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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
8 November, 1988 to 12 May 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline study performed in compliance with GLP, available as unpublished report, no restrictions, fully adequate for assessment.

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Directive 84/449/EEC, Part B, B.7
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
(1981)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)
EC Number:
404-310-0
EC Name:
Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)
Cas Number:
10591-85-2
Molecular formula:
C30H28N2S4
IUPAC Name:
N,N-dibenzyl[(dibenzylcarbamothioyl)disulfanyl]carbothioamide

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Sprague-Dawley CD rat, outbred, SPF quality

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of formulations
Samples of formulations prepared during weeks 1, 2, 3 and 4 were analysed to check the accuracy of preparation.
Concentration of the test article in vehicle was determined weekly on days 6, 13, 20 and 27.
TBzTD was determined to be stable for at least 4 hours in propylene glycol at all concentrations tested. TBzTD formed a homogeneous suspension in propylene gl ycol at all concentrations tested.
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Examinations

Statistics:
The following statistical methods were used to analyse the body weight, food consumption, organ weights and clinical laboratory data:

Univariate one-way analysis of variance was used to assess the significance of intergroup differences.

If the variables could be assumed to follow a normal distribution, the Dunnett-test (many to one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups.

The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.

A11 tests we re two-s i ded and in all cases p < 0.05 was accepted as the lowest level of significance.

Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.

Individual values, means, standard deviations and statistics were rounded off before printing. For example, test statistics were calculated on the basis of exact values for means and pooled variances and then rounded off to two decimal places. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values References:

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One male of the control and one female receiving 200 mg/kg/day showed slight diarrhoea on days 8 and 2, respectively.
No clinical signs were noted in treated males and in females receiving 50 or 1000 mg/kg/day.
One control male (animal 5) showed a broken left upper incisor on day 12 and a broken right upper incisor on day 14. One male receiving 50 mg/kg/day (animal 7) showed a broken left upper incisor on day 12.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female (animal 39) died on day 11 of dosing. This early death was in the absence of any signs of toxicity, not considered to be treatment related.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and body weight gain of treated animals remained similar to those of control rats over the study period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no differences in appetite between treated and control animals during the 29 day observation period.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Changes in red blood cell parameters between treated and control animals, included a statistically significant increase in red blood cell counts and hemoglobin in females receiving 1000 mg/kg/day and a statistically significant decrease in red cell distribution width in females receiving 50, 200 or 1000 mg/kg/day.
However, these values were within the range normally seen in rats of this age and strain and therefore not considered to be of toxicological significance.
Total white blood cell counts achieved a level of statistical significance in their difference from controls for females receiving 50 or 200 mg/kg/day, but in the absence of any corresponding effect in females receiving 1000 mg/kg/day and in treated males, these increases were considered to have arisen by chance and to be of no biological significance.
Eosinophils were noted as statistically significant high in comparison with control levels for females receiving 1000 mg/kg/day. However, of the 4 values measured, only 2 values fell outside the normal expected range. Therefore, in the absence of consistent response, a treatment related distribution or similar response in males this finding is considered to be the result of extreme biological variation and not directly related to the treatment.
Other differential white blood cell counts did not differ significantly from control values.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no toxicologically significant differences in blood chemistry parameters between control and treated animals of both sexes.
Statistically significant differences arising between Calcium of males receiving 50 mg/kg/day, Sodium of males receiving 200 mg/kg/day, GOT of females receiving 1000 mg/kg/day and Albumin of females receiving 200 or 1000 mg/kg/day in comparison with controls were within biologically normal limits and considered to have occurred fortuitously.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Spleen weights of treated females were slightly, but statistically significantly decreased in comparison with control weights. However, after correction for body weight, these decreases attained a level of statistical significance only for females receiving 200 mg/kg/day.
However, all values were within the range normally seen for rats of this age and strain.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Pelvic dilatation of the kidneys was noted in 2 females receiving 50 mg/kg/day. This finding is known to occur spontaneously in rats of this age and strain and not considered of toxicological significance.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
A small number of microscopic findings were noted in the rats examined. These microscopic findings did not distinguish treated rats from controls and were findings commonly noted in rats of this age and strain.
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed at the highest dose tested
Remarks on result:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related effects observed at this dose level
Remarks on result:
other: original NCD unit is mg/kg/day. The accuracy of preparat on testing revealed that the concentrations analyzed were in agreement with the concentrations prepared

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No treatment-related changes were noted in any dose group up to 1000 mg/kg bw per day. From the results presented in this study a no effect level (NOEL) was established at 1000 mg/kg/day.
Executive summary:

The sub-acute toxicity of tetrakis(phenylmethyl)thioperoxydi(carbothioamide) (TBzTD) was investgated according to OECD 407: Repeated Dose 28-day Oral Toxicity Study in Rodents. TBzTD was administered daily by gavage to SPF-bred Sprague-Dawley rats. The study comprised of four groups.

5 male and 5 female rats were assigned to each of the following dose levels:

0 mg/kg bw per day (control)

50 mg/kg bw per day

200 mg/kg bw per day

1000 mg/kg bw per day

No treatment-related changes were noted in any dose group. From the results presented in this study a no effect level (NOEL) was established at 1000 mg/kg/day.