4
and 6 months. Haemoglobin concentration decreased marginally only at 1 month. Slight
5
increase in thyroid weight at 745 ppm and decreased serum T4 at 98 and 745 ppm. LOEL 98
6
ppm. Ref. Lewis TR et al., J. Environ. Pathol. Toxicol. 1979 2 233-249
7
8
As above, continuous exposure = 0.05 mg / L
Daily dose =
0.05 x 1440
4
= 18 mg / kg
PDE =
18 x 50
2.5 x 10 x 2 x 1 x 5
= 3.6 mg / day
Limit =
3.6 x 1000
10
= 360 ppm
9
10
Human
11
Probable human oral lethal dose has been estimated to be 0.5-5 g/kg. Occupational exposure
12
to very high levels has been reported, with gross conversion of haemoglobin to
13
methaemoglobin and sulphaemoglobin. Nitromethane is a weak narcotic. It inactivates
14
Page 69
draft 7 page
69
histidase, and has been used experimentally to produce an animal model for the study of the
1
human genetic disorder characterised by histidinaemia.
2
3
Conclusion
4
The PDE for nitromethane is 0.5 mg/day.
5
Page 70
draft 7 page
70
1
PYRIDINE
2
Genotoxicity
3
Negative in all tests reported.
4
Refs. Aesbacher HV et al., Fd. Chem. Tox. 1989 27 (4) 227-32
5
Ishidate M and Odoshima S. Mut. Res. 1977 48 337-54
6
Abe S and Sasaki M. J. Ntl. Cancer Inst. 1977 58 (6) 1635-41
7
Florin I et al., Toxicol. 1980 15 219-32.
8
Carcinogenicity
9
No effect on tumour incidence when twice weekly s/c injections given to F344 rats for one
10
year - animals retained after treatment. Animals were examined after a delay. NEL 100
11
mg/kg. Ref. Mason MM et al., Clin. Tox. 1971 4 (2) 185-204
12
13
For continuous dosing =
100 x 2
7
= 28.6 mg / kg
14
15
PDE =
28.6 x 50
5 x 10 x 10 x 1 x 1
= 2.86 mg / day
16
17
Limit =
2.86 x 1000
= 286 ppm
10
18
19
Reproductive Toxicity
20
No data available.
21
Toxicity
22
Slightly increased liver weights at 10 mg/kg in 90 day gavage study in Sprague-Dawley rats.
23
Bile duct proliferation and vacuolated hepatocytes at 50 mg/kg. Virtual NOEL 10 mg/kg.
24
Ref. Anderson RC 1987 EPA Doc No. 530/SW-88/016A
25
26
Page 71
draft 7 page
71
PDE =
10 x 50
5 x 10 x 1 x 1 x 5
= 2 mg / day
1
2
Limit =
2 x 1000
10
= 200 ppm
3
4
Human Results
5
Transient symptoms (nausea, headache etc) but with no liver or kidney damage after exposure
6
to 125 ppm 4 h/day for 2 weeks.
7
Symptoms of CNS injury reported from chronic exposure from 6-12 ppm.
8
Ref. Teisinger J. J. Ind.Hyg. Tox. 1948 30 58.
9
Pyridine is a permitted direct food additive
10
Ref. 21 CFR 172.515 (1988).
11
12
Conclusion
13
The PDE for pyridine is 2.0 mg/day.
14
Page 72
draft 7 page
72
1
SULFOLANE
2
3
Genotoxicity
4
Sulfolane gave negative results in Ames test assays. Chinese hamster ovary cell sister
5
chromatid exchange assay and gene conversion assay with Saccharomyces cerevisae and in a
6
rat micronucleus test.
7
Refs. Shimizu H et al., Sangyo Igaku 1985 27 (6) 400-419
8
EPA Doc. No. FYI-OTS-0484-0304. Fiche No. OTS0000304-0 (1982)
9
Glaxo Wellcome R&D - Unpublished data
10
A positive result was obtained in a mouse lymphoma forward mutation assay
11
Ref. EPA Doc. No. FYI-OTS-0484-0304. Fiche No. OTS0000304-0 (1982)
12
13
Carcinogenicity
14
No data available
15
16
Reproductive Toxicity
17
Subcutaneous doses of 25, 100 or 400 mg/kg were given to Sprague-Dawley rats daily from
18
day 6-15 of gestation. Loss of condition and reduced maternal weight gain was noted at the
19
intermediate and high dose levels. Foetal weight was marginally reduced at the high dose
20
level but there were no embryolethal or teratogenic effects.
21
Ref. Glaxo Wellcome unpublished data. NOEL for teratogenicity 400 mg/kg
22
23
PDE =
400 x 50
5 x 10 x 1 x 1 x 1
= 400 mg / day
24
25
Limit =
400 x 1000
10
= 40,000 ppm
26
27
Page 73
draft 7 page
73
Animal Toxicity
1
1g/kg cream containing 40% w/w sulfolane was applied to the shaven skin of albino rats daily
2
for 31 days. No adverse effects were noted.
3
Ref. Glaxo Wellcome unpublished data.
4
NOEL 1g/kg of 40% w/w sulfolane cream = 400 mg/kg sulfolane
5
6
PDE =
400 x 50
5 x 10 x 10 x 1 x 1
= 40 mg / day
7
8
Limit =
40 x 1000
10
= 4000 ppm
9
10
Sprague-Dawley rats were exposed by inhalation to 495 mg/m
3
8h/day, 5 days/week for 27
11
days of exposure. All animals survived and no effects on weight gain were noted. All
12
animals had chronic lung and chronic liver inflammation. A slight decrease in WBC count
13
was also noted. Ref. Andersen ME et al., Toxicol. Appl. Pharmacol. 1977 40 463-472
14
LOEL is 495 mg/m
3
= 0.495 mg/L
15
16
Continuous exposure =
0.495 x 8 x 5
24 x 7
= 0.118 mg / L
Daily dose =
0.118 x 290
0.425
= 80.5 mg / kg
17
18
PDE =
80.5 x 50
5 x 10 x 10 x 1 x 5
= 1.61 mg / day
19
20
Limit =
1.61 x 1000
10
= 161 ppm
21
22
Male Sprague-Dawley rats were exposed by inhalation to 2.8, 4 or 20 mg/m
3
23 h/day for 3
23
months. Females were also exposed at the high level. No adverse effects were seen.
24
Page 74
draft 7 page
74
Ref. Andersen ME et al., Toxicol. Appl. Pharmacol. 1977 40 463-72
1
NOEL 20mg/m
3
= 0.02 mg/L
2
3
Continuous exposure =
0.02 x 23
24
= 0.019 mg / L
Daily dose =
0.019 x 290
0.425
= 13 mg / kg
4
5
PDE =
13 x 50
5 x 10 x 5 x 1 x 1
= 2.6 mg / day
6
7
Limit =
2.6 x 1000
10
= 260 ppm
8
9
Guinea pigs were exposed by inhalation to 200 mg/m
3
23 h per day for one month. All
10
animals survived with no effects on weight gain. Chronic pleuritis and fatty vacuolation of the
11
liver was noted. These changes were considered adaptive.
12
Ref. Andersen ME et al., Toxicol. Appl. Pharmacol. 1977 40 463-72
13
NOEL 200 mg/m
3
= 0.2 mg/L
14
15
Continuous exposure =
0.2 x 23
24
= 0.19 mg / L
Daily dose =
0.19 x 430
0.5
= 165 mg / kg
16
17
PDE =
165 x 50
10 x 10 x 10 x 1 x 1
= 8.25 mg / day
18
19
Limit =
8.25 x 1000
10
= 825 ppm
20
Page 75
draft 7 page
75
1
Guinea pigs were exposed by inhalation to 20 or 159 mg/m
3
23 h/day for 3 months. No
2
adverse effects were noted. Ref. Andersen ME et al., Toxicol. Appl. Pharmacol. 1977 40
3
463-72. NOEL 159 mg/m
3
= 0.16 mg/L
4
5
Continuous exposure =
0.16 x 23
24
= 0.15 mg / L
Daily dose =
0.15 x 430
0.5
= 129 mg / kg
6
7
PDE =
129 x 50
10 x 10 x 5 x 1 x 1
= 12.9 mg / day
8
9
Limit =
12.9 x 1000
10
= 1290 ppm
10
11
ADME
12
Rapid and complete absorption from the GI tract in rats. Easy passage through blood-brain
13
and placental barriers. Mainly eliminated by kidneys.
14
Ref. Zhan Zhenhua et al., J W CUMS 1988 19 (1) 61-4
15
16
Whole body autoradiography studies indicate widespread distribution following a single s/c
17
injection of 50 mg/kg to Sprague-Dawley rats. Radio label was still measurable in the lens of
18
the eye 4 weeks after exposure.
19
Ref. Glaxo Wellcome unpublished data.
20
21
Conclusion
22
The PDE for sulfolane is 1.6 mg/day.
23
Page 76
draft 7 page
76
1
TETRALIN
2
3
Genotoxicity
4
Not mutagenic with or without metabolic activation in bacterial (Ames) test, at up to 3
5
umol/plate (limited by toxicity).
6
Ref. Florin I et al., Toxicology 1980 18 219-232
7
8
Carcinogenicity
9
No data available.
10
11
Reproductive Toxicity
12
No data available.
13
14
Toxicity
15
Oral LD50 in rats 2.86 g/kg.
16
Dermal LD50 in rabbits 17.3 mL/kg.
17
Ref. Smyth HF et al., Arch. Indust. Hyg. Occup. Med. 1951 4 119
18
Inhalation LCLo in guinea pigs 275 ppm for seventeen 8h exposures.
19
Ref. Sandmeyer EE Alicyclic Hydrocarbons. In: Clayton GD and Clayton FE (eds), Patty's
20
Industrial Hygiene and Toxicology, 3rd Rev. Ed., Vol. 2B, p. 3241, Wiley, New York.
21
22
One report (experimental design poorly defined) indicated that two guinea pigs exposed to a
23
presumably saturated atmosphere, evidently for 30 min/day for 6 days, developed cataracts.
24
Ref. Badinand A et al., Arch. Mal. Prof. 1947 8 124-130
25
Rabbits given 0.2-1.0 mL tetralin/day orally for 30-40 days also developed cataracts.
26
Ref. Gerarde HW in Toxicology and Biochemistry of Aromatic Hydrocarbons 1960, 234-235,
27
Elsevier, NY
28
Weanling rats fed diet containing 2% tetralin for at least 2 months did not develop cataracts,
29
but cataractogenesis was observed in rats given 0.25% or more dietary β-tetralol within a few
30
weeks.
31
Ref. Fitzhugh OG and Buschke WH Arch. Ophthalmol. 1949 41 572-582
32
Page 77
draft 7 page
77
The species differences may be related to the amount of β-tetralol formed; this appears to be a
1
more significant metabolite in rabbits than in rats. Very limited evidence suggests that β-
2
tetralol is not a major metabolite in man. Refs. Elliott TH and Hanam J Biochem. J. 1968 108
3
551-559; Drayer DE and Reidenberg MM Drug Metab. Dispos. 1973 1 577-579
4
For rabbits: LOEL = 0.2 mL/day = 194 mg/day = 194/4 = 48.5 mg/kg
5
6
PDE =
48.5 x 50
2.5 x 10 x 10 x 1 x 10
= 0.97 mg / day
7
8
Limit =
0.97 x 1000
10
= 97 ppm
9
10
Male Fischer 344 rats given 0.5 mL/kg (485 mg/kg) orally every other day for 14 days
11
(maximum tolerated regimen). Only kidneys examined histologically; damage characteristic of
12
hydrocarbon nephropathy. This is a rat-specific finding related to the presence of α-2µ
13
globulin in that species, and is not of relevance to risk assessment for man. Ref. Serve MP et
14
al., J. Toxicol. Environ. Health 1989 26 267-275. Virtual NEL = 243 mg/kg per day.
15
16
PDE =
243 x 50
5 x 10 x 10 x 1 x 1
= 24.3 mg / day
17
18
Limit =
24.3 x 1000
10
= 2430 ppm
19
20
Human
21
Nausea, vomiting and evidence of mild, reversible renal and hepatic involvement in a woman
22
who ingested approximately 250 mL of Cuprex containing 31.5% tetralin. Human lethal dose
23
estimated to be 0.5-5 g/kg.
24
Ref. Drayer DE and Reidenberg MM Drug Metab. Dispos. 1973 1 577-579
25
Cases of occupational toxicity have also been recognised. Production of green-coloured urine
26
is characteristic.
27
28
Conclusion
29
The PDE for tetralin is 1.0 mg/day.
30
Page 78
draft 7 page
78
1
TOLUENE
2
Genotoxicity
3
Negative results in in vitro studies. Small increase (2-3 fold) in micronuclei after 2 I/P
4
injections up to 0.5 ml/kg. Negative in sperm morphology assay up to 1.5 ml/kg I/P.
5
Refs. NTP Tech Report No. 371. NIH Pub. No. 90-2563 (1990)
6
Bos RP et al., Mut. Res. 1981 88 273-9
7
Gerner-Smidt P and Friedrich U. Mut. Res. 1978 58 313-16
8
Topham JC Mut. Res. 1980 74 379-87
9
Mohtashamipur E et al., Arch. Toxicol. 1985 58 106-9.
10
Carcinogenicity
11
Rat No evidence of carcinogenicity in F344 rats given 1200 ppm by inhalation 6.5 h/day, 5
12
days/week for 2 years. Ref. NTP Tech Report No. 371 NIH Pub. No. 90-2563 (1990)
13
14
1200 ppm =
1200 x 92.13
24.45
= 4521 mg / m = 4.52 mg / L
3
15
16
For continuous dosing =
4.52 x 6.5 x 5
24 x 7
= 0.874 mg / L
17
18
Daily dose =
0.874 x 290
0.425
= 596 mg / kg
19
20
PDE =
596 x 50
5 x 10 x 1 x 1 x 1
= 596 mg / day
21
22
Limit =
596 x 1000
10
= 59,600 ppm
23
Page 79
draft 7 page
79
Mice 120, 600 or 1200 ppm by inhalation 6.5 h/day, 5 days/week for 2 years did not increase
1
tumour incidence in B6C3F1 mice. Ref. NTP Tech. Report No. 371. NIH Pub. No. 90-2563
2
(1990). As above continuous dose is 0.874 mg/L
3
4
Daily dose =
0.874 x 43
0.028
= 1342 mg / kg
5
6
PDE =
1342 x 50
12 x 10 x 1 x 1 x 1
= 559 mg / day
7
8
Limit =
559 x 1000
10
= 55,900 ppm
9
10
Reproductive Toxicity
11
CFY rats given 266 ppm by inhalation 8 h/day, days 1-21. No teratogenic effects, slight
12
decrease in foetal weight and some retardation in development. Ref: Hudak A and Ungvary
13
G. Toxicol. 1978 11 55-63
14
226 ppm =
226 x 92.13
24.45
= 1002 mg / m = 1 mg / L
3
15
16
For continuous dosing =
1 x 8
24
= 0.33 mg / L
17
18
Daily dose =
0.33 x 290
0.33 kg
= 290 mg / kg
19
20
PDE =
290 x 50
5 x 10 x 1 x 5 x 1
= 58 mg / day
21
22
Limit =
58 x 1000
10
= 5,800 ppm
23
24
Page 80
draft 7 page
80
CFLP mice given 133 ppm by inhalation 24 h/day, days 6-13. Slight decrease in foetal weight
1
and development but no teratogenic effects.
2
Ref. Hudak A and Ungvary G. Toxicol. 1978 11 55-63
3
4
133 ppm =
133 x 92.13
24.45
= 501 mg / m = 0.5 mg / L
3
5
6
Daily dose =
0.5 x 43
0.03 kg
= 717 mg / kg
7
8
PDE =
717 x 50
12 x 10 x 1 x 5 x 1
= 59.8 mg / day
9
10
Limit (ppm) =
59.8 x 1000
10
= 5980 ppm
11
12
Toxicity
13
CFY rats given 1000 mg/m
3
by inhalation 6 h/day, 5 days/week for 6 months. No
14
histological changes but increased liver weight and SER proliferation. These were regarded
15
as adaptive changes. NOAEL 1000 mg/m
3
.
16
Ref. Ungvary G et al., J. Hyg. Epidemial. Microbiol. Immunol. 1980 24 (3) 242-52
17
18
1000 mg / m = 1 mg / L
3
19
20
For continuous dosing =
1 x 6 x 5
24 x 7
= 0.179 mg / L
21
22
Daily dose =
0.179 x 290
0.425
= 122 mg / kg
23
24
Page 81
draft 7 page
81
PDE =
122 x 50
5 x 10 x 2 x 1 x 1
= 61 mg / day
1
2
Limit =
61 x 1000
10
= 6100 ppm
3
4
Rats and mice given 312, 625, 1,250, 2,500 or 5,000 mg/kg by gavage, dosed 5 days/week
5
for 13 weeks. All animals receiving 5,000 mg/kg died during the first week and deaths were
6
also noted at the 2,500 mg/kg level. Brain lesions were noted in rats at 1,250 mg/kg and
7
liver and kidney weights were increased at lower dosage. These changes were regarded as
8
adaptive. NOEL 625 mg/kg. Ref. NTP Document TR371 1990
9
10
For continuous dosing =
625 x 5
7
= 446 mg / kg
11
12
PDE =
446 x 50
5 x 10 x 10 x 5 x 1
= 8.9 mg / day
13
14
Limit =
8.9 x 1000
10
= 890 ppm
15
16
Human Results
17
Workers exposed to 100-1100 ppm had liver enlargement and moderate decrease in RBC but
18
no leucopenia. Ref. Greenburg L et al., J.Am.Med. Asso;c. 1942 118 573
19
Two children born of mothers with long history of toluene inhalation had microcephaly, CNS
20
dysfunction hyperactivity and delayed development.
21
Ref. Hersh JH. J. Med. Genet. 1989 26 (5) 333-7
22
23
Conclusion
24
The PDE for toluene is 8.9 mg/day.
25
Page 82
draft 7 page
82
1
1,1,2-TRICHLOROETHENE
2
Genotoxicity
3
Generally negative results when pure, unstabilised trichloroethylene is used.
4
Trichloroethylene is often stabilised with 1,2-epoxybutane or epichlorohydrin, both of which
5
are known mutagens and are probably responsible for the positive results seen in some
6
studies. Refs. McGregor DB et al., Environ. Mol. Mutagen. 1989 13 197-202
7
Shimada T et al., Cell Biol. Toxicol. 1985 1 (3) 159-79
8
Ashby J. In Progress in Mut. Res. 1981 1 111-71.
9
Trichloroethylene should not be considered genotoxic.
10
Carcinogenicity
11
Rats Osborne-Mendel rats given 500 or 1000 mg/kg/day 5 days/week by gavage for 18
12
months did not develop tumours. NEL 1000 mg/kg.
13
Ref. NCI Tech Report No. 2 NIH Pub. No. 76-802 (1976)
14
15
For continuous exposure =
1000 x 5
7
= 714 mg / kg
16
17
PDE =
714 x 50
5 x 10 x 1 x 1 x 1
= 714 mg / day
18
19
Limit =
714 x 1000
10
= 71,400 ppm
20
21
Exposure to 100, 300, 600 ppm by inhalation 7 h/day, 5 days/week for 2 years produced
22
dose-related increase in Leydig cell tumours in Sprague-Dawley rats and renal tumours at the
23
high dose level only. LOEL = 100 ppm Ref. Maltoni C et al., Ann. N.Y. Acad. Sci. 1988
24
534 316-42
25
26
Page 83
draft 7 page
83
100 ppm =
100 x 131.4
24.45
= 537 mg / m = 0.537 mg / L
3
1
2
For continuous exposure =
0.537 x 7 x 5
24 x 7
= 0.112 mg / L
3
4
Daily dose =
0.112 x 290
0.425
= 76 mg / kg
5
6
PDE =
76 x 50
5 x 10 x 1 x 10 x 10
= 0.76 mg / day
7
8
Limit =
0.76 x 1000
10
= 76 ppm
9
10
Mice B6C3F1 mice given 1200 or 2400 mg/kg (males), 900 or 1800 mg/kg (females) by
11
gavage 5 days/week for 18 months developed hepatocellular carcinomas.
12
Ref. NCI Tech Report No. 2 NIH Pub. No. 76-802 (1976). LOEL 900 mg/kg
13
14
For continuous exposure =
900 x 5
7
= 643 mg / kg
15
16
PDE =
643 x 50
12 x 10 x 1 x 10 x 10
= 2.68 mg / day
17
18
Limit =
2.68 x 1000
10
= 268 ppm
19
20
Reproductive Toxicity
21
Rats given 1800 ppm by inhalation 6h/day, 7 days/week before and during gestation showed
22
no effects on maternal weight gain or litter size and weight.
23
Page 84
draft 7 page
84
Ref. Dorfmueller MA et al., Toxicol. 19 79 14 153-66
1
2
1800 ppm =
1800 x 131.4
24.45
= 9674 mg / m = 9.7 mg / L
3
3
4
For continuous exposure =
9.7 x 6
24
= 2.43 mg / L
5
6
Daily dose =
2.43 x 290
0.33
2135 mg / kg
7
8
PDE =
2135 x 50
5 x 10 x 1 x 1 x 1
= 2135 mg / day
9
10
Limit (ppm) =
2135 x 1000
10
= 213,500 ppm
11
12
Toxicity
13
Doses of 17.9 mg/kg/day and above in drinking water to mice for 6 months suppressed cell
14
mediated immune responses to sheep red blood cells and inhibited bone marrow stem cell
15
colonization. LOEL 17.9 mg/kg.
16
Ref. Sanders V et al., Toxicol. Appl. Pharmacol. 1982 62 358-68.
17
18
PDE =
17.9 x 50
12 x 10 x 1 x 1 x 2
= 3.73 mg / day
19
20
Limit =
3.73 x 1000
10
= 373 ppm
21
22
In mice doses above 18.4 mg/kg in drinking water caused hepatic changes in 6 month study.
23
NOAEL 18.4 mg/kg.
24
Page 85
draft 7 page
85
Ref. Tucker A et al., Toxicol. Appl. Pharmacol. 1982 62 351-57
1
2
PDE =
18.4 x 50
12 x 10 x 1 x 1 x 2
= 3.83 mg / day
3
4
Limit (ppm) =
3.83 x 1000
10
= 383 ppm
5
6
Human Results
7
Large cohort study failed to show association between exposure and mortality due to cancer
8
Ref. Shindell S and Slack U J. Occup. Med. 1985 27 (8) 577-79
9
10
Metabolism
11
Qualitatively similar metabolism in mice, rats and humans. One of its metabolites,
12
trichloroacetic acid, can stimulate peroxisome proliferation in mouse livers.
13
14
Conclusion
15
The PDE for 1,1,2-trichloroethene is 0.8 mg/day.
16
Page 86
draft 7 page
86
1
XYLENE
2
(Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethylbenzene).
3
Genotoxicity
4
Consistently negative in in vitro studies and in micronucleus test in mice with 2 x 0.5 ml/kg
5
I/P.
6
Refs. Bos R P et al., Mut. Res. 1981 88 273-79
7
NTP Tech Report No. 327 NIH Pub. No. 87-2583 (1986)
8
Gerner-Smidt P and Friedrich U. Mut. Res. 1978 58 313-16
9
Mohtashamipur E et al., Arch. Toxicol. 1985 58 106-9
10
Carcinogenicity
11
250 or 500 mg/kg by gavage in corn oil to F344 rats 5 days/week for 2 years gave no
12
evidence of carcinogenicity. Ref. NTP Tech. Report No. 327 NIH Pub. No. 87-2583(1986)
13
14
For daily dosing =
500 x 5
7
= 357 mg / kg
15
16
PDE =
357 x 50
5 x 10 x 1 x 1 x 1
= 357 mg / day
17
18
Limit =
357 x 1000
10
= 35,700 ppm
19
20
Mice In same reference - no carcinogenic effects at 1000 mg/kg 5 days/week for 2 years in
21
B6C3F1 mice.
22
As above PDE = 360 mg/day
23
24
Limit = 36,000 ppm
25
26
Page 87
draft 7 page
87
Reproductive Toxicity
1
CD-1 mice given 0.6 - 4.8 mL/kg by gavage in cottonseed oil days 6-15.
2
4.8 mL/kg was lethal, maternal toxicity at 3.6 mL/kg, increased resorptions at 3 mL/kg, foetal
3
weight decreased from 2.4 mL/kg, cleft palate, open eyes and exencephaly from 1.2 mL/kg.
4
(SG = 0.86) NEL 0.6 mL/kg x 0.86 = 520 mg/kg
5
Ref. Marks TA et al., J. Tox. Environ. Health 1982 9 97-105.
6
7
PDE =
520 x 50
12 x 10 x 1 x 10 x 1
= 21.7 mg / day
8
9
Limit =
21.7 x 1000
= 2170 ppm
10
10
11
Toxicity
12
In F344 rats reduced weight gain at 1000 mg/kg by gavage in corn oil for 13 weeks. NEL
13
500 mg/kg. Ref. NTP Tech Report No. 327 NIH Publ No. 87-2583 (1986)
14
15
PDE =
500 x 50
5 x 10 x 5 x 1 x 1
= 100 mg / day
16
17
Limit =
100 x 1000
10
= 10,000 ppm
18
19
Conclusion
20
The PDE for xylene is 21.7 mg/day.
21