Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Assessment of data available.
Adequacy of study:
key study
Study period:
November 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Assessment performed utilising all relevant data available.

Data source

Reference
Reference Type:
other: Assessment of data
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to guideline
Guideline:
other: Assessment of relevant data
Principles of method if other than guideline:
A review has been undertaken utilising the relevant mammalian data available.
GLP compliance:
no
Remarks:
Conducted in compliance with ISO 9001 accreditation

Test material

Constituent 1
Chemical structure
Reference substance name:
6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol
EC Number:
201-618-5
EC Name:
6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol
Cas Number:
85-60-9
Molecular formula:
C26H38O2
IUPAC Name:
6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol
Test material form:
other: Not applicable
Details on test material:
Not applicable
Radiolabelling:
no

Test animals

Species:
other: Not applicable
Details on test animals or test system and environmental conditions:
Not applicable

Administration / exposure

Route of administration:
other: Not applicable
Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable.
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose / concentration:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable

Results and discussion

Preliminary studies:
Not applicable
Main ADME resultsopen allclose all
Type:
absorption
Results:
No evidence of absorption
Type:
distribution
Results:
No evidence to indicate distribution
Type:
metabolism
Results:
No definitive information about potential metabolism
Type:
excretion
Results:
Biotransformation of any absorbed substance is anticipated and the resulting metabolites could be eliminated either in urine or bile as well as faecal matter

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Acute oral and dermal toxicity studies showed no treatment related effects and therefore provide no evidence of absorption by either route. In a repeated dose oral toxicity study, effects were observed with the livers of high dose animals, including increased organ weights, instances of hepatocellular hypertrophy, karyomegaly, multinucleated hepatocytes, increased mitoses and macrophages with distended cytoplasm were present in sinusoids and portal areas of livers from both sexes at the highest dose level. These observations coincided with slight changes to the serum chemistry parameters suggesting the liver as likely route or adsorption and metabolism of the substance. Exposure in both a screening reproductive toxicity test and developmental toxicity test indicates no effects to parent or F1 animals and no adverse effects were indicated by mutagenicity testing.
Details on distribution in tissues:
There is no experimental evidence to indicate distribution except, perhaps, to the liver in the repeated dose oral toxicity study. The Pow value obtained by testing may be suggestive of potential for accumulation, but bioaccumulation potential determined by QSAR suggests that accumulation is not a high concern.
Details on excretion:
There is no experimental evidence to indicate a route of excretion but the parent substance is not sufficiently water-soluble for elimination in its unchanged form in urine or bile, but may be eliminated in faecal matter. Biotransformation of any absorbed substance is, however, anticipated and the resulting metabolites could be eliminated either in urine or bile as well as faecal matter. As the parent substance is non-volatile and could not be eliminated via the lungs in expired air.

Metabolite characterisation studies

Details on metabolites:
The studies conducted provide no definitive information about potential metabolism, except the liver effects observed in the repeat dose are suggestive that biotransformation of any absorbed substance would be expected. The available mutagenicity data suggests that metabolism to genotoxic/ mutagenic metabolites is not a concern for this substance.

Applicant's summary and conclusion

Conclusions:
The substance is a di cresol of molecular weight that does not preclude absorption. No specific predictions about toxicokinetic behaviour can be made from the chemical structure. The substance is a non-volatile powder of non-respirable particle size, so inhalation exposure is not anticipated. Non-enzymatic hydrolysis is unlikely so exposure to degradants is not applicable.
Executive summary:

The substance is a di cresol of molecular weight that does not preclude absorption.  No specific predictions about toxicokinetic behaviour can be made from the chemical structure.  The substance is a non-volatile powder of non-respirable particle size, so inhalation exposure is not anticipated.  Non-enzymatic hydrolysis is unlikely so exposure to degradants is not applicable.

 

Absorption:

Acute oral and dermal toxicity studies showed no treatment related effects and therefore provide no evidence of absorption by either route.  In a repeated dose oral toxicity study, effects were observed with the livers of high dose animals, including increased organ weights, instances of hepatocellular hypertrophy, karyomegaly, multinucleated hepatocytes, increased mitoses and macrophages with distended cytoplasm were present in sinusoids and portal areas of livers from both sexes at the highest dose level. These observations coincided with slight changes to the serum chemistry parameters suggesting the liver as likely route or adsorption and metabolism of the substance.  Exposure in a screening reproductive toxicity test and developmental toxicity test indicate no effects to parent or F1 animals and no adverse effects were indicated by mutagenicity testing.

 

Distribution:

There is no experimental evidence to indicate distribution except, perhaps, to the liver in the repeated dose oral toxicity study.  The Pow value obtained by testing may be suggestive of potential for accumulation, but bioaccumulation potential determined by QSAR suggests that accumulation is not a high concern.

 

Metabolism:

The studies conducted provide no definitive information about potential metabolism, except the liver effects observed in the repeat dose are suggestive that biotransformation of any absorbed substance would be expected. The available mutagenicity data suggests that metabolism to genotoxic/ mutagenic metabolites is not a concern for this substance.

 

Excretion:

There is no experimental evidence to indicate a route of excretion but the parent substance is not sufficiently water-soluble for elimination in its unchanged form in urine or bile, but may be eliminated in faecal matter. Biotransformation of any absorbed substance is, however, anticipated and the resulting metabolites could be eliminated either in urine or bile as well as faecal matter.  As the parent substance is non-volatile and could not be eliminated via the lungs in expired air.

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