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Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Over 10 weeks
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
Mammalian metabolic systems are expected to transform both dithiocarbamates and test substance by the same pathway, and both metabolites share the key thiuram disulphide functionality which will be the toxicologically-active portion of the molecules. Thus, it is considered to be a health-precautionary approach to read-across the mammalian cell gene mutation (mouse lymphoma) data on ziram & smaller dithiocarbamates to fill the corresponding gap in the Zinc diisononyldithiocarbamate dataset as the information is in the public domain with added benefit of reduction in further animal testing.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2001

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Ziram
EC Number:
205-288-3
EC Name:
Ziram
Cas Number:
137-30-4
Molecular formula:
C6H12N2S4Zn
IUPAC Name:
zinc bis(dimethyldithiocarbamate)
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
not specified

Administration / exposure

Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
Over a 10 week period
Details on study schedule:
Not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/L air (nominal)
Remarks:
For two generations
Dose / conc.:
72 mg/kg bw/day (nominal)
Remarks:
For two generations
Dose / conc.:
207 mg/kg bw/day (nominal)
Remarks:
For two generations
Dose / conc.:
540 mg/kg bw/day (nominal)
Remarks:
For two generations
Dose / conc.:
5.3 mg/kg bw/day (actual dose received)
Remarks:
F0 males
Dose / conc.:
14.8 mg/kg bw/day (nominal)
Remarks:
F0 males
Dose / conc.:
37.5 mg/kg bw/day (nominal)
Remarks:
F0 males
Dose / conc.:
6.1 mg/kg bw/day (nominal)
Remarks:
F0 females
Dose / conc.:
16.8 mg/kg bw/day (nominal)
Remarks:
F0 females
Dose / conc.:
42.8 mg/kg bw/day (nominal)
Remarks:
F0 females
Dose / conc.:
5.6 mg/kg bw/day (nominal)
Remarks:
F1 males
Dose / conc.:
16.7 mg/kg bw/day (nominal)
Remarks:
F1 males
Dose / conc.:
42.7 mg/kg bw/day (nominal)
Remarks:
F1 males
Dose / conc.:
6.3 mg/kg bw/day (nominal)
Remarks:
F1 females
Dose / conc.:
18.4 mg/kg bw/day (nominal)
Remarks:
F1 females
Dose / conc.:
47.5 mg/kg bw/day (nominal)
Remarks:
F1 females
No. of animals per sex per dose:
30
Control animals:
yes
Positive control:
None listed

Examinations

Parental animals: Observations and examinations:
Food consumption, weight change, hair loss, sores, water consumption, lactation.
Oestrous cyclicity (parental animals):
Not listed
Sperm parameters (parental animals):
Not listed
Litter observations:
Weight
Postmortem examinations (parental animals):
No histopathological effects. Weight loss
Postmortem examinations (offspring):
No histopathological effects. Weight loss

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight gains in high-dose males were significantly less than the controls during study weeks 18-10, 20-21 (83% cf) and 21-22 (90% cf).
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Males showed initial weight loss during the first week. Following that the was no significant difference during the test only at the highest dose.
Females showed significant weight loss compared to controls during the entire period of the test.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced compared to control
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No gross treatment related effects.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No gross treatment related effects.
Reproductive performance:
no effects observed
Description (incidence and severity):
No gross treatment related effects.

Effect levels (P0)

Key result
Dose descriptor:
LOAEL
Effect level:
37.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Lower body weights compared to controls beginning at day 4 precull up till day 14 and through lactation up to day 21.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Lower body weights compared to controls beginning at day 4 precull up till day 14 and through lactation up to day 21.
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 specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Effect levels (P1)

Key result
Dose descriptor:
LOAEL
Effect level:
37.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Absolute body weights for high-dose F1 females were significantly lower than the controls for the entire premating period (89-92%, study weeks 19-23, p<0.05; weeks 24-30, p<0.01). Significnatly lower body weight gains (67-87%) occurred only during study weeks 18-19 (p<0.05, 23-24 and 24-25 (p<0.01).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption by the high-odse F1 females was also significantly less than the controls throughout remating (p<0.01; weeks 21-22 and 28-29, p<0.05).
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Diferences in absolute and relative organs weights of the high-dose male and female F0 and F1 groups as compared to controls are consistent with reduced body weights of these animals.
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Key result
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
37.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F2 generation

General toxicity (F2)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
37.5 mg/kg bw/day (nominal)
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified

Applicant's summary and conclusion

Executive summary:

This structural analogue has been used to typify the behaviour of zinc dithiocarbamate compounds. As the ligands in Arbestab Z are far larger there is less likelihood that there will be as significant effects on developmental toxicity from the dimethyl analogue compared to the isononyl ligands in Arbestab Z. This is a worsst case scenario but typifies the possible biochemical interations in mammalian foetal development.