Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Assessment of toxicokinetic behaviour
Adequacy of study:
supporting study
Reliability:
other: Assessment of toxicokinetic behaviour
Rationale for reliability incl. deficiencies:
other:

Data source

Reference
Reference Type:
other: summary
Title:
Assessment of toxicokinetic behavviour
Author:
Krueger I.
Year:
2010
Bibliographic source:
Assessment of toxicokinetic behavviour

Materials and methods

Principles of method if other than guideline:
other: Assessment of toxicokinetic behaviour
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
other: Assessment of toxicokinetic behaviour

Test animals

Species:
other: Assessment of toxicokinetic behaviour

Administration / exposure

Route of administration:
other: Assessment of toxicokinetic behaviour
Vehicle:
other: Assessment of toxicokinetic behaviour
Duration and frequency of treatment / exposure:
Assessment of toxicokinetic behaviour
Doses / concentrations
Remarks:
Doses / Concentrations:
Assessment of toxicokinetic behaviour
No. of animals per sex per dose:
Assessment of toxicokinetic behaviour

Results and discussion

Preliminary studies:
Assessment of toxicokinetic behaviour

Any other information on results incl. tables

No studies on toxicokinetics of 6,6'-di-tert-butyl-2,2'-methylendi-p-cresol (DBMC) are available. However, considering the toxicokinetic profile of structural analogues and taking into account the experiences with DBMC in acute and repeated dose toxicity studies, a characterization of DBMC toxicokinetics can be conducted.

DBMC is a solid powder with a low vapour pressure (calculated to be below 0.1hPa, 20°C) under normal ambient conditions, therefore inhalation exposure to the vapour might be negligible.

DBMC is practically insoluble in water (0.007 g/l at 20°C). However, the molecular mass of 342 g/mol and the n-octanol/water coefficient (log Pow of 6.25) suggest intestinal absorption subsequent to oral ingestion. This assumption is confirmed by data from acute oral toxicity studies and repeated dose toxicity studies. However, acute toxicity is low because LD50 values are high (greater than or even to 5000 mg/kg bw, Hagan 1952, Garlanda 1962, Stasenkova 1977, Sumitomo Chemical 1977, Takaki 1994, EPA 1992 Monsanto study); systemic availability was indicated by clinical signs like hypoactivity and ataxia at doses = 2500 mg/kg bw (EPA 1992 Monsanto study). In addition, studies with repeated oral dosing of rats indicating bioavailability of the compound by showing dose related toxic effects at doses > 12.7 mg/kg bw, predominantly in the testes and liver. Available repeated dose toxicity studies are a subacute toxicity study with rats (MHWJ 1996), subchronic toxicity studies with rats (Bayer AG 1982, Takagi 1994) or dogs (American Cyanamid Company 1965), a chronic feeding study with rats (Takagi 1994) and a reproduction toxicity screening study (MHWJ 1999). The determined NOAELs in these studies were in the order of 10 mg/kg bw/day.

DBMC showed a very low irritating potential in humans (Kimmerle 1958, American Cyanamid Company 1959) and rabbits (EPA 1992 Monsanto study). In addition, Vulkanox BKF had a very low skin sensitization potential in humans (American Cyanamid Company 1959). Furthermore, the dermal LD50 of above 2000 mg/kg and the absence of significant signs of systemic toxicity when dosed once at 2000 mg/kg bw (EPA 1992 Monsanto study) reveal a low toxic potential of DBMC after dermal exposure.

The formation of DNA reactive metabolites in unlikely, since in vitro and in vivo mutagenicity tests (Ames assay MHWJ 1996, RCC 1986a, in vitro chromosome aberration assay MHWJ 1996, in vivo micronucleus assay RCC 1986b ) show negative results. In addition, the cytotoxicity of the test substance DBMC was reduced in the presence of the rat liver microsomal fraction. This suggests that detoxification of DBMC occurs as a result of liver enzyme activity or even as a detoxification by non-specific protein-binding.

Applicant's summary and conclusion

Executive summary:

Assessment of toxicokinetic behaviour