Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)

Endpoint summary

Description of key information

No adverse effect was observed in the oral 28 -day repeated toxicituy study performed with TBzTD up to 1000 mg/kg/day.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

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:

28 days

Frequency of treatment:

daily

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

200 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION Yes
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

yes

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 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 showed a broken left upper incisor on day 12.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One female 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.

Description (incidence and severity):

n/a

Description (incidence and severity):

n/a

Ophthalmological findings:

not examined

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.

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

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.

Neuropathological findings:

not examined

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:

not examined

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

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 group of 5 male and 5 female rats : 0, 50, 200 and 1000 mg/kg/day.

No treatment-related changes (mortalility, clinical sign, bodyweight, food consumption, hematology, biochemistry, organ weight, macroscopic and microscopic examinations) were noted in any dose group.

Based on the results, 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:

The study is considered as reliable.

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

28 -day repeated toxicity study

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 group of 5 male and 5 female rats : 0, 50, 200 and 1000 mg/kg/day.

No treatment-related changes (mortality, clinical sign, bodyweight, food consumption, hematology, biochemistry, organ weight, macroscopic and microscopic examinations) were noted in any dose group.

Based on the results, a no effect level (NOEL) was established at 1000 mg/kg/day.

Justification for classification or non-classification

Based on the available data, no classification for repeated toxicity is required for TBzTD according to the Regulation EC n°1272/2008.