Sodium diethyldithiocarbamate

Carcinogenicity

Description of key information

A carcinogenicity study with rats and with mice, which received sodium diethyldithiocarbamate (SDEC) tryhydrate in diet for 2 years, showed no increased tumor incidence. Anhydrous SDEC and its 26% aquesous solution are concluded to be non-carcinogenic.

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

Principles of method if other than guideline:

Groups of 50 rats of each sex were administered sodium diethyldithiocarbamate trihydrate in diet at one of two doses, either 1250 or 2500 ppm, for 104 weeks. All surviving rats and mice were killed at the end of administration of the test chemical and the necropsies and histopathological analysis were 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 animal farm (Frederick, Md.).
- Age at study initiation: 6 weeks
- Weight at study initiation: males 90 to 105 g, averating at least 100 g; females 80 to 95 g, averaging at least 90 g
- Housing: polycarbonate cages (Lab Products Inc., Gar field, N.J.), 19 x 10-1/2 x 8 inches
- Diet: presterilized Wayne Sterilizable Lab Meal, provided ad libitum in suspended stainless steel hoppers and replenished at least three times per week
- Water: acidified to pH 2.5, supplied a£ libitum from glass bottles
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 24
- Humidity (%): 45 to 55
- Air changes (per hr): 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: every 1 to 1-1/2 weeks in 6- to 12-kg batches
- Mixing appropriate amounts with: 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, 111.), 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.
- Storage temperature of food: 5 °C

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily

Post exposure period:

None

Dose / conc.:

1 250 ppm (nominal)

Dose / conc.:

2 500 ppm (nominal)

No. of animals per sex per dose:

Test groups: 50/sex/dose, control 16 untreated male rats, 20 untreated female rats

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based on preliminary sub-chronic study

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily. Observations for 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 a month

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; gross examination of major tissues, major organs, and all gross lesions. Necropsies were also performed on all animals found dead, unless precluded in whole or in part by autolysis or cannibalization.
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, sub lingual, and submaxillary), liver, pancreas, esophagus, stomach (glandular and nonglandular), 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.

Statistics:

Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Taronefs (1975) extensions of Cox methods for testing for a dose-related trend. One-tailed P values have been reported for all tests except the departure from linearity test, which is only, reported when its two-tailed P value is less than 0.05. 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.

Clinical signs:

no effects observed

Description (incidence and severity):

Clinical signs occurred at low incidences in control and dosed rats.

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 rats, 38/50 (76%) of the high-dose group, 35/50 (70%) of the low-dose group, and 14/16 (88%) of the control group lived to the end of the bioassay. In females, 45/50 (90%) of the high-dose group, 45/50 (90%) of the low-dose group, and 16/20 (80%) of the control group lived to the end of the bioassay.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of the high-dose males were lower than those of the corresponding controls; mean body weights of the low-dose males were essentially unaffected by administration of the test chemical. Mean body weights of both the high- and low-dose female rats were lower than those of the corresponding controls, and were dose related throughout the bioassay.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

There was an unusual incidence and distribution of cataracts of the eye in the dosed female rats. Cataracts were observed in the eyes of 0/20 control, 14/50 low-dose, and 6/50 high-dose female rats. Only eyes that were grossly abnormal were required to be examined microscopically. Eyes without gross abnormalities were not processed for histopathologic examination. Since only grossly abnormal eyes were examined microscopically, the significance of this observation is not known.

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Several other inflammatory, degenerative, and proliferative lesions commonly seen in aged F344 rats occurred with approximately equal frequency in dosed and control animals.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

A variety of neoplasms commonly seen in aged F344 rats occurred with approximately equal frequency in dosed and control rats. There were a few instances in which neoplasms occurred only, or with increased frequency, in the dosed rats. The incidence, distribution, and nature of these neoplasms are similar to those occurring in aged F344 rats.

Dose descriptor:

NOAEL

Effect level:

> 180 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

No tumor increase observed at the highest dose tested. The NOAEL in mg/kg bw/day was calculated based on the test substance concentration in diet of 2500 ppm using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998).

Dose descriptor:

NOAEL

Effect level:

> 141 mg/kg bw/day (actual dose received)

Based on:

other: anhydrous substance

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

No tumor increase observed at the highest dose tested. The NOAEL in mg/kg bw/day was calculated based on the test substance concentration in diet of 2500 ppm using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998).

Critical effects observed:

no

Conclusions:

There was no evidence of carcinogenic potential. NOAEL for SDEC trihydrate is 180 mg/kg bw/day. Based on this for its anhydrous form the NOAEL for this study 141 mg/kg bw/day.

Executive summary:

In a carcinogenicity study SDEC trihydrate was administered to two groups of 50 male and 50 female Fischer 344 rats, via the oral route in diet, daily for 104 weeks at dietary concentrations of 1250, and 2500 ppm. Control group consisted of 16 males and 20 females. Dose selection was based on previous sub-chronic study. All surviving rats were killed at the end of administration of the test chemical. The incidence of mortality was not affected by treatment and there were no toxicologically significant, compound-related effects on the clinical condition of the animals. Mean body weights of the high-dose males were lower than those of the corresponding controls; mean body weights of the low-dose males were essentially unaffected by administration of the test chemical. Mean body weights of both the high- and low-dose female rats were lower than those of the corresponding controls, and were dose related throughout the study. There was an unusual incidence and distribution of eye cataracts in the female rats. Eyes without gross abnormalities were not processed for histopathologic examination. Since only grossly abnormal eyes were examined microscopically, the significance of this observation is not known. Histopathological examination revealed several inflammatory, degenerative, and proliferative lesions commonly seen in aged F344 rats, occurring with approximately equal frequency in dosed and control animals. A variety of neoplasms commonly seen in aged F344 rats occurred with approximately equal frequency in dosed and control rats. There were a few instances in which neoplasms occurred only, or with increased frequency, in the dosed rats. The incidence, distribution, and nature of these neoplasms are similar to those occurring in aged F344 rats. Based on these findings the NOAEL of the study was 180 mg/kg bw/day  (2500 ppm) for the test material, and 141 mg/kg bw/day for the anhydrous form.

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:

comparable to guideline study with acceptable restrictions

Principles of method if other than guideline:

Groups of 50 mice of each sex were administered sodium diethyldithiocarbamate trihydrate in diet at one of two doses, either 500 or 4000 ppm, for either 108 or 109 weeks. All surviving mice were killed at the end of administration of the test chemical and the necropsies and histopathological analysis were 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 animal farm (Frederick, Md.).
- Age at study initiation: 6 weeks
- Weight at study initiation: males 18 to 22 g, average at least 19.5 g; females 17 to 21 g, average at least 18.5 g
- Housing: polycarbonate cages (Lab Products Inc., Gar field, N.J.), 11-1/2 x 7-1/2 x 5 inches
- Diet: presterilized Wayne Sterilizable Lab Meal, provided ad libitum in suspended stainless steel hoppers and replenished at least three times per week
- Water: acidified to pH 2.5, supplied ab libitum from glass bottles
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 24
- Humidity (%): 45 to 55
- Air changes (per hr): 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: every 1 to 1-1/2 weeks in 6- to 12-kg batches
- Mixing appropriate amounts with: 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, 111.), 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.
- Storage temperature of food: 5 °C

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

108 and 109 weeks

Frequency of treatment:

Daily

Post exposure period:

None

Dose / conc.:

500 ppm (nominal)

Dose / conc.:

4 000 ppm (nominal)

No. of animals per sex per dose:

Test groups: 50/sex/dose, control 20/sex

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based on preliminary subchronic study

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily. Observations for 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 a month

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; gross examination of major tissues, major organs, and all gross lesions. Necropsies were also performed on all animals found dead, unless precluded in whole or in part by autolysis or cannibalization.
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, sub lingual, and submaxillary), liver, pancreas, esophagus, stomach (glandular and nonglandular), 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.

Statistics:

Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Taronefs (1975) extensions of Cox methods for testing for a dose-related trend. One-tailed P values have been reported for all tests except the departure from linearity test, which is only, reported when its two-tailed P value is less than 0.05. 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.

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The result of the Tarone test for dose-related trend in mortality is not significant in either sex. In female mice, the result of the Cox test comparing the high-dose and matched-control groups is significant (P = 0.025), but in the negative direction. In male mice, 38/50 (76%) of the high-dose group, 41/50 (82%) of the low-dose group, and 17/20 (85%) of the control group lived to the end of the bioassay. In females, 42/50 (84%) of the high-dose group, 40/50 (80%) of the low-dose group, and 11/20 (55%) of the control group lived to the end of the bioassay.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of the dosed male and female mice were lower than those of corresponding control groups, and were dose related throughout the bioassay.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Several other inflammatory, degenerative, and proliferative lesions commonly seen in aged F344 rats occurred with approximately equal frequency in dosed and control animals

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

One of the most prevalent tumors in the mice in this study was alveolar/bronchiolar adenoma or carcinoma. Among female mice there were 15 animals with these tumors in dosed groups (low-dose 7/49, or 14%; high-dose 8/50, or 16%) and none in the female controls. However, among male mice there was little difference in the incidences of these tumors in the dosed and control groups (controls 6/19, or 32%; low-dose 14/50, or 28%; high-dose 14/49, or 28%).
There were also a number of hepatocellular tumors in both dosed and control mice. The incidence was higher in males than in females, and there was no apparent increase in the incidence of the tumors in dosed animals over controls. In addition to these neoplastic lesions, other tumors were observed that were of single occurrence or very low incidence. All were tumors that may be expected in mice of this strain and, therefore, were not considered to be related to the test compound.
The occurrence of lung tumors in female dosed mice and their absence in control females was not believed to be significant, because of the smaller number of control animals and because the incidence of these tumors was higher in control males than in dosed males. Based on the histopathologic examination, there was no conclusive evidence in this study that sodium diethyldithiocarbamate was carcinogenic when given to B6C3F1 mice at the doses used.

Dose descriptor:

NOAEL

Effect level:

> 635 mg/kg bw/day (actual dose received)

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

No tumor increase observed at the highest dose tested. The NOAEL in mg/kg bw/day was calculated based on the test substance concentration in diet of 5000 ppm using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998).

Dose descriptor:

NOAEL

Effect level:

> 496 mg/kg bw/day (actual dose received)

Based on:

other: anhydrous substance

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

No tumor increase observed at the highest dose tested. The NOAEL in mg/kg bw/day was calculated based on the test substance concentration in diet of 5000 ppm using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998).

Critical effects observed:

no

Conclusions:

No conclusive evidence on carcinogenicity observed. Based on the findings the NOAEL of the study is mg/kg bw/day (2500 ppm) for the test material SDEC trihydrate, and 141 mg/kg bw/day for the anhydrous form.

Executive summary:

In a carcinogenicity study SDEC dihydrate was administered to two groups of 50 male and 50 female B6C3F1 mice, via the oral route in diet, daily for 108-109 weeks at dietary concentrations of 500, and 4000 ppm. Control group consisted of 16 males and 20 females. Dose selection was based on previous sub-chronic study. All surviving mice were killed at the end of administration of the test chemical and the necropsies and histopathological analysis were performed. The incidence of mortality was not affected by treatment and there were no toxicologically significant, compound-related effects on the clinical condition of the animals. Mean body weights of the dosed male and female mice were lower than those of corresponding control groups, and were dose related throughout the study. Histopathological examination revealed several inflammatory, degenerative, and proliferative lesions commonly seen in aged F344 rats, occurring with approximately equal frequency in dosed and control animals. One of the most prevalent tumors seen was alveolar/bronchiolar adenoma or carcinoma. Among female mice there were 15 animals with these tumors in dosed groups (low-dose 7/49, or 14%; high-dose 8/50, or 16%) and none in the female  controls. However, among male mice there was little difference in the incidences of these tumors in the dosed and control groups. All tumors observed may be expected in mice of this strain and, therefore, were not considered to be related to the test compound.The occurrence of lung tumors in female dosed mice and their absence in control females was not believed to be significant, because of the smaller number of control animals and because the incidence of these tumors was higher in control males than in dosed males. Based on the histopathologic examination, there was no conclusive evidence in this study that SDEC was carcinogenic when given to B6C3F1 mice at the doses used. Based on these findings the NOAEL of the study was 635 mg/kg bw/day (5000 ppm) for the test material, and 496 mg/kg bw/day for the anhydrous form of SDEC.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

NTP studies

Justification for classification or non-classification

Based on the evidence from the available oral carcinogenicity study with rats and mice, anhydrous SDEC and its 26% aqueous solution do not need to be classified for carcinogenicity in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

A carcinogenicity study with rats and mice, conducted by NTP (NTP, 1979), was available for assessment. Groups of 50 rats of each sex were administered sodium diethyldithiocarbamate trihydrate (SDEC) at one of two doses, either 1250 or 2500 ppm in diet, for 104 weeks. Groups of 50 mice of each sex were administered sodium diethyldithiocarbamate (SDEC) at doses 500 or 4000 ppm for 108 or 109 weeks. All surviving rats and mice were killed at the end of administration of the test chemical and histopathological, clinical chemistry and haematological examinations were performed.

Mean body weights of all dosed groups of rats and mice were lower than those of corresponding controls and were dose related throughout the bioassay except those of the low-dose male rats, which were essentially unaffected by administration of the test chemical. Survivals of the rats and mice were unaffected, and no other clinical signs could be related to administration of the test chemical. No tumors occurred in the rats or mice of either sex at incidences that were significantly higher in the dosed groups than in the control groups. Based on the result of the study, sodium diethyldithiocarbamate (SDEC) was concluded to be non-carcinogenic.