6,6'-di-tert-butyl-4,4'-thiodi-m-cresol

Endpoint summary

Description of key information

Sub-chronic and chronic toxicity of 4,4'-thiobis(6-tert-butyl-3-cresol) was tested in seven studies with rats and mice, during 15 and 28 days, 13 weeks, and 2 years.  

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

December 29, 1986 - December 12, 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is performed under GLP conditions, guidelines for testing are not mentioned. Appendices with raw data are missing.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male and female rats were fed during 2 years with test substance.

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

2 years

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:
0, 500, 1000, 2500 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

115 males, 75 females

Control animals:

yes

Observations and examinations performed and frequency:

Hematology, clinical chemistry, and urinalysis evaluations were performed on 15 male and 15 female rats from each group at 3,9, and 15 months. Also at 15 months, an additional 10 male and 10 female rats from each group were evaluated for histopathology, hematology, and clinical chemistry.
Forty male rats per group were evaluated for neurotoxic effects.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Details on results:

Doses of 20, 40-45, and 120-125 mg/kg bw did not affect survival rates or induce overt signs of toxicity. At the high dose, body weights were slightly decreased. The liver appeared to be the target organ showing decreases in relative weight and significant increases in the incidences and (occasionally) severity of histological lesions such as Kupffer cell hypertrophy, cytoplasmic vacuolisation, fatty change basophilic foci, and mixed cell foci. Serum activities of alanine aminotransferase, alkaline phosphatase, and sorbitol hydrogenase were increased as well. Results of haematology evaluations at 3 and 9 months in one group of animals and at 15 months in two groups showed variable results. No effects were seen on the kidneys of male rats, but in high-dose females, relative weights and the severity of nephropathy were significantly increased when compared to controls.
Treatment did not induce statistically significant increases in the incidences of any tumour in any of the treated groups. On the contrary, for mammary gland tumours, there were significant negative trends in the incidences of fibroadenomas, decreases being significant in the mid- and high-dose group, and of fibroadenomas, adenomas, or carcinomas combined.
Based on the slight, but significant increase in the relative liver weights and in incidences of histological lesions in females at 45 mg/kg bw, the Gezondheisraad concluded that the NOAEL in this 2-year rat feed study is 20 mg/kg bw/day.

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: The NOAEL is proposed in an overview of these data in a report of the Gezondheidsraad 2005.

Critical effects observed:

not specified

none.

Conclusions:

Male and female F344/N rats were treated with 0, 500, 1000, 2500 ppm 4,4'-thiobis(6-tert-butyl-3-cresol) once daily during 2 years. All rats survived to the end of the study. Based on the slight, but significant increase in the relative liver weights and in incidences of histological lesions in females at 45 mg/kg bw, the Gezondheisraad concluded that the NOAEL in this 2-year rat feed study is 20 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Seven Klimisch 2 studies are available.

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 - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In seven independent experiments (sub)chronic toxicity of 4,4'-thiobis(6 -tert-butyl-3 -cresol) was tested in rats and mice during 15 and 28 days, 13 weeks, and 2 years of treatment. Weight-of-evidence was applied to derive a NOAEL for repeated dose toxicity.

In one study (28 days treatments of rats) a NOEL of 15 mg/kg/day in male and female rats was found.

In two other studies (15 days and 13 weeks treatment of rats), a NOAEL was not determined, but severe mortality was observed from 300 mg/kg bw/day onwards. In another study (2 years treatment of rats), a NOAEL of 20 mg/kg bw/day was found. Based on weight-of evidence approach the NOAEL (oral) was set at 20 mg/kg/day.

In mice the following data are reported; in two studies (15 days and 13 weeks treatment of mice), a NOAEL was not determined, but severe mortality was observed from 500 mg/kg bw/day onwards. In another study (2 years treatment of mice), a NOAEL of 60 mg/kg bw for male mice and 110 mg/kg/bw for female mice was found.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Study with the longest duration (2 years)

Justification for classification or non-classification

Classification according to the CLP Regulation (EC) 1272/2008 and the Dangerous Substance Directive 67/548/EC is not considered appropriate as no deaths, serious morphological changes or functional disturbance at the lower dose levels were observed.