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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Aug 1990- 29Oct 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
Adopted in 1981
Deviations:
no
Principles of method if other than guideline:
- Principle of test:Assess systemic toxicity of Zinc Diisononyldithiocarbamate (ZDiD) to the rat
- Short description of test conditions: ZDiD was administered to groups of twenty rats (10 males & 10 females for up to 13 weeks by admixture with the diet at fixed dose levels of 6, 60 and 500mg/kg/day with a group of twenty control rats received untreated diet alone. All animals were examined macroscopically on days 92 and 93 and the end of observation period. Histological examination of tissues was then intiated for the control and intermediate dosage, 60mg/kg/day.
- Parameters analysed / observed:
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis[bis(3,5,5-trimethylhexyl)dithiocarbamate-S,S']zinc
EC Number:
283-381-8
EC Name:
Bis[bis(3,5,5-trimethylhexyl)dithiocarbamate-S,S']zinc
Cas Number:
84604-96-6
Molecular formula:
C38H76N2S4Zn
IUPAC Name:
bis({[bis(3,5,5-trimethylhexyl)carbamothioyl]sulfanyl})zinc
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
BN 204 8789017
Date received - 1990
Expiry - stable for duration of study ( stored in dark at room temp)
Purity - n/a
Appearance- white powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
50 male and 50 females CD rats of Sprague Dawley orogin (Crl:CD (SD) BR VAF Plus
Ordered from Charles River
Sex:
male/female
Details on test animals or test system and environmental conditions:
Rats were 28 1 days old. and in weight range 63-81g

On arrival five animals from both gender was randomnly selected and used for health check purposes. For remaining rats a 14 day acclimitisation period was allowed after delivery and before start of treatments. Veterinary examination was performed on all animals before start of study.

Administration / exposure

Route of administration:
oral: feed
Details on route of administration:
test substance was administered by admixture with the diet. A pre-mix was prepared each week by grinding the test substnace directly into SDS lab animal diet no 2 & mixing in a Turbula mixer, until homogeneity ( minimum 7 mins mixing)
Vehicle:
other: SDS lab Animal diet 2
Details on oral exposure:
Samples of diets prepared during weeks 1, 6, 13 were analysed to check accuracy of preparation and performed by Huntingdon analytical services and found satisfactory
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of diets prepared during weeks 1, 6, 13 were analysed to check accuracy of preparation and performed by Huntingdon analytical services and found satisfactory
Duration of treatment / exposure:
Required dose of test item was administered to treated groups through out study by changing the concentrations of test material in diet on a weekly basis.
Frequency of treatment:
fed daily for 90 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg diet
Remarks:
control group of 10 males and 10 females
Dose / conc.:
6 mg/kg diet
Remarks:
10 females and 10 males
Dose / conc.:
60 mg/kg diet
Remarks:
10 females and 10 males
Dose / conc.:
500 mg/kg diet
Remarks:
10 males and 10 females
No. of animals per sex per dose:
10 females and 10 males
Control animals:
yes, plain diet
Details on study design:
All rats were weighed at time of allocation of animals per group, then at weekly intervals throughout the study.- see table 1 in attachments
Positive control:
none

Examinations

Observations and examinations performed and frequency:
mortality, clinical signs twice a day, bodyweight weekly, food consumption (food intake per rat was calculated from the amount of food consumed in each cage and the number of rats surviving in each cage, efficiency of food utilisation, intake of test substance at weekly intervals, water consumption, daily monitoring, ophthalmoscopy before dosing and at week 13. Clinical pathology- Haematology, biochemistry, faecal analysis, terminal studies, organ weight analysis, macroscopic analysis and microscopic pathology. Statistical analysis was used for bodyweight, food consumption, organ weight and clinical pathology data.
Sacrifice and pathology:
Yes, see attachment A
Statistics:
Yes- see attachment A

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
High dose group - systemic toxicity at this dosage was marked clinical signs (lethargy, reduced mean bodyweight and decreased food consumption.

Mortality:
mortality observed, treatment-related
Description (incidence):
High dose groups only
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight summary attached
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
For the mid and low dose groups, no adverse effets were seen in clinical signs, bodyweights, food and water consumption, efficiency of food utilisation, opthalmoscopy, biochemistry and microscopic pathology, there were no notable differences between rats treated with zinc diisononyl dithiocarbamate at 6, or 60mg/kg.day and that of controls
Food efficiency:
no effects observed
Description (incidence and severity):
Mid and low dose groups
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Analysis of blood revealed reduced PCV, Haemoglobin, RBC (males) and MCV values in high and mid dose groups

High dose group- 500mg/kg/day- reduced PCV, haemoglobin, RBC, MCV, increased reticulocyte and platelet levels, decrease in lymphocyte values and total white cell count. Blood slides showed polychomasia, hypochronasia and anisocytosis plus presence of Howell Jolly bodies

Low dose groups, no abnormal blood slides
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
slight biochemical changes observed at low and mid dose group, in creatinine, albumin and decreased cholesterol. All the changes were attributed to chance, being minor in nature and within the ranges of natural parameter variation for rats of this age and strain ( historical control data)
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Organ weights recorded at each post mortem examination at week 14 were analysed adjusting for final bodyweights as covariate, where appropriate. Results revealed an increase in adjusted adrenal weight for males treated with test item at 60mg/kg day in comparison with control as the only significant change
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related changes were observed following histopathological examination of preapred tissues from controls and rats of mid dose group.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
immunology

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
60 mg/kg bw/day (nominal)
System:
endocrine system
Organ:
adrenal glands
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
Administration of test substance in the diet of group at 500mg/kg/day resulted in treatment related deaths with the remainder of rats sacrificed for reasons of animal welfare before end of study. Pre-death findings included clinical signs, reduced body weights and food consumption. Analysis of blood samples revealed evidence of decreased red and white cell activity with further haematological and various biochemical parameters affected. The decrease in red cell values were accompanied by morphological changes, polychromasia, hypochromasia, anisocytosis, Howell Jolly bodies and nucleated red blood cells.

Few of the above changes were noted among rats in group 60mg/kg.day although a continuation of the anaemic and white cell efects, decreased PCV, haemoglobin, MCHC, MCV, lymphocyte and total white cell values with increased counts of platelets and reticulocyte. Despite the lack of histopathologcial changes, the haematological changes precluded the NOTEL as 60mg/kg/day.

The only notable finding at 6mg/kg/day was a decrease in MCHC values for male rats ( 2 out of 10 animals) No further haemtological findings were evident in PCV, RBC count, Hb, nor MVC, % reticulocytes and since this adpated response (variation also seen in controls) was minor and not considered of toxicological importance, a NOAEL was established at 6mg/kg/day
Executive summary:

NOAEL for test substance on repeat exposure was set at 6mg/kg/day