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Toxicological information

Neurotoxicity

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Administrative data

Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Treatment initiation: 08 Sep 1992, final day of sacrifice: 10 Dec 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study with acceptable restrictions (Different species; insufficient number of tests and animals for histopathological examinations)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: US-EPA FIFRA, Guideline 82-5
Deviations:
yes
Remarks:
Rats instead of hens; Tests were performed on weeks -1, 4, 8, 13 and not once a week; Histopathology was performed on solely 6 rats from control dose and maximal dose; No biochemical measurements (NTE assay) were performed.
Principles of method if other than guideline:
US-EPA FIFRA, Guideline 82-5 is in general accordance with OECD guideline 424, and US-EPA OPPTS 870.6200.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Thiram
EC Number:
205-286-2
EC Name:
Thiram
Cas Number:
137-26-8
Molecular formula:
C6H12N2S4
IUPAC Name:
thiram
Details on test material:
- Name of test material (as cited in study report): Thiram technical
- Physical state: Off-white powder
- Analytical purity: 98.76 %
- Lot/batch No.: G-0245
- Stability under test conditions: The stability of the test substance and test substance preparations in vehicle were confirmed by analysis.
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 125 and 500 ppm
Basis:
nominal in diet
Based on food consumption data, the following intake rates were calculated: 0, 1.5-2.3, 5.9-10.2 and 22.8-40.2 mg/kg bw/day for males; 0, 1.8-2.6, 6.9-10.1 and 21.6-43.9 mg/kg bw/day for females
No. of animals per sex per dose:
15
Control animals:
yes, plain diet

Results and discussion

Effect levels

open allclose all
Dose descriptor:
LOEL
Effect level:
ca. 5.9 - 10.2 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Systemic toxicity 125 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
LOEL
Effect level:
ca. 6.9 - 10.1 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Systemic toxicity 125 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
LOEL
Effect level:
ca. 22.8 - 40.2 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Neurotoxicity 500 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
LOEL
Effect level:
ca. 21.6 - 43.9 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Neurotoxicty 500 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
NOEL
Effect level:
ca. 1.5 - 2.3 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Systemic toxicity 30 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
NOEL
Effect level:
ca. 1.8 - 2.6 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Systemic toxicity 30 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
NOEL
Effect level:
ca. 5.6 - 10.2 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Neurotoxicity 125 ppm (nominal)
Remarks on result:
other:
Dose descriptor:
NOEL
Effect level:
ca. 6.9 - 10.1 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Neurotoxicity 125 ppm (nominal)
Remarks on result:
other:

Any other information on results incl. tables

Concentration verification analyses of the tests diets showed analytical values ranging from 90.8 to 107.2 % of nominal values.

Clinical signs of toxicity: No mortalities and no treatment-related clinical signs were observed during the study in any animal.

Body weight:

0 and 30 ppm group:   No effects

125 ppm group: Reduced body weight gain in males during week 1. In week 2 a compensatory increase was observed. Decreased body weights and/or body weight gains were observed occasionally after week 2 in females.

500 ppm group: Body weight was decreased (6-7%) in both sexes during week 1. In week 2 a compensatory increase was observed, but body weights continued to be significant lower throughout the study.

The initial decrease in body weight was consistent with the dose-related decrease in food consumption.

Food consumption:

Food consumption was dose-dependent decreased. During week 1 food consumption of males was reduced by 4, 16, and 47 % in the 30, 125, and 500 ppm dose group, respectively. For females food consumption was reduced by 16 and 53 % in the 125 and 500 ppm group, respectively. This general pattern persisted throughout the study, although the differences observed at 125 and 30 ppm in males were less consistent and of smaller magnitude (about 4-8 %) than those observed in the 500 ppm males (9-16 %). In females, decreases of food consumption of 9-12 % were occasionally seen for the 125 ppm group. In the high dose females decreases of 9-17 % were consistently observed during the study.

Functional Observational Battery (FOB):

The FOB did not reveal a consistent or striking profile of effects, which could be considered evidence of neurotoxicity. However, males in the high-dose group showed an increase in the number of rears, and an increased incidence of hyperactivity during week 8 and 13. Because males tend to have a low level of activity under these test conditions relative to females, it is difficult to discern the effects of test substances, which depress activity. Statistically significant increases in the number of rears and the incidence of hyperactivity were also detected in females at 30, 125, and 500 ppm during week 8.

Motor activity: There were no significant treatment-related differences observed in both sexes.

Pathology:

Neuropathology: Brain weights of high dose males and females were statistically less than controls. The relative brain weights were significantly increased. In females of the 125 ppm group relative brain weights were also significantly increased. However, these findings were considered an effect of thiram on the overall growth, rather than a specific effect on the nervous system.

There were no gross pathological findings in any animal.

Histopathology: No treatment-related effects.

Overview of significant functional observational battery findings:

 Time exposure        Week 4        Week 8        Week 13
 Group (ppm)  30  125  500  30  125  500  30  125  500
 Males                          
 rears               i
 arousal               ia 
 body weight         d    
 Females                          
 rears       ib  ib  ib       
 arousal       ib ib  ib       
 forelimb grip strength    db db             
 body weight    d      d    d  d

statistically significant increased (i) or decreased (d) compared to control group

a: not statistically significant, however, considered to be biologically significant

b: the biological significance is questionable

Applicant's summary and conclusion