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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Although the study was not conducted according to the recommended guidelines, it provides scientific valid information to assess the subchronic effects of the substance.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1986

Materials and methods

Principles of method if other than guideline:
Groups of 10 male mice and 10 female mice were treated with 0.1 ml of dimethylsulfoxide (DMSO) solutions containing 0, 5, 10, 20 or 30 mg of BHT topically applied 3 times weekly for 4 weeks. Pneumotoxicity was investigated.

Groups of 10 male rats and 10 female rats were treated 3 times weekly for 4 weeks with either 240 mg BHT in 0.6 ml of DMSO or 0.6 ml of DMSO alone and groups of 10 male hamsters were treated 3 times weekly with 480 mg of BHT in 1.2 ml of DMSO or 1.2 ml of DMSO alone.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): BHT
- purity: food aditive grade >98%
- Source: Wako Pure Chemical Co. Ltd., Osaka

Test animals

Species:
other: mice, rats and hamsters
Strain:
other: CD-1 mice, F-344 rats and Syrian golden hamsters
Sex:
male/female

Administration / exposure

Type of coverage:
not specified
Vehicle:
DMSO
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
3 times weekly
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Mice: 0, 5, 10, 20 or 30 mg BHT (0, 145, 289, 578 or 867 mg/kg in males and 0, 208, 415, 830 and 1245 mg/kg in females)
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
Rats: 0 or 240 mg BHT (0 or 1967 mg/kg in males and 0 or 2286 mg/kg in females)
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
Hamsters: 0 or 480 mg BHT (0 or 3097 mg/kg in males)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
yes, concurrent vehicle

Results and discussion

Target system / organ toxicity

Key result
Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Lung damage was noted in CD-1 mice dermally treated with BHT (males: 145-867 mg/kg bw/day; females: 208-1245 mg/kg bw/day) for four weeks. Similar treatment of F 344 rats (ca. 2000 mg/kg bw/day) and of hamsters (ca. 3100 mg/kg bw/day) was tolerated without adverse effects other than a slight growth retardation. These data suggest that reactive metabolites rather than the parent compound are responsible for the lung damage. Variation in metabolic pathways involved in production of reactive intermediates could provide a basis for the observed nonreactive individual animal, species and sex difference in the pneumotoxicity of BHT.
Executive summary:

Groups of 10 male mice and 10 female mice were treated with 0.1 ml of dimethylsulfoxide (DMSO) solutions containing 0, 5, 10, 20 or 30 mg of BHT topically applied 3 times weekly for 4 weeks. Pneumotoxicity was investigated. Groups of 10 male rats and 10 female rats were also treated 3 times weekly for 4 weeks with either 240 mg BHT in 0.6 ml of DMSO or 0.6 ml of DMSO alone and groups of 10 male hamsters were treated 3 times weekly with 480 mg of BHT in 1.2 ml of DMSO or 1.2 ml of DMSO alone. Lung damage was noted in CD-1 mice dermally treated with BHT (males: 145-867 mg/kg bw/day; females: 208-1245 mg/kg bw/day) for four weeks. Between day 4 and 8 of the study dose-dependent respiratory distress with subsequent mortality was observed in all dose groups, except for males at 145 mg/kg bw/day. Autopsy revealed congestion and enlargement of the lung; histologically, degeneration and necrosis of the type I alveolar epithelial cells and an increased number of type II cells was found. The skin at the site of application showed epidermal hyperplasia. Other organs appeared normal in all dose groups. Similar treatment of F 344 rats (ca. 2000 mg/kg bw/day) and of hamsters (ca. 3100 mg/kg bw/day) was tolerated without adverse effects other than a slight growth retardation. These data suggest that reactive metabolites rather than the parent compound are responsible for the lung damage. Variation in metabolic pathways involved in production of reactive intermediates could provide a basis for the observed nonreactive individual animal, species and sex difference in the pneumotoxicity of BHT.