Potassium dimethyldithiocarbamate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance zinc(bis) dimethyldithiocarbamate (CAS No. 137-30-4). In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on an read-across substance

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

Data about the area covered by the test material and occlusion are not reported.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ziram

EC Number:

205-288-3

EC Name:

Ziram

Cas Number:

137-30-4

IUPAC Name:

zinc bis(dimethyldithiocarbamate)

Constituent 2

Reference substance name:

zinc bis dimethyldithiocarbamate

IUPAC Name:

zinc bis dimethyldithiocarbamate

Details on test material:

- Name of test material (as cited in study report): Ziram
- Lot/Batch number: 8331 AA
- Description: Creamy white powder
- Purity: 98.5%
- Stability: Stable

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England
- Age at study initiation: 10-12 weeks on arrival
- Weight at study initiation: fehlt noch

Administration / exposure

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: no data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg bw/day
- For solids, paste formed: Yes. Powder was moistened with water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

purity of ziram was analysed

Duration of treatment / exposure:

21 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

5

Control animals:

yes

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CLINICAL SIGNS
- Time schedule: once daily

MORTALITY
- Time schedule: once daily

DERMAL IRRITATION
- Time schedule for examinations: Prior to the first application and subsequent daily (erythema and eschar / oedema formation) .

BODY WEIGHT
- Time schedule for examinations: Prior to dosing and then once weekly.

FOOD CONSUMPTION
- Time schedule for examinations: Once weekly.

HAEMATOLOGY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: haematocrit, erythrocyte count, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, platelet count, total leukocyte count, differential leukocyte count, cell morphology, thrombotest

CLINICAL CHEMISTRY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: glucose, blood urea nitrogen, creatinine, total bilirubin, total cholesterol, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio

Sacrifice and pathology:

ORGAN WEIGHTS
From all animals sacrificed at termination.
- Organs: adrenals, liver, kidneys, testes with epididymides/ovaries

GROSS AND HISTOPATHOLOGY
All animals were sacrificed at study termination and a gross pathological examination was performed.
- Histopathology: from all animals of the control and highest dose group
- Organs: abnormal tissue, skin (treated and untreated), kidneys, liver

Statistics:

All analyses were carried out separately for male and female.
The following tests were used for food and water consumption, bodyweight, relative organ weight and clinical pathology data:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
- Analyses of variance were followed by a Student’s ‘t’ test and Williams’ test for a dose-related response, although only the one thought most appropriate for the response pattern observed has been reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).
Where appropriate for organ weight data, analysis of covariance was used in place of analysis of variance.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAIN
Bodyweight losses or reduced bodyweight gain was observed in females dosed at 1000 mg/kg bw/day.

FOOD CONSUMPTION
Reduction was measured for females dosed at 1000 mg/kg bw/day in week 1. Food consumption was also reduced in the following weeks but did not achieve statistical significance.

HAEMATOLOGY
Significant lower lymphocyte counts for females dosed at 1000 mg/kg bw/day.

CLINICAL CHEMISTRY
Liver enzymes GOT and GPT were increased in females dosed at 1000 mg/kg bw/day and in case of GOT also at 300 mg/kg bw/day.
Increased levels of bilirubin amongst females and cholesterol amongst both sexes dosed at 1000 mg/kg bw/day were also observed.

GROSS PATHOLOGY
Increased incidence of irregular cortical scarring of the kidney in all groups was not considered to be treatment-related.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

300 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: = 312.6 mg KDDC (a.s.)/kg bw/day = 625.2 mg KDDC (50% solution as supplied)/kg bw/day, based on significantly increased GOT-levels for females

2

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: = 104.2 mg KDDC (a.s.)/kg bw/day = 208.4 mg KDDC (50%)/kg bw/day

Target system / organ toxicity

Critical effects observed:

not specified