Registration Dossier

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
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:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: compact
Details on test material:
Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2
- Name of test material (as cited in study report): Ziram
-IUPAC Name zinc bis dimethyldithiocarbamate
- Lot/Batch number: 8331 AA
- Description: Creamy white powder
- Purity: 98.5%
- Stability: Stable
-Molecular formula:C6H12N2S4Zn
-Molecular weight range :305.8419
-SMILES notation :CN(C)C(=S)S[Zn]SC(=S)N(C)
-InChI=1/2C3H7NS2.Zn/c2*1-4(2)3(5)6;/h2*1-2H3,(H,5,6);/q;;+2/p-2/rC6H12N2S4Zn/c1-7(2)5(9)11-13-12-6(10)8(3)4/h1-4H3

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals 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
- five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg

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
Details on study design:
Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.
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):
no effects observed
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

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.
Dose descriptor:
NOAEL
Effect level:
169 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

On a molecular weight scaled basis, the NOAELwould be 169 mg/kg bw

(300x 172.24) /305.84 = 169 mg/kg bw

Applicant's summary and conclusion

Conclusions:
On a molecular weight scaled basis, the NOAELwould be 169 mg/kg bw(300x 172.24) /305.84 = 169 mg/kg bw
The NOAEL was 169 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin
Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide:
They arise from the reaction of the amine with CS2



Executive summary:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.