APPENDIX 4. TOXICOLOGICAL DATA FOR CLASS 1 SOLVENTS
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1
1
APPENDIX 4. TOXICOLOGICAL DATA FOR CLASS 1 SOLVENTS
2
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2
1
BENZENE
2
Category: Human carcinogen (IARC 1)
3
Not teratogenic
4
5
Toxic Effects:
6
Benzene causes central nervous system depression and destroys bone marrow, leading to
7
injury in the hematopoietic system.
8
9
Carcinogenesis:
10
There is sufficient evidence to establish that benzene is a human carcinogen (lymphatic and
11
hematopoietic cancers). In animal studies, Zymbal gland tumors, preputial gland tumors, skin
12
carcinomas, mammary gland tumors and leukemia are observed.
13
14
Genotoxicity:
15
Chromosomal aberration and DNA adducts tests are positive but other mutagenicity tests are
16
negative.
17
18
Assessment:
19
From the data of human leukemia and exposure concentrations of benzene, it was calculated
20
that a daily intake of 0.02 mg was associated with a lifetime excess cancer risk of 10
-5
(IRIS).
21
The guideline value for benzene is 0.02 mg per day (2 ppm).
22
References
23
Reviews: IARC Monographs 93 (1982)
24
Toxicological Profile ATSDR/TP 92/03
25
Pharmacopieal Forum (1991) Jan-Feb
26
Integrated Risk Information System (IRIS). US EPA, 1990.
27
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3
1
CARBON TETRACHLORIDE
2
Category
3
Possible human carcinogen (IARC 2B).
4
5
Genotoxicity
6
Not mutagenic with or without metabolic activation in bacterial (Ames) test with S.
7
typhimurium or E. coli.
8
Refs. McCann J and Ames BN Proc. Natl Acad. Sci. 1976 73 950-954
9
Barber ED et al., Mutat. Res. 1981 90 31-48
10
Uehleke H et al., Mutat. Res. 1976 38 114
11
Uehleke H et al., Xenobiotica 1977 7 393-400
12
De Flora S, Carcinogenesis 1981 2 283-298
13
De Flora S et al., Mutat. Res. 1984 133 161-198
14
Negative for induction of umu gene expression in S. typhimurium TA1535/pSK1002 when
15
tested at up to 5.3 mg/mL.
16
Ref. Nakamura S et al., Mutat. Res. 1987 192 239-246
17
Induced DNA repair in E. coli strains, in the absence of metabolic activation.
18
Ref. De Flora S et al., Mutat. Res. 1984 133 161-198
19
De Flora S et al., Mutat. Res. 1984 134 159-165
20
Induced gene convertants, recombinants and revertants at high concentrations in S. cerevisiae
21
without microsomal activation (not tested with S9).
22
Ref. Callen DF et al., Mutat. Res. 1980 77 55-63
23
Positive for lambda prophage induction endpoint of Microscreen assay in presence of
24
metabolic activation.
25
Ref. Rossman TG et al., Mutat. Res. 1991 260 349-367
26
Caused DNA single strand breaks in alkaline elution/rat hepatocyte assay at 3 mM (viability
27
approximately 45%).
28
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4
Ref. Sina JF et al., Mutat. Res. 1983 113 357-391
1
Positive in DNA strand break test in mouse lymphoma cells at ≥ 6.55 x 10
-3
M.
2
Ref. Garberg P et al., Mutat. Res. 1988 203 155-176
3
Positive at low rate in 1 of 2 media in SHE transformation assay.
4
Ref. Amacher DE and Zelljadt I Carcinogenesis 1983 4 291-295
5
Negative for SCE and chromosome aberrations in rat liver cell line RL
1
or CHO cells, with or
6
without microsomal activation.
7
Refs. Dean BJ and Hodson-Walker G Mutat. Res. 1979 64 329-337
8
Loveday K et al., Environ. Mol. Mutagen. 1990 16 272-303
9
Negative in chromosome aberration test in bone marrow in vivo.
10
Ref. Lil'p IG Soviet Genet. 1983 18 1467-1472
11
Negative in mouse lymphoma TK+/- assay, in presence of metabolic activation (not carried
12
out without S9).
13
Ref. Wangenheim J and Bolcsfoldi G Mutagenesis 1988 3 193-205
14
Negative in rat hepatocyte UDS assay in vivo at up to 400 mg/kg.
15
Ref. Mirsalis JC and Butterworth BE Carcinogenesis 1980 1 621-625
16
Bermudez E et al., Environ. Mol. Mutagen. 1982 4 667-679
17
Binds to calf thymus DNA in vitro following activation by microsomes from phenobarbitone-
18
pretreated rats.
19
Ref. DiRenzo AB et al., Toxicol. Lett. 1982 11 243-252
20
Apparently binds in vivo to hepatic DNA (mouse) and RNA (rat) if animals are pretreated
21
with 3-methylcholanthrene.
22
Ref. Rocchi P et al., Int. J. Cancer 1973 11 419-425
23
24
Overall, there is no convincing evidence for genotoxicity.
25
26
27
28
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5
Carcinogenicity
1
Mice Strain A mice were given 0.16, 0.32, 0.64, 1.28 or 2.5 g/kg orally (1-5 days between
2
doses for 30 doses), and the animals examined at 150 days. There were no hepatomas in
3
animals given 30 doses of 2.5 g/kg over 30 days, but a significant number in all groups that
4
received 0.16 g/kg or more over a period of 90 days or more.
5
Ref. Eschenbrenner AB and Miller E J. Natl. Cancer Inst. 1944 4 385-388
6
7
PDE
160 x 50
12 x 10 x 1 x 10 x10
0.67 mg / day
=
=
8
9
Limit
0.67 x 1000
10
67 ppm
=
=
10
11
Strain A mice were given approximately 40, 80, 160 or 320 mg/kg (30 doses at 4-day
12
intervals) or 10, 20, 40 or 80 mg/kg (120 daily doses) orally. The mice were 3 months old
13
when first dosed, and were examined for the presence of hepatomas at 8 months of age.
14
Hepatomas were present in all groups except at 10 mg/kg/day.
15
Ref. Eschenbrenner AB and Miller E J. Natl. Cancer Inst. 1946 6 325-341
16
17
PDE
10 x 50
12 x 10 x 10 x 10 x1
0.04 mg / day
=
=
18
19
Limit (ppm)
0.04 x 1000
10
4 ppm
=
=
20
21
B6C3F1 mice received 1250 or 2500 mg/kg orally, 5 days/week for 78 weeks, and were
22
killed 12-14 weeks later. The incidence of hepatocellular carcinomas and adrenal tumours was
23
significantly increased at both doses.
24
Ref. Weisburger EK Environ. Health Perspect. 1977 21 7-16
25
26
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6
For continuous exposure
1250 x 5
7
= 893 mg / kg
=
1
2
PDE
893 x 50
12 x 10 x 1 x 10 x10
3.7 mg / day
=
=
3
4
Limit
3.7 x 1000
10
370 ppm
=
=
5
6
Rats Osborne-Mendel rats received 47 or 94 (males) or 80 or 160 (females) mg/kg orally, 5
7
days/week for 78 weeks, and were killed 32 weeks later. There was a small increase in
8
incidence of hepatocellular carcinoma, and a greater increase in the incidence of neoplastic
9
nodules, without dose-relationship.
10
Ref. Weisburger EK Environ. Health Perspect. 1977 21 7-16
11
12
For continuous exposure
47 x 5
7
= 33.6 mg / kg
=
13
14
PDE
33.6 x 50
5 x 10 x 1 x 10 x10
0.34 mg / day
=
=
15
16
Limit
0.34 x 1000
10
34 ppm
=
=
17
18
Wistar, Osborne-Mendel, Japanese, Black and Sprague-Dawley rats were given 1.3 mL/kg (2
19
g/kg) by subcutaneous injection twice weekly. Black and Sprague-Dawley animals died with
20
severe cirrhosis at between 5 and 18 weeks. There was a significant increase in incidence of
21
hepatocellular carcinoma in Wistar, Osborne-Mendel and Japanese rats surviving for 68
22
weeks or more.
23
Ref. Reuber MD and Glover EL J. Natl. Cancer Inst. 1970 44 419-427
24
25
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7
For continuous exposure
2000 x 2
7
= 571 mg / kg
=
1
2
PDE
571 x 50
5 x 10 x 1 x 10 x10
5.7 mg / day
=
=
3
4
Limit
5.7 x 1000
10
570 ppm
=
=
5
6
Several other earlier and/or grossly inadequately designed oral, inhalation or subcutaneous
7
carcinogenicity studies in mouse, hamster and trout have been carried out. Note that in no
8
study conducted to a currently acceptable design has an entirely convincing no-effect dose for
9
tumorigenesis been determined. The studies reported by Weisburger are of adequate length,
10
and of generally sufficient design, but the lowest doses used were 1250 mg/kg/day in mice,
11
and 47 mg/kg/day in rats. The investigations of Eschenbrenner and Miller are relatively short,
12
and only hepatocellular tumours were scored.
13
14
Hamsters Syrian golden hamsters given approximately 200 mg/kg once weekly for 7 weeks,
15
followed by approximately 100 mg/kg for 30 weeks, and survivors killed 25 weeks later.
16
There were liver cell carcinomas in animals dying or being killed from week 43 onwards.
17
Total numbers used in this study were low, and it appears that no concurrent controls were
18
employed. Ref. Della Porta G et al., J. Natl. Cancer Inst. 1961 26 855-863
19
20
For continuous exposure
100 x 1
7
= 14.3 mg / kg
=
21
22
PDE
14.3 x 50
10 x 10 x 1 x 10 x10
0.07 mg / day
=
=
23
24
Limit
0.07 x 1000
10
7 ppm
=
=
25
26
Reproductive Toxicity
27
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8
Sprague-Dawley rats exposed by inhalation to 300 or 1000 ppm, 7h/day on days 6 through 15
1
of gestation. Foetal body weight and crown-rump length were significantly reduced at both
2
concentrations, and probably associated with reduced maternal food consumption and body
3
weight gain. The incidence of sternebral anomalies was claimed to be increased at 1000 ppm,
4
but in the control group exposed to air concurrently with the 300 ppm group the incidence
5
was as high as in the group exposed to 1000 ppm. LOEL (foetotoxicity) = 300 ppm. Ref.
6
Schwetz BA et al., Toxicol. Appl. Pharmacol. 1974 28 452-464
7
8
300 ppm
300 x 153.84
24.45
1888 mg / m = 1.89 mg / L
3
=
=
9
10
For continuous exposure
1.89 x 7
24
= 0.55 mg / L
=
11
12
Daily dose
0.55 x 290
0.330
= 483 mg / kg
=
13
14
PDE
483 x 50
5 x 10 x 1 x 1 x10
48.3 mg / day
=
=
15
16
Limit
48.3 x 1000
10
4830 ppm
=
=
17
18
This appears to be the only satisfactory teratogenicity study to have been conducted. Other
19
studies suggest that very large doses result in foetal death, i.e. that carbon tetrachloride is
20
foetotoxic, but not teratogenic.
21
22
Rats given 80 or 200 ppm in the diet (carbon tetrachloride intake up to 10-18 mg/kg/day),
23
commencing two weeks after weaning. Females mated for 5 successive pregnancies (once to
24
control, 4 times to treated males), beginning at 3 months of age. No effects on pregnancy rate
25
or litter parameters. Worst case NOEL = 10 mg/kg/day.
26
Ref. Alumot E et al., Food Cosmet. Toxicol. 1976 14 105-110
27
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9
1
PDE
10 x 50
5 x 10 x 1 x 1 x1
10 mg / day
=
=
2
3
Limit
10 x 1000
10
1000 ppm
=
=
4
5
Large doses of carbon tetrachloride cause testicular (seminiferous tubule and interstitial cell)
6
damage and affect the oestrous cycle in females, but the significance of the changes is
7
impossible to assess, some evidence is contradictory, and the effects of low doses have not
8
been explored.
9
10
Toxicity
11
Oral LD50 in mice 8.26 g/kg.
12
Ref. Wenzel DG and Gibson RD J. Pharm. Pharmacol. 1951 3 169-176
13
Oral LD50 in rats 2.81 g/kg.
14
Ref. Smyth HF et al., Toxicol. Appl. Pharmacol. 1970 17 498-503
15
Oral LD50 in dogs 2.3 g/kg.
16
Ref. Klaasen CD and Plaa GL Toxicol. Appl. Pharmacol. 1967 10 119-131
17
Dermal LD50 in rabbits and guinea pigs > 14 g/kg.
18
Ref. Roudabush RL et al., Toxicol. Appl. Pharmacol. 1965 7 559-565
19
Intraperitoneal LD50 in mice 4.675 g/kg.
20
Ref. Gehring PJ Toxicol. Appl. Pharmacol. 1968 13 287-298
21
Subcutaneous LD50 in mice 31 g/kg.
22
Ref. Plaa GL et al., J. Pharmacol. Exp. Ther. 1958 123 224-229
23
24
There is a vast literature on the toxicity of carbon tetrachloride in animals, largely dealing
25
with the characteristics and mechanism of liver damage. Low hepatotoxic doses of carbon
26
tetrachloride produce characteristic fatty livers. Higher exposures result in centrilobular
27
necrosis; cirrhosis and hepatic tumours may develop after prolonged administration.
28
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10
Hepatotoxicity is dependent on activation by cytochrome P450, and agents that induce
1
monooxygenase activity (including ethanol and barbiturates) markedly increase the
2
hepatotoxicity of carbon tetrachloride.
3
Refs. e.g. Recknagel RO and Glende EA CRC Crit. Rev. Toxicol. 1973 2 263-297
4
Glende EA et al., Biochem. Pharmacol. 1976 25 2163-2170
5
Kalf GF et al., Annu. Rev. Pharmacol. Toxicol. 1987 27 399-427
6
7
Other target organs include kidney, testes and lung.
8
Refs. e.g. Chen W-J et al., Lab. Invest. 1977 36 388-394
9
New PS et al., J. Am. Med. Assoc. 1962 181 903-906
10
11
Many papers report the outcome of administration of one or a few doses of carbon
12
tetrachloride. The following comprise a large proportion of those involving administration for
13
10 days or more that have been reported during the last 50 years.
14
15
Mice CD-1 mice treated orally for 90 days at 12, 120, 540 or 1200 mg/kg/day. Dose-related
16
altered serum parameters of liver damage and histopathological changes (including necrosis
17
and fatty degeneration) at 12 mg/kg/day and above. LOEL = 12 mg/kg/day.
18
Ref. Hayes JR et al., Fund. Appl. Toxicol. 1986 7 454-463
19
20
PDE
12 x 50
12 x 10 x 5 x 1 x10
0.10 mg / day
=
=
21
22
Limit
0.10 x 1000
10
10 ppm
=
=
23
24
CD-1 mice given 1.2, 12 or 120 mg/kg orally, 5 days/week, for 90 days. Dose-related altered
25
serum parameters of liver damage and histopathological changes at 12 mg/kg/day and above.
26
Minimal necrosis in single animal at 1.2 mg/kg/day. Virtual NOEL = 1.2 mg/kg/day.
27
Ref. Condie LW et al., Fund. Appl. Toxicol. 1986 7 199-206
28
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11
1
For continuous exposure
1.2 x 5
7
= 0.857 mg / kg
=
2
3
PDE
0.857 x 50
12 x 10 x 5 x 1 x1
0.071 mg / day
=
=
4
5
Limit
0.071 x 1000
10
7.1 ppm
=
=
6
7
Rats Wistar rats exposed by inhalation to 5, 10, 25, 50, 100, 200 or 400 ppm, 7h/day on 127-
8
146 occasions during a period of 173-205 days. Fatty degeneration of the liver at 10 ppm or
9
more; cirrhosis at 50 ppm or more; evidence of increased mortality at 100 ppm or more.
10
Biochemical changes were present above 5 ppm. NOEL = 5 ppm (145 exposures in 205
11
days). Ref. Adams EM et al., AMA Arch. Ind. Hyg. 1952 6 50-66
12
13
5 ppm
5 x 153.84
24.45
31.5 mg / m = 0.0315 mg / L
3
=
=
14
15
For continuous exposure
0.0315 x 7 x 145
24 x 205
= 0.0065 mg / L
=
16
17
Daily dose
0.0065 x 290
0.425
= 4.44 mg / kg
=
18
19
PDE
4.44 x 50
5 x 10 x 2 x 1 x1
2.2 mg / day
=
=
20
21
Limit
2.2 x 1000
10
220 ppm
=
=
22
23
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12
Long-Evans or Sprague-Dawley rats exposed continuously for 90 days to atmospheres
1
containing 61 or 6.1 mg/m
3
. Hepatic damage at 61 mg/m
3
, NOEL 6.1 mg/m
3
= 0.0061mg/L
2
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
3
4
Daily dose
0.0061 x 290
0.425
= 4.16 mg / kg
=
5
6
PDE
4.16 x 50
5 x 10 x 5 x 1 x1
0.8 mg / day
=
=
7
8
Limit
0.8 x 1000
10
80 ppm
=
=
9
10
Male F344 rats given 5, 10, 20 or 40 mg/kg/day for 10 days. Increased AST and ALT at 20
11
and 40 mg/kg/day, at least minimal hepatic vacuolar degeneration at all doses, hepatic
12
necrosis at 10 mg/kg/day and more. No consistent changes in parameters of immune function.
13
LOEL = 5 mg/kg/day.
14
Ref. Smialowicz RJ et al., Fund. Appl. Toxicol. 1991 17 186-196
15
16
PDE
5 x 50
5 x 10 x 10 x 1 x5
0.10 mg / day
=
=
17
18
Limit
0.10 x 1000
10
10 ppm
=
=
19
20
Male F344 rats given 20 or 40 mg/kg orally, 5 days/week for 12 weeks. Dose-related
21
retardation of growth, alterations in serum parameters of liver damage, hepatic necrosis,
22
vacuolar degeneration and cirrhosis at both doses. LOEL = 20 mg/kg/day.
23
Ref. Allis JW et al., Fund. Appl. Toxicol. 1990 15 558-570
24
25
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13
For continuous exposure
20 x 5
7
= 14.3 mg / kg
=
1
2
PDE
14.3 x 50
5 x 10 x 5 x 1 x10
0.28 mg / day
=
=
3
4
Limit
0.28 x 1000
10
28 ppm
=
=
5
6
Male Sprague-Dawley rats given 1, 10 or 33 mg/kg orally, 5 days/week for 12 weeks.
7
Retarded growth at 33 mg/kg, and dose-related alterations in serum parameters of liver
8
damage at 10 and 33 mg/kg. Hepatic centrilobular vacuolisation at 10 mg/kg, and extensive
9
degenerative lesions and hyperplastic nodules at 33 mg/kg. NOEL = 1 mg/kg.
10
Ref. Bruckner JV et al., Fund. Appl. Toxicol. 1986 6 16-34
11
12
For continuous exposure
1 x 5
7
= 0.714 mg / kg
=
13
14
PDE
0.714 x 50
5 x 10 x 5 x 1 x1
0.14 mg / day
=
=
15
16
Limit
0.14 x 1000
10
14 ppm
=
=
17
18
Guinea Pigs of heterogeneous origin exposed by inhalation to 5, 10, 25, 50, 100, 200 or 400
19
ppm, 7h/day on 93-184 occasions during a period of 126-258 days. Fatty degeneration of the
20
liver at 10 ppm or more; cirrhosis at 25 ppm or more; renal tubular degeneration at 200 ppm
21
and more; increased mortality at 100 ppm or more. Biochemical changes were present above
22
5 ppm. NOEL = 5 ppm (143 exposures in 203 days).
23
Ref. Adams EM et al., AMA Arch. Ind. Hyg. 1952 6 50-66
24
25
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14
5 ppm
5 x 153.84
24.45
31.5 mg / m = 0.0315 mg / L
3
=
=
1
2
For continuous exposure
0.0315 x 7 x 143
24 x 203
= 0.0065 mg / L
=
3
4
Daily dose
0.0065 x 430
0.500
= 5.6 mg / kg
=
5
6
PDE
5.6 x 50
10 x 10 x 2 x 1 x1
1.4 mg / day
=
=
7
8
Limit
1.4 x 1000
10
140 ppm
=
=
9
10
Hartley guinea pigs exposed continuously for 90 days to atmospheres containing 61 or 6.1
11
mg/m
3
. Hepatic damage and some deaths at 61 mg/m
3
, slight reduction in body weight gain
12
at 6.1 mg/m
3
. LOEL 6.1 mg/m
3
= 0.0061mg/L.
13
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
14
15
Daily dose
0.0061 x 430
0.500
= 5.25 mg / kg
=
16
17
PDE
5.25 x 50
10 x 10 x 5 x 1 x5
0.1 mg / day
=
=
18
19
Limit
0.1 x 1000
10
10 ppm
=
=
20
21
Rabbits White rabbits exposed by inhalation to 10, 25, 50 or 100 ppm, 7h/day on 139-178
22
occasions during a period of 197-248 days. Fatty degeneration and cirrhosis of the liver at 25
23
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15
ppm or more; significant depression of growth at 100 ppm. NOEL = 10 ppm (139 exposures
1
in 197 days). Ref. Adams EM et al., AMA Arch. Ind. Hyg. 1952 6 50-66
2
3
10 ppm
10 x 153.84
24.45
62.9 mg / m = 0.0629 mg / L
3
=
=
4
5
For continuous exposure
0.0629 x 7 x 139
24 x 197
= 0.0129 mg / L
=
6
7
Daily dose
0.0129 x 1440
4
= 4.64 mg / kg
=
8
9
PDE
4.64 x 50
2.5 x 10 x 2 x 1 x1
4.6 mg / day
=
=
10
11
Limit
4.6 x 1000
10
460 ppm
=
=
12
13
New Zealand white rabbits exposed continuously for 90 days to atmospheres containing 61 or
14
6.1 mg/m
3
. Hepatic damage at 61 mg/m
3
, reduced body weight gain at 6.1 mg/m
3
. LOEL 6.1
15
mg/m
3
= 0.0061 mg/L Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
16
17
Daily dose
0.0061 x 1440
4
= 2.2 mg / kg
=
18
19
PDE
2.2 x 50
2.5 x 10 x 5 x 1 x5
0.18 mg / day
=
=
20
21
Limit
0.18 x 1000
10
18 ppm
=
=
22
23
Page 16
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16
Dogs Beagle dogs exposed continuously for 90 days to atmospheres containing 61 or 6.1
1
mg/m
3
. Hepatic damage at 61 mg/m
3
, some evidence of reduced body weight gain at 6.1
2
mg/m
3
. LOEL 6.1 mg/m
3
= 0.0061 mg/L
3
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
4
5
Daily dose
0.0061 x 9000
11.5
= 4.77 mg / kg
=
6
7
PDE
4.77 x 50
2 x 10 x 5 x 1 x5
0.48 mg / day
=
=
8
9
Limit
0.48 x 1000
10
48 ppm
=
=
10
11
Monkeys Rhesus monkeys exposed by inhalation to 25, 50 or 100 ppm, 7h/day on 148-198
12
occasions during a period of 212-277 days. Of two monkeys exposed to 100 ppm, slight
13
growth depression in both, some cloudy swelling in the liver of one, and slight fatty
14
degeneration throughout the liver of the other. NOEL = 50 ppm (198 exposures in 277 days).
15
Ref. Adams EM et al., AMA Arch. Ind. Hyg. 1952 6 50-66
16
17
50 ppm
50 x 153.84
24.45
315 mg / m = 0.315 mg / L
3
=
=
18
19
For continuous exposure
0.315 x 7 x 198
24 x 277
= 0.0657 mg / L
=
20
21
Daily dose
0.0657 x 1150
2.5
= 30.2 mg / kg
=
22
23
PDE
30.2 x 50
10 x 10 x 2 x 1 x1
7.6 mg / day
=
=
24
25
Page 17
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17
Limit
7.6 x 1000
10
760 ppm
=
=
1
2
Human
3
Carbon tetrachloride is extremely lipophilic; it is readily absorbed in animals and, apparently,
4
in humans after oral ingestion. Fatal human poisonings by carbon tetrachloride have been
5
reported since 1909, and deaths continue to occur occasionally following either inhalation or
6
ingestion. Toxicity is exacerbated by alcoholism or concurrent exposure to alcohol and carbon
7
tetrachloride. Liver and renal damage are the most common effects.
8
Refs. Veley VH 1909 Lancet 1162-1163
9
Hardin BL 1954 Ind. Med. Surg. 23 93-105
10
11
The genotoxicity of carbon tetrachloride is unconvincing, and liver tumorigenesis in animal
12
species may be related to chronic damage and regenerative cell proliferation. This standpoint
13
generally has been taken in setting occupational exposure limits for carbon tetrachloride.
14
There are only a few anecdotal cases in which exposure has been linked with hepatic tumours
15
in man. Limited epidemiological studies indicate an excess of some cancers in communities
16
exposed to chlorinated hydrocarbons, but the general limitations of the studies and mixed
17
solvent exposure do not allow firm conclusions to be drawn regarding the carcinogenic
18
potential of carbon tetrachloride in man.
19
Refs. e.g. Tracey JP and Sherlock P N.Y. State J. Med. 1968 8 2202-2204
20
Simler M et al., Strasbourg Med. 1964 15 910-917
21
Blair A et al., Am. J. Pub. Health 1979 69 508-511
22
Capurro PU Clin. Toxicol. 1979 14 285-294
23
24
Carbon tetrachloride is classed by IARC in Group 2B (possibly carcinogenic in humans), by
25
NTP in Group 2 (reasonably anticipated to be a carcinogen), by ACGIH as A2 (suspected
26
human carcinogen) and by NIOSH and OSHA as a carcinogen, without further classification.
27
28
29
30
Page 18
draft 7 page
18
Environmental Impact
1
2
Under the revised Montreal Protocol, production and use of carbon tetrachloride are
3
scheduled to be phased out by the year 2000 by ratifying parties (excluding 10-year
4
derogations for developing nations), because of its contribution to atmospheric ozone
5
depletion (ozone-depleting potential 0.9, similar to that of fully chlorinated CFCs).
6
7
Conclusion
8
9
Possible human carcinogen. Animal carcinogen (balance of evidence suggests probably by
10
non-genotoxic mechanism). Hepatotoxic at low doses in man and laboratory species.
11
Production scheduled to be phased out in 2000 under Montreal Protocol.
12
13
The guideline value for carbon tetrachloride is 0.04 mg/day (4 ppm).
14
Page 19
draft 7 page
19
1
1,2-DICHLOROETHANE
2
3
Category: Possible human carcinogen (IARC 2B). Not teratogenic
4
5
Toxic Effects:
6
Repeated exposure induces anorexia, nausea, abdominal pain, irritation of mucous
7
membranes, dysfunction of liver and kidney and neurological disorders. Depression of
8
leukocyte, antibody-forming cell and cellular immunity was found in mice; necrosis of
9
cerebellum and hyperplasia and inflammation of forestomach were observed in male rats after
10
oral administration.
11
12
Carcinogenesis:
13
There is no evidence of carcinogenicity in humans. Forestomach cancer, hemangiosarcoma,
14
breast cancer, uterine cancer and respiratory tract cancer were found in rats or mice after
15
gavage treatment.
16
17
Genotoxicity:
18
The balance of evidence indicates 1,2-dichloroethane is potentially genotoxic.
19
20
Assessment:
21
Excess cancer risk at 10
-5
is 0.05mg/day for 50 kg human based on hemangiosarcoma using a
22
linearized multistage model without body surface correction.
23
The guideline value for 1,2-dichloroethane is 0.05 mg per day (5 ppm).
24
References
25
Reviews; Environmental Health Criteria 62 (1987)
26
IARC Monographs 20 (1979)
27
NCI (1978) TR-55.
28
Page 20
draft 7 page
20
1
1,1-DICHLOROETHENE
2
Genotoxicity
3
Some positive in vitro results in Ames test and mouse lymphoma, results being enhanced in
4
presence of liver microsomal samples. Negative results in in vitro SCE and chromosome
5
abberation studies and in CHE cells. Negative results in vivo in micronucleus test, UDS assay
6
and dominant lethal assay.
7
Refs. Mortelmans K et al., Environ. Mutagen 1986 8 1-119.
8
Greim H et al., Biochem. Pharmacol. 1975 24 2013-17.
9
Bronzetti G et al., Mut. Res. 1981 89 179-85.
10
McGregor D et al., Environ. Mol. Mutagen. 1991 17 (2) 122-9.
11
Drevon C and Kuroki T. Mut. Res. 1979 67 (2) 173-82.
12
Sawanda M et al., Mut. Res. 1987 187 (3) 157-63.
13
Reitz RH et al., Toxicol. Appl. Pharmacol. 1980 52 (3) 357-70.
14
Anderson D et al., Biochem. Pharmacol. 1977 21 71-8.
15
Carcinogenicity
16
Positive results have been reported after inhalation exposure; however, no increase in tumour
17
incidence is noted following oral administration.
18
Swiss mice exposed to 25 ppm 4 h/day, 5 days/week for 52 weeks and retained until 98
19
weeks showed an increased incidence of renal adenocarcinomas, mainly in males.
20
Ref. Maltoni C. Environ. Health Perspect 1977 21 1-5. LOEL = 25 ppm
21
22
25 ppm
25 x 96.94
24.45
99.1 mg / m
0.099 mg / L
3
=
=
=
23
24
For continuous dosing
0.099 x 4 x 5
24 x 7
= 0.012 mg / L
=
25
26
Page 21
draft 7 page
21
Daily dose
0.012 x 43
0.028
18.1 mg / kg
=
=
1
2
PDE
18.1 x 50
12 x 10 x 1 x 10 x 10
0.08 mg / day
=
=
3
4
Limit
0.08 x 1000
10
8 ppm
=
=
5
6
Sprague-Dawley rats given 100 ppm 4-7 h/day, 5 days/week for 2 years. Others were
7
exposed in utero and then for 2 years following birth and showed an increased incidence of
8
leukaemia.
9
Ref. Cotti G et al., Ann. NY Acad. Sci. 1988 534 160-68
10
11
100 ppm
100 x 96.94
24.45
396 mg / m
0.4 mg / L
3
=
=
=
12
13
For continuous dosing =
0.4 x 4 x 5
24 x 7
0.047 mg / L
=
14
15
Daily dose =
0.047 x 290
0.425
= 32 mg / kg
16
17
PDE =
32 x 50
5 x 10 x 10 x 10 x 1
= 0.32 mg / day
18
19
Limit =
0.32 x 1000
10
= 32 ppm
20
21
B6C3F1 mice given 2 and 10 mg/kg by gavage 5 days/week for 2 years showed no increase in
22
tumour incidence (except leukaemia which was discounted because it only occurred in low
23
dose females).
24
Page 22
draft 7 page
22
Ref. NTP Programme Tech. Report 228 1982. NEL 10 mg/kg.
1
2
For continuous dosing =
10 x 5
7
= 7.14 mg / kg
3
4
PDE =
7.14 x 50
12 x 10 x 1 x 1 x 1
= 2.98 mg / day
5
6
Limit =
2.98 x 1000
10
= 298 ppm
7
8
Sprague-Dawley rats given time-weighted average of 7, 10 and 20 mg/kg (males) and 9, 14
9
and 30 mg/kg (females) for 2 years in drinking water. No increase in tumour incidence was
10
noted. Ref. Quast JF et al., Fund. Appl. Toxicol. 1983 3 55-62. NOEL = 20 mg/kg
11
12
PDE =
20 x 50
5 x 10 x 1 x 1 x 1
20 mg / day
=
13
14
Limit =
20 x 1000
10
= 2000 ppm
15
16
Reproductive toxicity
17
Rats given 200 mg/L in drinking water days 6-15 showed no adverse effects and offspring
18
were normal.
19
Ref. Norris JM in Proceedings of Technical Association of Pulp and Paper Industries
20
Conference, Chicago 1977. NEL
200 mg / L
=
21
22
Rat drinks 30 mg / day
Daily consumption =
200 x 30
1000
6 mg / day
=
23
Page 23
draft 7 page
23
1
Dose =
6
0.33
= 18.2 mg / kg
2
3
PDE =
18.2 x 50
5 x 10 x 1 x 1 x 1
18.2 mg / day
=
4
5
Limit
18.2 x 1000
10
= 1820 ppm
=
6
7
Rats given 20-160 ppm by inhalation 7 h/day days 6-15. Embryo and foetal toxicity
8
associated with maternal toxicity but no teratogenic effects.
9
Ref. Norris JM in Proceedings of Technical Association of Pulp and Paper Industries
10
Conference, Chicago 1977.
11
12
20 ppm =
20 x 96.94
24.45
= 79 mg / m
0.08 mg / L
3
=
13
14
For continuous dosing =
0.08 x 7
24
= 0.023 mg / L
15
16
Daily dose =
0.023 x 290
0.33
= 20.2 mg / kg
17
18
PDE =
20.2 x 50
5 x 10 x 1 x 1 x 10
= 2.02 mg / day
19
20
Limit =
2.02 x 1000
10
= 202 ppm
21
22
Rabbits dosed at 20-160 ppm by inhalation 7 h/day days, 6-18 showed embryo and foetal
23
toxicity associated with maternal toxicity but no teratogenic effects.
24
Page 24
draft 7 page
24
Ref. Norris JM in Proceedings of Tech. Assoc. of Pulp and Paper Industries Conference,
1
Chicago 1977.
2
As above, continual exposure = 0.023 mg/L
3
4
Daily dose =
0.023 x 1440
4
= 8.28 mg / kg
5
6
PDE =
8.28 x 50
2.5 x 10 x 1 x 1 x 10
= 1.66 mg / day
7
8
Limit =
1.66 x 1000
10
= 166 ppm
9
10
Sprague-Dawley rats given 200 mg/L in drinking water in a multigeneration study. No
11
adverse effects seen in 6 sets of litters. Ref. Nitschke KD et al., Fund. Appl. Toxicol. 1983 3
12
75-9.
13
As above PDE is 18.2 mg/day (limit 1820 ppm).
14
15
Animal toxicity
16
Sprague-Dawley rats exposed to 10 and 40 ppm by inhalation 6 h/day, 5 days/week for 5
17
weeks then to 25 and 75 ppm for up to 18 months. Liver changes were noted at 6 months but
18
these reversed after end of treatment. LOEL 25 ppm.
19
Ref. Quast JF et al., Fund. Appl. Toxicol. 1986 6 (1) 105-44
20
21
25 ppm =
25 x 96.94
24.45
= 99.12 mg / m = 0.10 mg / L
3
22
23
For continuous dosing =
0.1 x 6 x 5
24 x 7
= 0.018 mg / L
24
25
Page 25
draft 7 page
25
Daily dose =
0.018 x 290
0.425
= 12.3 mg / kg
1
2
PDE =
12.3 x 50
5 x 10 x 1 x 1 x 10
= 1.23 mg / day
3
4
Limit =
1.23 x 1000
10
= 123 ppm
5
6
Sprague-Dawley rats given TWA of 7, 10 and 20 mg/kg (males) and 9, 14 and 30 mg/kg
7
(females) in drinking water for 2 years. Minimal hepatocellular swelling and midzonal fatty
8
changes in females at all levels and in high dose males. These were considered to be adaptive
9
changes. NEL = 20 mg/kg. Ref. Quast JF et al., Fund. Appl. Toxicol. 1983 3 (1) 55-62
10
11
PDE =
20 x 50
5 x 10 x 1 x 1 x 1
= 20 mg / day
12
13
Limit =
20 x 1000
10
= 2000 ppm
14
15
Conclusion
16
The guideline value for 1,1-dichloroethene is 0.08 mg/day (8 ppm).
17
Page 26
draft 7 page
26
1
1,1,1-TRICHLOROETHANE
2
Category
3
Not classifiable as to carcinogenicity to humans (IARC 3).
4
5
Genotoxicity
6
Plate incorporation assays for reverse mutation in Salmonella typhimurium strains TA98,
7
TA100, TA1535, TA1537 and TA1538, or in E. coli strains, using liquid TCE are
8
consistently negative, as are assays using pre-incubation or a fluctuation protocol. There are
9
indications of mutagenicity in strains TA100 and TA1535 in vapour phase assays in
10
desiccators, although in the most unequivocally positive test the results suggest that activity
11
may be due to an epoxide stabiliser such as butylene oxide. Results of Shimada et al., appear
12
to confirm that activity is due to the stabiliser. Negative for induction of umu gene expression
13
in S. typhimurium TA1535/pSK1002 when tested at up to 666 ug/mL. Negative in SOS
14
Chromotest (induction of sfiA gene expression in E. coli).
15
Refs. reviewed in Fielder RJ and Williams SD 1,1,1-Trichloroethane (Toxicity Review 9)
16
1984 Health and Safety Executive, HMSO, London
17
Haworth S et al., Environ. Mutagenesis 1983 suppl. 1 3-142
18
Nakamura S et al., Mutat. Res. 1987 192 239-246
19
Quillardet P et al., Mutat. Res. 1985 147 79-95
20
Shimada T et al., Cell Biol. Toxicol. 1985 1 159-179
21
Negative for gene mutation and mitotic recombination in yeasts.
22
No clear evidence for DNA damage in microorganisms.
23
Refs. reviewed in Fielder RJ and Williams SD 1,1,1-Trichloroethane (Toxicity Review 9)
24
1984 Health and Safety Executive, HMSO, London
25
Not mutagenic at TK locus in TK6 human lymphoblasts at 500 ug/mL.
26
Ref. Penman BW and Crespi CL Environ. Mol. Mutagen. 1987 10 35-60
27
No increase in number of SCE in CHO cells at up to 10 ug/mL (with S9) in one study.
28
Negative for SCE without S9 (up to 1000 ug/mL), equivocal for SCE with S9 (tested to 500
29
Page 27
draft 7 page
27
ug/mL) in another. In the second, chromosome aberration response positive without S9,
1
negative with S9.
2
Perry PE and Thomson EJ in Evaluation of Short Term Tests for Carcinogens. Prog.
3
Mutat. Res. 1 (eds. de Serres FJ and Ashby J) 1981 Elsevier pp 560-569
4
Galloway SM et al., Environ. Mol. Mutagen. 1987 10 (suppl. 10) 1-175
5
No increase in number of micronucleated polychromatic erythrocytes in mice in 3 studies
6
(various protocols, intraperitoneal doses of up to 2000 mg/kg).
7
Negative for sex-linked recessive lethal mutation in Drosophila at 25 ppm in diet.
8
No dominant lethal effect in mice when males given up to 5.8 mg/mL in drinking water for 14
9
weeks.
10
No unscheduled DNA synthesis in HeLa cells (± S9) or in primary cultures of rat hepatocytes.
11
Refs. reviewed in Fielder RJ and Williams SD 1,1,1-Trichloroethane (Toxicity Review 9)
12
1984 Health and Safety Executive, HMSO, London
13
Positive in one BHK-21 cell transformation assay (± S9), and negative in another. Positive for
14
transformation in Fischer rat embryo F-1706 line. Positive in BALB/c-3T3 cells (but
15
stabilisers may have been present in the test material).
16
Refs. reviewed in Fielder RJ and Williams SD 1,1,1-Trichloroethane (Toxicity Review 9)
17
1984 Health and Safety Executive, HMSO, London
18
Tu AS et al., Cancer Lett. 1985 28 85-92
19
20
In summary, the ability of 1,1,1-trichloroethane to produce point mutations in bacteria has
21
been investigated thoroughly, generally with negative results. There is no evidence to suggest
22
that gene or chromosomal damage is produced in mammalian cells. In vitro cell
23
transformation assays in BHK cells gave conflicting results, but it is known that
24
reproducibility in this system may give problems. Results in the F-1706 transformation assay
25
were positive without S9, regarded as surprising because trichloroethane would not be
26
expected to be directly acting in this system. Overall evidence of mutagenic potential is
27
limited.
28
29
30
Carcinogenicity
31
Page 28
draft 7 page
28
Only two studies, one in mice and one in rats, that conform to current standards, particularly
1
as regards survival or duration of dosing, have been located (Quast et al, 1988). The
2
remainder provide only supporting data.
3
4
Mice B6C3F1 mice exposed by inhalation to 150, 500 or 1500 ppm production grade
5
trichloroethane (purity approximately 94%, containing 5% stabilisers), 6h/day, 5 days/week
6
for 2 years. There was no evidence of toxicity or oncogenicity at any dose. NOEL = 1500
7
ppm. Ref. Quast JF et al., Fund. Appl. Toxicol. 1988 11 611-625
8
9
1500 ppm =
1500 x 133.42
24.45
= 8185 mg / m
mg / L
3
= 819
.
10
11
For continuous exposure =
8.19 x 6 x 5
24 x 7
= 1.46 mg / L
12
13
Daily dose =
1.46 x 43
0.028
= 2242 mg / kg
14
15
PDE =
2242 x 50
12 x 10 x 1 x 1 x 1
= 934 mg / day
16
17
Limit =
934 x 1000
10
= 93,400 ppm
18
19
In an NCI programme study, B6C3F1 mice were given a time-weighted average of 2807 or
20
5615 mg/kg, 5 days/week for 78 weeks (doses increased twice from initial), and killed 13
21
weeks later. There was no evidence for an increase in any tumour type, but poor survival
22
made this study inadequate for proper assessment.
23
Ref. NCI. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity, Technical Report
24
Series 3, US DHEW, 1977
25
26
Page 29
draft 7 page
29
Rats F344 rats exposed by inhalation to 150, 500 or 1500 ppm production grade
1
trichloroethane (purity approximately 94%, containing 5% stabilisers), 6h/day, 5 days/week
2
for 2 years. Body weight gain slightly decreased in females at 1500 ppm. Minimal hepatic
3
effects at interim, but not terminal, kills in males and females exposed to 1500 ppm. No
4
evidence of oncogenicity. NOEL for tumours = 1500 ppm. Ref. Quast JF et al., Fund. Appl.
5
Toxicol. 1988 11 611-625
6
7
1500 ppm =
1500 x 133.42
24.45
= 8185 mg / m
mg / L
3
= 819
.
8
9
For continuous exposure =
8.19 x 6 x 5
24 x 7
= 1.46 mg / L
10
11
Daily dose =
1.46 x 290
0.425
= 996 mg / kg
12
13
PDE =
996 x 50
5 x 10 x 1 x 1 x 1
= 996 mg / day
14
15
Limit =
996 x 1000
10
= 99,600 ppm
16
17
In an NCI programme study, Osborne-Mendel rats were given 750 or 1500 mg/kg, 5
18
days/week for 78 weeks, and killed 32 weeks later. There was no evidence for an increase in
19
any tumour type, but poor survival rendered this study inadequate for proper assessment.
20
Ref. NCI. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity, Technical Report
21
Series 3, US DHEW, 1977
22
23
Sprague-Dawley rats exposed by inhalation to 875 or 1750 ppm, 6h/day, 5 days/week for 12
24
months, and killed 18 months later. There were no adverse findings, except for focal
25
hepatocellular alterations in females at 1750 ppm.
26
Page 30
draft 7 page
30
Ref. Rampy LW et al., in Proceedings of the First International Congress of Toxicology (eds.
1
Plaa GL and Duncan WAM) 1978 NY Academic Press p 562
2
3
Reproductive Toxicity
4
5
Swiss-Webster mice exposed to 875 ppm, 7h/day, on days 6-15 of gestation. There was no
6
evidence of maternal toxicity, foetotoxicity or teratogenicity.
7
Ref. Schwetz BA et al., Toxicol. Appl. Pharmacol. 1975 32 84-96
8
9
875 ppm =
875 x 133.42
24.45
= 4775 mg / m
mg / L
3
= 4 78
.
10
11
For continuous exposure =
4.78 x 7
24
= 1.39 mg / L
12
13
Daily dose =
1.39 x 43
0.03
= 1992 mg / kg
14
15
PDE =
1992 x 50
12 x 10 x 1 x 1 x 1
= 830 mg / day
16
17
Limit =
830 x 1000
10
= 83,000 ppm
18
19
Swiss mice given 0.58, 1.75 or 5.83 mg/mL in drinking water in two-generation study
20
modified to include assessment of teratogenicity. There were no effects on fertility, gestation,
21
viability, lactation indices, or pup survival and growth. No teratogenicity was observed.
22
NOEL = 5.83 mg/mL.
23
Ref. Lane RW et al., Toxicol. Appl. Pharmacol. 1982 63 409-421
24
25
Assuming water intake of 6 mL/day and body weight of 30 g
26
Page 31
draft 7 page
31
1
Daily dose =
5.83 x 6
0.03
= 1166 mg / kg
2
3
PDE =
1166 x 50
12 x 10 x 1 x 1 x 1
= 486 mg / day
4
5
Limit =
486 x 1000
10
= 48600 ppm
6
7
Sprague-Dawley rats exposed to 875 ppm, 7h/day, on days 6-15 of gestation. There was no
8
evidence of maternal toxicity, foetotoxicity or teratogenicity.
9
Ref. Schwetz BA et al., Toxicol. Appl. Pharmacol. 1975 32 84-96
10
11
875 ppm =
875 x 133.42
24.45
= 4775 mg / m
mg / L
3
= 4 78
.
12
13
For continuous exposure =
4.78 x 7
24
= 1.39 mg / L
14
15
Daily dose =
1.39 x 290
0.330
= 1221 mg / kg
16
17
PDE =
1221 x 50
5 x 10 x 1 x 1 x 1
= 1221 mg / day
18
19
Limit =
1221 x 1000
10
= 122,100 ppm
20
21
Long-Evans rats exposed by inhalation to 2100 ppm, 6h/day on days 1-20 of gestation, with
22
or without premating exposure (6h/day, 5 days/week for 2 weeks) showed no maternal
23
Page 32
draft 7 page
32
toxicity, but mean foetal weight was reduced, and there were skeletal and soft tissue
1
variations indicative of retarded development.
2
Ref. York RG et al., J. Toxicol. Environ. Health 1982 9 251-266
3
4
2100 ppm =
2100 x 133.42
24.45
= 11459 mg / m
mg / L
3
= 115.
5
6
For continuous exposure =
11.5 x 6
24
= 2.88 mg / L
7
8
Daily dose =
2.88 x 290
0.330
= 2531 mg / kg
9
10
PDE =
2531 x 50
5 x 10 x 1 x 1 x 10
= 253 mg / day
11
12
Limit =
253 x 1000
10
= 25,300 ppm
13
14
In a study reported only in abstract, it was claimed that there were cardiac abnormalities
15
(persistent ductus arteriosus and atrial hypoplasia or displacement) in 15/52 offspring of
16
Sprague-Dawley rats given 10 ppm in drinking water from 7 days before, and during,
17
cohabitation, the females then being exposed through gestation and lactation. Ref. Dapson
18
SC et al., Teratology 1984 29 25A
19
20
These findings are entirely at odds with other evidence of lack of reproductive toxicity with
21
1,1,1-trichloroethane, and the following study was conducted to investigate further.
22
23
Male and female Sprague-Dawley rats were given 3, 10 or 30 ppm in drinking water for 14
24
days before cohabitation and during cohabitation. Females continued to be exposed through
25
either gestation days (GD) 1-20, or GD 1-20 + lactation. Males showed no adverse effects.
26
There was no maternal toxicity, no effect on gestational or litter parameters, except for a
27
Page 33
draft 7 page
33
slight increase in mortality from implantation to post-natal day 1 at 30 ppm (considered to be
1
due to high loss in one litter), and no increase in cardiac or other malformations. NOEL = 30
2
ppm. Refs. George JD et al., Fund. Appl. Toxicol. 1989 13 641-651
3
George JD et al., Developmental toxicity evaluation of 1,1,1-trichloroethane administered to
4
Sprague-Dawley rats. Part I. Postnatal evaluation, Final Study Report, 1987, NTIS Accession
5
No. PB88131321/AS
6
George JD et al., Developmental toxicity evaluation of 1,1,1-trichloroethane administered to
7
Sprague-Dawley rats. Part II. Teratological evaluation, Final Study Report, 1987, NTIS
8
Accession No. PB88134101
9
10
Assuming water intake of 30 mL/day and body weight of 330 g
11
12
Daily dose =
0.03 x 30
0.330
= 2.7 mg / kg
13
14
PDE =
2.7 x 50
5 x 10 x 1 x 1 x 1
= 2.7 mg / day
15
16
Limit =
2.7 x 1000
10
= 140 ppm
17
The PDE calculated from this study is disregarded since no toxicity was observed.
18
19
Toxicity
20
Oral LD50 in mice 11.24 g/kg (no inhibitor), 9.7 g/kg (+ inhibitor).
21
Oral LD50 in rats 10.3-12.3 g/kg (no inhibitor), 11.0-14.3 g/kg (+ inhibitor).
22
Oral LD50 in rabbits 5.66 g/kg (no inhibitor), 10.5 g/kg (+ inhibitor).
23
Oral LD50 in guinea pigs 9.47 g/kg (no inhibitor), 8.6 g/kg (+ inhibitor).
24
Ref. Torkelson TR et al., Am. Ind. Hyg. Assoc. J. 1958 19 353-362
25
Inhalation LC50 in mice (30 min exposure, 24h observation) 22240 ppm.
26
Ref. Woolverton WL and Balster RL Toxicol. Appl. Pharmacol. 1981 59 1-7
27
Page 34
draft 7 page
34
Inhalation LC50 in rats (15 min exposure) 38000 ppm.
1
Ref. Clark DG and Tinston DJ Human Toxicol. 1982 1 239-247
2
Intraperitoneal LD50 in rats 5.08 g/kg.
3
Ref. Klaasen CD and Plaa GL Biochem. Pharmacol 1969 18 2019-2027
4
Dermal LD50 in rabbits > 15.8 g/kg.
5
Ref. Torkelson TR et al., Am. Ind. Hyg. Assoc. J. 1958 19 353-362
6
7
Mice B6C3F1 mice given 1000, 1780, 3160, 5620 or 10000 mg/kg/day, 5 days/week for 6
8
weeks, then observed for 2 weeks. No histopathology carried out. Deaths at 10000
9
mg/kg/day; NOEL = 5620 mg/kg/day.
10
Ref. NCI. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity, Technical Report
11
Series 3, US DHEW, 1977
12
13
Daily dose =
5620 x 5
7
= 4014 mg / kg / day
14
15
PDE =
4014 x 50
12 x 10 x 10 x 10 x 1
= 16.7 mg / day
16
17
Limit =
16.7 x 1000
10
= 1670 ppm
18
19
Male CF-1 mice exposed by inhalation to 250 or 1000 ppm continuously for 14 weeks. Only
20
liver examined, including EM. Marked liver damage at 1000 ppm, effects at 250 ppm
21
minimal. LOEL = 250 ppm.
22
Ref. McNutt NS et al., Lab. Invest. 1975 32 642-654
23
24
250 ppm =
250 x 133.42
24.45
= 1364 mg / m
mg / L
3
= 136
.
25
26
Page 35
draft 7 page
35
Daily dose =
1.36 x 43
0.028
= 2088 mg / kg
1
2
PDE =
2088 x 50
12 x 10 x 5 x 1 x 5
= 34.8 mg / day
3
4
Limit =
34.8 x 1000
10
= 3480 ppm
5
6
Rats Osborne-Mendel rats given 1000, 1780, 3160, 5620 or 10000 mg/kg/day, 5 days/week
7
for 6 weeks, then observed for 2 weeks. No histopathology carried out. Some deaths at 5620
8
and 10000 mg/kg/day and reduced weight gain in survivors; NOEL = 3160 mg/kg/day.
9
Ref. NCI. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity, Technical Report
10
Series 3, US DHEW, 1977
11
12
Daily dose =
3160 x 5
7
= 2257 mg / kg
13
14
PDE =
2257 x 50
5 x 10 x 10 x 10 x 1
= 22.6 mg / day
15
16
Limit =
22.6 x 1000
10
= 2260 ppm
17
18
Male Wistar rats exposed by inhalation to 204 ppm, 8h/day, 5 days/week, for 14 weeks. No
19
detectable effects, including at microscopic examination of a limited number of tissues. NOEL
20
= 204 ppm.
21
Ref. Eben A and Kimmerle G Arch. Toxicol. 1974 31 233-242
22
23
204 ppm =
204 x 133.42
24.45
= 1113 mg / m
mg / L
3
= 111
.
24
25
Page 36
draft 7 page
36
For continuous exposure =
1.11 x 8 x 5
24 x 7
= 0.26 mg / L
1
2
Daily dose =
0.26 x 290
0.425
= 177 mg / kg
3
4
PDE =
177 x 50
5 x 10 x 5 x 1 x 1
= 35.4 mg / day
5
6
Limit =
35.4 x 1000
10
= 3540 ppm
7
8
Long-Evans or Sprague-Dawley rats exposed continuously for 90 days to atmospheres
9
containing 754 or 2059 mg/m
3
. Non-specific lung changes, but no effects considered to be
10
treatment-related. NOEL 2059 mg/m
3
= 2.06 mg/L
11
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
12
13
Daily dose =
2.06 x 290
0.425
= 1405 mg / kg
14
15
PDE =
1405 x 50
5 x 10 x 5 x 1 x 1
= 280 mg / day
16
17
Limit =
280 x 1000
10
= 28,000 ppm
18
19
Rats exposed by inhalation to 5000 ppm, 7h/day, on 31 of 44 days. No effect, except for
20
transiently reduced weight gain in females. LOEL = 5000 ppm.
21
Ref. Adams EM et al., Arch. Ind. Hyg. Occup. Med. 1950 1 225-236
22
23
5000 ppm =
5000 x 133.42
24.45
= 27284 mg / m
mg / L
3
= 27 3.
24
Page 37
draft 7 page
37
1
For continuous exposure =
27.3 x 7 x 31
24 x 44
= 5.61 mg / L
2
3
Daily dose =
5.61 x 290
0.425
= 3828 mg / kg
4
5
PDE =
3828 x 50
5 x 10 x 10 x 1 x 5
= 76.6 mg / day
6
7
Limit =
76.6 x 1000
10
= 7660 ppm
8
9
Rats exposed to 500 ppm by inhalation, 7h/day, 5 days/week for 6 months. No evidence of
10
toxicity, including at microscopic examination of limited tissue list.
11
Ref. Torkelson TR et al., Am. Ind. Hyg. Assoc. J. 1958 19 353-362
12
13
500 ppm =
500 x 133.42
24.45
= 2728 mg / m
mg / L
3
= 2 73
.
14
15
For continuous exposure =
2.73 x 7 x 5
24 x 7
= 0.57 mg / L
16
17
Daily dose =
0.57 x 43
0.425
= 389 mg / kg
18
19
PDE =
389 x 50
5 x 10 x 2 x 1 x 1
= 77.8 mg / day
20
21
Limit =
77.8 x 1000
10
= 7780 ppm
22
23
Page 38
draft 7 page
38
Rabbits New Zealand White rabbits exposed continuously for 90 days to atmospheres
1
containing 754 or 2059 mg/m
3
. Reduced weight gain at 2059 mg/m
3
. Other changes (non-
2
specific lung and one death at lower concentration) not considered to be treatment-related.
3
NOEL 754 mg/m
3
= 0.754 mg/L.
4
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
5
6
Daily dose =
0.754 x 1440
4
= 271 mg / kg
7
8
PDE =
271 x 50
2.5 x 10 x 5 x 1 x 1
= 108.4 mg / day
9
10
Limit =
108.4 x 1000
10
= 10,840 ppm
11
12
Rabbits exposed by inhalation to 5000 ppm, 7h/day, on 31 of 44 days. No effect, except for
13
slightly reduced weight gain. LOEL = 5000 ppm.
14
Ref. Adams EM et al., Arch. Ind. Hyg. Occup. Med. 1950 1 225-236
15
16
5000 ppm =
5000 x 133.42
24.45
= 27284 mg / m
mg / L
3
= 27 3.
17
18
For continuous exposure =
27.3 x 7 x 31
24 x 44
= 5.61 mg / L
19
20
Daily dose =
5.61 x 1440
4
= 2019 mg / kg
21
22
PDE =
2019 x 50
2.5 x 10 x 10 x 1 x 5
= 80.8 mg / day
23
24
Page 39
draft 7 page
39
Limit =
80.8 x 1000
10
= 8080 ppm
1
2
Guinea pigs Hartley guinea pigs exposed continuously for 90 days to atmospheres containing
3
754 or 2059 mg/m
3
. Non-specific lung changes, but no effects considered to be treatment-
4
related. NOEL 2059 mg/m
3
= 2.06 mg/mL.
5
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
6
7
Daily dose =
2.06 x 430
0.500
= 1772 mg / kg
8
9
PDE =
1772 x 50
10 x 10 x 5 x 1 x 1
= 177 mg / day
10
11
Limit =
177 x 1000
10
= 17700 ppm
12
13
Guinea pigs exposed by inhalation to 5000 ppm, 7h/day, on 32 of 45 days. Reduced weight
14
gain and hepatic fatty degeneration in both sexes; testicular degeneration in males. LOEL =
15
5000 ppm. Ref. Adams EM et al., Arch. Ind. Hyg. Occup. Med. 1950 1 225-236
16
17
5000 ppm =
5000 x 133.42
24.45
= 27284 mg / m
mg / L
3
= 27 3.
18
19
For continuous exposure =
27.3 x 7 x 32
24 x 45
= 5.66 mg / L
20
21
Daily dose =
5.66 x 430
0.500
= 4867 mg / kg
22
23
PDE =
4867 x 50
10 x 10 x 10 x 1 x 10
= 24.3 mg / day
24
Page 40
draft 7 page
40
1
Limit =
24.3 x 1000
10
= 2430 ppm
2
3
Guinea pigs exposed by inhalation to 3000 ppm, 7h/day, on 20 of 29 days, 1500 ppm on
4
44/60 days, 650 ppm on 65/92 days or 650 ppm on 40/57 days. Hepatic fatty degeneration at
5
3000 ppm; transiently reduced weight gain at all concentrations. LOEL = 1500 ppm.
6
Ref. Adams EM et al., Arch. Ind. Hyg. Occup. Med. 1950 1 225-236
7
8
1500 ppm =
1500 x 133.42
24.45
= 8185 mg / m
mg / L
3
= 819
.
9
10
For continuous exposure =
8.19 x 7 x 44
24 x 70
= 1.75 mg / L
11
12
Daily dose =
1.75 x 430
0.500
= 1505 mg / kg
13
14
PDE =
1505 x 50
10 x 10 x 10 x 1 x 5
= 15 mg / day
15
16
Limit =
15 x 1000
10
= 1500 ppm
17
18
Guinea pigs exposed to 500 ppm by inhalation, 7h/day, 5 days/week for 6 months. No
19
evidence of toxicity, including at microscopic examination of limited tissue list. Ref.
20
Torkelson TR et al., Am. Ind. Hyg. Assoc. J. 1958 19 353-362
21
22
500 ppm =
500 x 133.42
24.45
= 2728 mg / m
mg / L
3
= 2 73
.
23
24
Page 41
draft 7 page
41
For continuous exposure =
2.73 x 7 x 5
24 x 7
= 0.57 mg / L
1
2
Daily dose =
0.57 x 430
0.500
= 490 mg / kg
3
4
PDE =
490 x 50
10 x 10 x 2 x 1 x 1
= 122 mg / day
5
6
Limit =
122 x 1000
10
= 12200 ppm
7
8
Dogs Beagle dogs exposed continuously for 90 days to atmospheres containing 754 or 2059
9
mg/m
3
. Slightly reduced weight gain at 2059 mg/m
3
. Non-specific lung changes, but no
10
effects considered to be treatment-related. NOEL 754 mg/m
3
= 0.754 mg/L.
11
Ref. Prendergast JA Toxicol. Appl. Pharmacol. 1967 10 270-289
12
13
Daily dose =
0.754 x 9000
11.5
= 590 mg / kg
14
15
PDE =
590 x 50
2 x 10 x 5 x 1 x 1
= 295 mg / day
16
17
Limit =
295 x 1000
10
= 29,500 ppm
18
19
Human
20
1,1,1-Trichloroethane is fairly lipid soluble, and is absorbed after exposure of skin or by
21
inhalation. No studies have been carried out by the oral route, but intoxication after ingestion
22
indicates that absorption occurs. One subject survived accidental ingestion of approximately
23
600 mg/kg without evidence of renal or hepatic dysfunction, although there was marked
24
gastrointestinal irritancy. Twenty-eight workers with long-term, repetitive, high exposures to
25
Page 42
draft 7 page
42
1,1,1-trichloroethane (levels unknown) showed evidence of a toxic encephalopathy, with
1
symptoms similar to those seen after exposure to other solvents. The principal finding at
2
autopsy of victims of occupational poisoning or solvent abuse has generally been lung
3
oedema. Repeated, controlled exposures to up to 500 ppm 1,1,1-trichloroethane produced
4
mild CNS disturbance.
5
Refs. Stewart RD and Andrews JT JAMA 1966 195 904-906
6
Stahl CJ et al., J. Forensic Sci. 1969 14 393-397
7
Hall FB and Hine CH J. Forensic Sci. 1966 11 404-413
8
Kelafant GA et al., Am. J. Indust. Med. 1994 25 439-446
9
Stewart RD et al., Arch. Environ. Health 1969 19 467-472
10
Very few studies have been carried out on workers exposed occupationally to 1,1,1-
11
trichloroethane for long periods. Multiple studies provide no convincing evidence of
12
genotoxicity of 1,1,1-trichloroethane itself. No anecdotal accounts suggesting carcinogenicity
13
in humans have been located, and the solvent gave negative results in 2-year rodent studies.
14
15
Environmental Impact
16
Under the revised Montreal Protocol, production and use of 1,1,1-trichloroethane are
17
scheduled to be phased out by the year 2005 by ratifying parties (excluding 10-year
18
derogations for developing nations), because of its contribution to atmospheric ozone
19
depletion (ozone-depleting potential 0.15, cf. 0.8-1.0 for fully halogenated CFCs, and short
20
residence time, but world production is high).
21
22
Conclusion
23
Animal toxicity generally low; not carcinogenic in well-designed studies. No evidence of
24
reproductive toxicity in adequate studies. Relatively low toxicity in man after acute or
25
repeated exposure.
26
The PDE for 1,1,1-trichloroethane is 15.0 mg/day (limit 1500 ppm). However, note that
27
production of 1,1,1-trichloroethane is scheduled to be phased out by 2005 under the Montreal
28
Protocol, because of atmospheric ozone depletion.
29