Sodium diethyldithiocarbamate

Endpoint summary

Description of key information

Sub-chronic toxicity studies with rats and mice were avalable for assessment with sodium diethyldithiocarbamate trihydrate, which were performed as a part of carcinogenicity study. In the study with rats, NOAEL was 425 mg/kg bw/day, based on a very slight increase in splenic hematopoiesis and a very small amount of vacuolation of renal tubular epithelium. Recalculated for anhydrous substance, this corresponds to 332 mg/kg bw/day, respectively.

In the study with mice, no effects were observed at the highest tested dose, resulting in NOAEL of 1305 mg/kg bw/day. Recalculated for anhydrous substance, this corresponds to 1019 mg/kg bw/day, respectively.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: 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:

Subchronic feeding study was conducted to estimate the maximum tolerated dose (MTD) of sodium diethyldithiocarbamate. Groups of five rats of each sex were fed diets containing sodium diethyldithiocarbamate trihydrate at doses 1250, 2500, 5000, 10000, 20000 and 40000 ppm. The period of administration of the test chemical was 7 weeks, followed by 1 week of additional observation. At the end of the study, all animals were killed and necropsy and histopathological examinations were performed.

GLP compliance:

no

Limit test:

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, average at least 100 g; females 80 to 95 g, average 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 oral 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:

7 weeks, followed by 1 week post-treatment observation

Frequency of treatment:

Daily

Dose / conc.:

1 250 ppm

Dose / conc.:

2 500 ppm

Dose / conc.:

5 000 ppm

Dose / conc.:

10 000 ppm

Dose / conc.:

20 000 ppm

Dose / conc.:

40 000 ppm

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Ten percent depression in body weight was the major criterion for estimation of MTD's. The doses required to produce this response were determined by the following procedure: first, least squares regressions of mean body weights versus days on study were used to estimate mean body weights of each of the dosed groups at day 49. Next, probits of the percent weights of dosed groups at day 49 relative to weights of corresponding control groups were plotted against the logarithms of the doses, and least squares regressions fitted to the data were used to estimate the doses required to induce 10% depression in weight.

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:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

NOAEL

Effect level:

425 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: The amount 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:

332 mg/kg bw/day (actual dose received)

Based on:

other: anhydrous substance

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: The amount 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:

not specified

Conclusions:

The NOAEL of SDEC trihydrate after repeated dosing in the rat is 425 mg/kg bw/d, which corresponds to a NOAEL of 332 mg/kg bw of anhydrous SDEC.

Executive summary:

In a subchronic feeding study with SDEC, groups of five  Fischer 344 rats of each sex were fed diets containing SDEC trihydrate at doses 1250, 2500, 5000, 10000, 20000 and 40000 ppm. The period of administration of the test chemical was 7 weeks, followed by 1 week of additional observation. At the end of the study, all animals were killed and necropsy and histopathological examinations were performed. Effects were seen in the body weight of animasl due to treatment. A 10% depression in body weight was used for the estimation of the maximum tolerated dose (MTD) of SDEC. In the histopathology examination a very slight increase in splenic hematopoiesis and a very small amount of vacuolation of renal tubular epithelium were noted at 10000 ppm and above. Based on this the NOAEL of this study for SDEC trihydrate was 425 mg/kg bw (5000 ppm), while the respective NOAEL for the anhydrous SDEC is 332 mg/kg bw/d.

Reference 2

Endpoint:

sub-chronic toxicity: 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:

Subchronic feeding study was conducted to estimate the maximum tolerated dose (MTD) of sodium diethyldithiocarbamate. Groups of five mice of each sex were fed diets containing sodium diethyldithiocarbamate trihydrate at doses 2500, 5000, 6000, 8000 and 10000 ppm. The period of administration of the test chemical was 7 weeks, followed by 1 week of additional observation for male mice; for female mice the period of administration of the test chemical was 12 weeks. At the end of the study, all animals were killed and necropsy and histopathological examinations were performed.

GLP compliance:

no

Limit test:

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, averating at least 19.5 g; females 17 to 21 g, averaging 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 oral 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:

7 weeks, followed by 1 week post-treatment observation for male mice; 12 weeks for female mice

Frequency of treatment:

Daily

Dose / conc.:

2 500 ppm

Dose / conc.:

5 000 ppm

Dose / conc.:

6 000 ppm

Dose / conc.:

8 000 ppm

Dose / conc.:

10 000 ppm

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Ten percent depression in body weight was the major criterion for estimation of MTD's. The doses required to produce this response were determined by the following procedure: first, least squares regressions of mean body weights versus days on study were used to estimate mean body weights of each of the dosed groups at day 49. Next, probits of the percent weights of dosed groups at day 49 relative to weights of corresponding control groups were plotted against the logarithms of the doses, and least squares regressions fitted to the data were used to estimate the doses required to induce 10% depression in weight.

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:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

NOAEL

Effect level:

> 1 305 mg/kg bw/day (actual dose received)

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

No effects observed at the highest dose tested. The amount in mg/kg bw/day was calculated based on the test substance concentration in diet of 10000 ppm using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998).

Dose descriptor:

NOAEL

Effect level:

> 1 019 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 effects observed at the highest dose tested. The amount in mg/kg bw/day was calculated based on the test substance concentration in diet of 10000 ppm using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998).

Critical effects observed:

not specified

Conclusions:

The NOAEL of SDEC trihydrate after repeated dosing in the mouse is 1305 mg/kg bw/d (10000 ppm), which corresponds to a NOAEL of 1019 mg/kg bw of anhydrous SDEC.

Executive summary:

In a subchronic feeding study with SDEC, groups of five B6C3F1 mice of each sex were fed diets containing SDEC trihydrate at doses 2500, 5000, 6000, 8000 and 10000 ppm. The period of administration of the test chemical was 7 weeks, followed by 1 week of additional observation. For female mice the period of administration of the test chemical was 12 weeks.  At the end of the study, all animals were killed and necropsy and histopathological examinations were performed. No effects of any toxicological significance were seen up until and including the highest dose level. Therefore, the NOAEL of this study for SDEC was 1305 mg/kg bw (10000 ppm), while the respective NOAEL for the anhydrous SDEC is 1019 mg/kg bw/d.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

425 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

NTP studies

Additional information

Two sub-chronic toxicity with mice and rats, performed as dose range-finding studies for the NTP carcinogenicity assay (NTP, 1979), were available for assessment. Groups of five rats and mice of each sex were fed diets containing sodium diethyldithiocarbamate (SDEC) in its trihydrate form at dose levels of 1250, 2500, 5000, 10000, 20000 and 40000 ppm for rats and 2500, 5000, 6000, 8000 and 10000 ppm for mice. Groups of five control animals of each species and sex were administered basal diet only. The period of administration of the test chemical was 7 weeks, followed by 1 week of additional observation for rats and male mice; for female mice the period of administration of the test chemical was 12 weeks. Each animal was weighed twice per week. The studies were conducted to estimate the maximum tolerated doses of sodium diethyldithiocarbamate, with 10% depression in body weight being the major criterion for estimation of MTD's. At the end of the subchronic studies, all animals were killed and necropsied. In the rat study, a NOAEL of 5000 ppm, corresponding 425 mg/kg bw/day (value calculated using the default values according to the report of Paulussen at al. (TNO report V98.390, 1998)) was established, based on a very slight increase in splenic hematopoiesis and a very small amount of vacuolation of renal tubular epithelium. Recalculated for anhydrous substance, this results in NOAEL of 332 mg/kg bw/day. No lesions related to the test chemical were observed in male and female mice at the highest dose level, resulting in NOAEL of 1305 mg/kg bw/day. Recalculated for anhydrous substance, this results in NOAEL of 1019 mg/kg bw/day.

Justification for classification or non-classification

Classification of sodium diethyldithiocarbamate is not warranted according to  EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. This is considered to be applicable to both substance in its manufactured and marketed form (as 26% aqueous solution) and to the anhydrous substance.