Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)

Endpoint summary

Description of key information

A 28-day repeated dose toxicity study (OECD 407 and GLP compliant) was performed and the NOAEL for repeated dose toxicity was found to be greater than 1000 mg/kg bw/day (highest dose tested).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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Guideline study performed in compliance with GLP, available as unpublished report, no restrictions, fully adequate for assessment.

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

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

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

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

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:

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

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

Critical effects observed:

not specified

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

An oral 28-day repeated dose toxicity study was performed according to OECD 407 and in compliance with GLP. The test substance was administered by daily oral gavage to male and female Wistar rats at dose levels of 50, 200 and 1000 mg/kg bw/day (5 rats/sex/dose level). Concurrent controls (5 rats/sex) received the vehicle, propylene glycol, alone. No toxicity was observed up to the highest dose level tested (1000 mg/kg bw/day) as evidenced by the absence of clinical signs of toxicity, body weight (gain), food consumption, haematology and clinical chemistry parameters, organ weights, macroscopic findings, and microscopic findings. Under the conditions of this assay the NOAEL for repeated dose was found to be greater than 1000 mg/kg bw/day.

Justification for classification or non-classification

Based on the results of the repeated dose toxicity test, the substance does not need to be classified according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.