Disulfiram

Carcinogenicity

Description of key information

Key, report number NCI-CG-TR-166, carcinogenicity study (107 weeks, rat):
NOAEL (systemic toxicity) 600 ppm, corresponding to approx. 12.5 mg/kg bw/day for males and females
NOAEL (carcinogenicity) 600 ppm, corresponding to approx. 12.5 mg/kg bw/day for males and females

 

Key, report number NCI-CG-TR-166, carcinogenicity study (108 weeks, mice):

NOAEL (systemic toxicity) 2000 ppm for males, corresponding to approx. 60 mg/kg bw/day, 500 ppm for females, corresponding to approx. 14.7 mg/kg bw/day

NOAEL (carcinogenicity) 2000 ppm for males, corresponding to approx. 60 mg/kg bw/day, 500 ppm for females, corresponding to approx. 14.7 mg/kg bw/day

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

adopted in 2018

Deviations:

yes

Remarks:

Food consumption was not examined.

Principles of method if other than guideline:

Male mice were exposed to 0, 500 and 2000 ppm test substance and female mice to 0, 100 and 500 ppm test substance in diet for 108 weeks.
Afterwards the animals were autopsied and gross and microscopic examination of major tissues, organs and all gross lesions was performed.

GLP compliance:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NCI Frederick Cancer Research Center
- Age at study initiation: 6 weeks
- Weight at study initiation: males 19.5 g (18 - 22 g), females 18.5 g (17 - 21 g)
- Housing: 5 per cage, in polycarbonate cages (Lab Products, Inc., Garfield, N. J.), 11-1/2 x 7-1/2 x 5 inches
- Diet: ad libitum, Wayne Sterilizable Lab Meal
- Water: acidified to pH 2.5, ad libitum from glass bottles
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24
- Humidity (%): 45 - 55
- Air change, times per hour: 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): every 1-1.5 weeks in 6 to 12 kg batches
- Mixing appropriate amounts with (Type of food): a known weight of the chemical was first mixed with an equal weight of autoclaved Wayne sterilizable Lab Meal with 4% fat (Allied Mills, Inc., Chicago, Ill) using a mortar and pestle. The mixing was continued with second and third additions of feed, and final mixing was performed with the remaining quantity of feed for a minimum of 15 minutes in a Patterson-Kelly twin-shell blender with an intensifer bar.
- Storage temperature of food: at 7 °C in plastic bags until used.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Uniformity of the mixtures was established by comparative analysis of samples taken from three different locations within the blender.

Duration of treatment / exposure:

108 weeks

Frequency of treatment:

Daily

Post exposure period:

continuously via the diet

Dose / conc.:

100 ppm

Remarks:

female mice (corresponding to approx. 2.9 mg/kg bw/day, calculated in accordance with Paulussen et al., 1998 (TNO report V98.390))

Dose / conc.:

500 ppm

Remarks:

male and female mice (corresponding to approx. 14.7 mg/kg bw/day, calculated in accordance with Paulussen et al., 1998 (TNO report V98.390))

Dose / conc.:

2 000 ppm

Remarks:

male mice (corresponding to approx. 60 mg/kg bw/day, calculated in accordance with Paulussen et al., 1998 (TNO report V98.390))

No. of animals per sex per dose:

20/sex/dose for control; 50/sex/dose for the test groups

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based on maximal tolerated dose established in a subchronic study
- Rationale for animal assignment (if not random): on a weight basis

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily. Observations on sick, tumor-bearing and moribund animals were recorded daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical examination and palpation for masses were performed each month.

BODY WEIGHT: Yes
- Time schedule for examinations: at least once per month


FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body
weight gain data: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes.

HISTOPATHOLOGY: Yes. The following tissues were examined microscopically: skin, lungs and bronchi, trachea, bone marrow (femur), spleen, lymph nodes (mesenteric and submandibular), thymus, heart, salivary glands (parotid, sublingual, and submaxillary), liver, pancreas, oesophagus, stomach (glandular and non-glandular), small and large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, mammary gland, uterus, ovary, brain (cerebrum and cerebellum), and all tissue masses.

Other examinations:

Peripheral blood smears were made for all animals, whenever possible.

Statistics:

Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958). Animals were statistically censored as of the time that they died of other than natural causes or were found to be missing; animals dying from natural causes were not statistically censored. Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extensions of Cox's methods for testing for a dose-related trend.
The incidence of neoplastic or nonneoplastic lesions has been given as the ratio of the number of animals bearing such lesions at a specific anatomic site (numerator) to the number of animals in which that site is examined (denominator).
The one-tailed Fisher exact test (Cox, 1970) was used to compare the tumor incidence of a control group with that of a group of dosed animals at each dose level.
The Cochran-Armitage test for linear trend in proportions, with continuity correction (Armitage, 1971), was also used.
A time-adjusted analysis was applied when numerous early deaths resulted from causes that were not associated with the formation of tumors. In this analysis, deaths that occurred before the first tumor was observed were excluded by basing the statistical tests on animals that survived at least 52 weeks, unless a tumor was found at the anatomic site of interest before week 52. When such an early tumor was found, comparisons were based exclusively on animals that survived at least as long as the animal in which the first observed tumor was found. Once this reduced set of data was obtained, the standard procedures for analyses of the incidence of tumors (Fisher exact tests, Cochran-Armitage tests, etc.) were followed.
Curves of the proportions surviving without an observed tumor were computed as in Saffiotti et al. (1972).

Clinical signs:

no effects observed

Description (incidence and severity):

Clinical signs occurred at comparable frequencies in the dosed and control groups of animals.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

not applicable

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The result of the Tarone test for dose-related trend in mortality was not significant in either sex. In male
mice, 46/50 (92%) of the high-dose group, 43/50 (86%) of the low-dose group, and 13/20 (65%) of the control group lived to the end of the bioassay. In females, 44/50 (88%) of the high-dose group, 39/50
(78%) of the low-dose group, and 16/20 (80%) of the control group lived to the end of the bioassay.
For a figure of the summarized results, see Attachment 1 in the attached background material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of dosed male and female mice were lower than those of corresponding controls
and the differences were dose related throughout the bioassay. However, no other clinical signs were observed and the lower body weight gain is therefore not considered to be an adverse effect.

For a figure of the summarized results, see Attachment 1 in the attached background material.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

not applicable

Food efficiency:

not examined

Description (incidence and severity):

not applicable

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

not applicable

Ophthalmological findings:

not examined

Description (incidence and severity):

not applicable

Haematological findings:

not specified

Description (incidence and severity):

not applicable

Clinical biochemistry findings:

not examined

Description (incidence and severity):

not applicable

Endocrine findings:

not specified

Description (incidence and severity):

The following ED-related parameters were investigated in the study: histopathology of mammary gland, prostate, ovaries, testis, thyroid, uterus, adrenals and pituitary. For details, please
refer to the respective result fields and the endpoint summary.

Urinalysis findings:

not examined

Description (incidence and severity):

not applicable

Behaviour (functional findings):

not examined

Description (incidence and severity):

not applicable

Immunological findings:

not examined

Description (incidence and severity):

not applicable

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

not applicable

Gross pathological findings:

no effects observed

Description (incidence and severity):

No effects were observed.

Neuropathological findings:

not examined

Description (incidence and severity):

not applicable

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

The large number of degenerative, proliferative and inflammatory lesions which were detected in anim
als of the dosed and control groups are commonly seen in aged B6C3F1 mice.

For summarized results, see Attachment 2 in the attached background material.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

In female mice, the result of the Cochran-Armitage test for positive dose-related trend in the incidence of animals with either alveolar/bronchiolar adenoma or carcinoma was significant (P = 0.036), but the results of the Fisher exact test were not significant. Thus, the occurrence of tumors of the
lung in the female mice cannot be clearly related to the administration of the test chemical.

Significant results in the negative direction are observed in the combined incidence of alveolar/bronchiolar adenoma and carcinoma and in the combined incidence of hepatocellular adenoma or carcinoma in male mice, in which the incidences in the control group exceededthose in the dosed groups.

For summarized results, see Attachment 2 in the attached background material.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity and carcinogenicity

Effect level:

2 000 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No treatment-related adverse effects observed at the highest dose tested.

Remarks on result:

other: corresponding to approx. 60 mg/kg bw/day. The calculation for the dose is described under "Any other information on results incl. tables".

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity and carcinogenicity

Effect level:

500 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No treatment-related adverse effects observed at the highest dose tested.

Remarks on result:

other: corresponding to approx. 14.7 mg/kg bw/day. The calculation for the dose is described under "Any other information on results incl. tables".

Key result

Critical effects observed:

no

No data on food consumption in the study were available. Therefore the NOAEL in mg/kg bw/day was calculated in accordance with Paulussen et al., 1998 (TNO report V98.390), as follows:

1) Food consumption was calculated in accordance with the following formula:

F = 0.065 W^0.7919, where W = body weight of mice, proposed default value of 45 g for male and female mice in a chronic study.

The food consumption calculated by this formula was 1.32 g/day.

2) Based on the concentration of the test substance in diet of 2000 ppm (2000 mg/kg diet) for male mice and 500 ppm (500 mg/kg diet) for female mice, the average consumed amount of the test substance per day was calculated as 1.32 g/day x 0.002 kg/1 kg diet = 2.7 mg/day for males and 1.32 g/day x 0.0005 kg/1 kg diet = 0.66 mg/day for females.

Based on the default value for the mouse body weight of 45 g, the NOAEL was calculated to correspond to 60 mg/kg bw/day for male mice and 14.7 mg/kg bw/day for female mice.

Conclusions:

The study was conducted similar to OECD guideline 451 with one deviation: Food consumption was not examined.
No adverse effects were observed at any treatment dose, therefore, the NOAEL for carcinogenicity and systemic toxicity was set at the highest dose level of 14.7 mg/kg bw/day for female rats and 60 mg/kg bw/day for male mice.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Predates GLP and OECD guidelines, minor restrictions in design and reporting, but otherwise adequate for assessment.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

adopted in 2018

Deviations:

yes

Remarks:

Food consumption was not examined.

Principles of method if other than guideline:

Male and female rats were exposed to 0, 300 and 600 ppm test substance in diet for 107 weeks. Afterwards the animals were autopsied and gross
and microscopic examination of major tissues, organs and all gross lesions was performed.

GLP compliance:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NCI Frederick Cancer Research Center
- Age at study initiation: 6 weeks
- Weight at study initiation: males average 100 g (90 - 105 g), females average 90 g (80 - 95 g)
- Housing: 4 per cage, in polycarbonate cages (Lab Products, Inc., Garfield, N. J.), 19 x 10-1/2 x 8 inches
- Diet: ad libitum, Wayne Sterilizable Lab Meal
- Water: acidified to pH 2.5, ad libitum from glass bottles
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24
- Humidity (%): 45 - 55
- Air change, times per hour: 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): every 1-1.5 weeks in 6 to 12 kg batches
- Mixing appropriate amounts with (Type of food): a known weight of the chemical was first mixed with an equal weight of autoclaved Wayne sterilizable Lab Meal with 4% fat (Allied Mills, Inc., Chicago, Ill) using a mortar and pestle. The mixing was continued with second and third additions of feed, and final mixing was performed with the remaining quantity of feed for a minimum of 15 minutes in a Patterson-Kelly twin-shell blender with an intensifer bar.
- Storage temperature of food: at 7 °C in plastic bags until used.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Uniformity of the mixtures was established by comparative analysis of samples taken from three different locations within the blender.

Duration of treatment / exposure:

107 weeks

Frequency of treatment:

continuously via the diet

Post exposure period:

None

Dose / conc.:

300 ppm

Remarks:

corresponding to approx. 6.25 mg/kg bw/day, doses were calculated in accordance with Paulussen et al., 1998 (TNO report V98.390)

Dose / conc.:

600 ppm

Remarks:

corresponding to approx. 12.5 mg/kg bw/day, doses were calculated in accordance with Paulussen et al., 1998 (TNO report V98.390)

No. of animals per sex per dose:

20/sex/dose for control; 50/sex/dose for the test groups

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based on maximal tolerated dose established in a subchronic study
- Rationale for animal assignment (if not random): on a weight basis

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily. Observations on sick, tumor-bearing and moribund animals were recorded daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical examination and palpation for masses were performed each month.

BODY WEIGHT: Yes
- Time schedule for examinations: at least once per month


FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body
weight gain data: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes.

HISTOPATHOLOGY: Yes. The following tissues were examined microscopically: skin, lungs and bronchi, trachea, bone marrow (femur), spleen, lymph nodes (mesenteric and submandibular), thymus, heart, salivary glands (parotid, sublingual, and submaxillary), liver, pancreas, oesophagus, stomach (glandular and non-glandular), small and large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, mammary gland, uterus, ovary, brain (cerebrum and cerebellum), and all tissue masses.

Other examinations:

Peripheral blood smears were made for all animals, whenever possible.

Statistics:

Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958). Animals were statistically censored as of the time that they died of other than natural causes or were found to be missing; animals dying from natural causes were not statistically censored. Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extensions of Cox's methods for testing for a dose-related trend.
The incidence of neoplastic or nonneoplastic lesions has been given as the ratio of the number of animals bearing such lesions at a specific anatomic site (numerator) to the number of animals in which that site is examined (denominator).
The one-tailed Fisher exact test (Cox, 1970) was used to compare the tumor incidence of a control group with that of a group of dosed animals at each dose level.
The Cochran-Armitage test for linear trend in proportions, with continuity correction (Armitage, 1971), was also used.
A time-adjusted analysis was applied when numerous early deaths resulted from causes that were not associated with the formation of tumors. In this analysis, deaths that occurred before the first tumor was observed were excluded by basing the statistical tests on animals that survived at least 52 weeks, unless a tumor was found at the anatomic site of interest before week 52. When such an early tumor was found, comparisons were based exclusively on animals that survived at least as long as the animal in which the first observed tumor was found. Once this reduced set of data was obtained, the standard procedures for analyses of the incidence of tumors (Fisher exact tests, Cochran-Armitage tests, etc.) were followed.
Curves of the proportions surviving without an observed tumor were computed as in Saffiotti et al. (1972).

Clinical signs:

no effects observed

Description (incidence and severity):

Clinical signs occurred at comparable frequencies in the dosed and control groups of animals.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

not applicable

Mortality:

mortality observed, non-treatment-related

Description (incidence):

For male rats, the result of the Tarone test for dose-related trend in mortality is not significant. In females, the result is significant (p = 0.005), but in the negative direction. In male rats, 36/50 (72%) of the high-dose group, 39/50 (78%) of the low-dose group, and 13/20 (65%) of the control group lived to the end of the bioassay. In females, 46/50 (92%) of the high-dose group, 40/50 (80%) of the low-dose group, and 13/20 (65%) of the control group lived to the end of the bioassay.

For a figure of the summarized results, see Attachment 1 in the attached background material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of dosed male and female rats were lower than those of corresponding controls and the differences were dose related throughout the bioassay. However, no other clinical signs were observed and the lower body weight gain is therefore not considered to be an adverse effect.

For a figure of the summarized results, see Attachment 1 in the attached background material.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

not applicable

Food efficiency:

not examined

Description (incidence and severity):

not applicable

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

not applicable

Ophthalmological findings:

not examined

Description (incidence and severity):

not applicable

Haematological findings:

not examined

Description (incidence and severity):

not applicable

Clinical biochemistry findings:

not examined

Description (incidence and severity):

not applicable

Endocrine findings:

not specified

Description (incidence and severity):

The following ED-related parameters were investigated in the study: histopathology of mammary gland, prostate, ovaries, testis, thyroid, uterus, adrenals and pituitary. For details, please
refer to the respective result fields and the endpoint summary.

Urinalysis findings:

not examined

Description (incidence and severity):

not applicable

Behaviour (functional findings):

not examined

Description (incidence and severity):

not applicable

Immunological findings:

not examined

Description (incidence and severity):

not applicable

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

not applicable

Gross pathological findings:

no effects observed

Description (incidence and severity):

No gross pathological findings were observed.

Neuropathological findings:

not examined

Description (incidence and severity):

not applicable

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Several nonneoplastic changes were observed in the dosed and control groups. These findings
included degenerative, inflammatory, and cystic lesions which are usually observed in aged male and
female rats.

For summarized results, see Attachment 2 in the attached background material.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

A variety of neoplastic changes were noted in the control and dosed rats. There was no apparent relationship between the incidence of neoplasms and the administration of the test compound. Significant results in the negative direction are observed in the incidences of pituitary tumors in each sex of rat and in the incidences of tumors of the pituitary, the thyroid, and the mammary gland in female rats.

For summarized results, see Attachment 2 in the attached background material.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity and carcinogenicity

Effect level:

600 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment-related adverse effects were observed at the highest dose tested.

Remarks on result:

other: corresponding to approx. 12.5 mg/kg bw/day. The calculation for the dose is described under "Any other information on results incl. tables".

No data on food consumption in the study were available. Therefore the NOAEL in mg/kg bw/day was calculated in accordance with Paulussen et al., 1998 (TNO report V98.390), as follows:

1) Food consumption was calculated in accordance with the following formula:

F = 0.065 W^0.7919, where W = body weight of rats, proposed default value of 250 g for male and female rats in a chronic study.

The food consumption calculated by this formula was 5.2 g/day.

2) Based on the concentration of the test substance in diet of 600 ppm (600 mg/kg diet), the average consumed amount of the test substance per day was calculated as 5.2 g/day x 0.0006 = 3.1 mg/day.

Based on the default value for the rat body weight of 250 g, the NOAEL was calculated to correspond to 12.5 mg/kg bw/day.

Conclusions:

The study was conducted similar to OECD guideline 451 with one deviations: Food consumption was not examined.
No adverse effects were observed at any treatment dose, therefore, the NOAEL for carcinogenicity and systemic toxicity was set at the highest dose level of 12.5 mg/kg bw/day for male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

12.5 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The quality of the database is good comprising two carcinogenicity studies in rodent species (rat and mouse), similar to OECD TG 451, pre-GLP. Both studies are considered of sufficient quality and validity, fulfilling the criteria of a key study. Thus, both are suitable for assessment of the present endpoint.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

Please refer to the respective endpoint summary. 

Justification for classification or non-classification

The available data on carcinogenicity is conclusive but not sufficient for classification according to the Regulation 1272/2008 (EC) (CLP Regulation).

Additional information

In a carcinogenicity study, disulfiram was administered to rats up to the MTD, e. g. 600 ppm, in the diet for 107 weeks (National Toxicology Program, 1979). Except for effects on bodyweight gain, no other treatment-related effects were observed throughout the study. No effect on tumour incidence was reported and the NOAEL for carcinogenicity was therefore established at 600 ppm corresponding to approx. 12.5 mg/kg bw/day, the highest dose tested for male and female animals.

In a simultaniously performed carcinogenicity study in mice, male and female animals received disulfiram in the diet for 108 weeks (National Toxicology Program, 1979). The only systemic effect was a decrease in the body weight which was observed in all dosed animals. Since there was no increase in tumour induction., the NOAEL was set at 500 and 2000 ppm corresponding to approx. 14.7 and 60 mg/kg bw/day for females and males, respectively.