Sodium diethyldithiocarbamate

Repeated dose toxicity: oral

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Materials and methods

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

Test material

Test material information

Constituent 1

Reference substance name:

Sodium diethyldithiocarbamate

EC Number:

205-710-6

EC Name:

Sodium diethyldithiocarbamate

Cas Number:

148-18-5

Molecular formula:

C5H11NS2.Na

IUPAC Name:

sodium (diethylcarbamothioyl)sulfanide

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 250 ppm

Doses / concentrations 2

Dose / conc.:

2 500 ppm

Doses / concentrations 3

Dose / conc.:

5 000 ppm

Doses / concentrations 4

Dose / conc.:

10 000 ppm

Doses / concentrations 5

Dose / conc.:

20 000 ppm

Doses / concentrations 6

Dose / conc.:

40 000 ppm

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes, plain diet

Examinations

Observations and examinations performed and frequency:

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

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

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

Effect levels

1

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).

2

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).

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

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.