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Additional toxicological data

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Endpoint:
additional toxicological information
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
29.06.1999 to 15.11.2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Type of study / information:
In vitro metabolism of D4 by human liver microsomes
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In vitro metabolism of D4 by human liver microsomes
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Octamethylcyclotetrasiloxane
EC Number:
209-136-7
EC Name:
Octamethylcyclotetrasiloxane
Cas Number:
556-67-2
Molecular formula:
C8H24O4Si4
IUPAC Name:
2,2,4,4,6,6,8,8-octamethyl-1,3,5,7,2,4,6,8-tetroxatetrasilocane

Results and discussion

Any other information on results incl. tables

14C-D4 was metabolized by human liver microsomes to one major metabolite (M8). Although the conversion of D4 to M8 did not exceed 10%, the formation of M8 was not proportional to protein concentration or incubation time. The results of the experiment to assess 14C-D4 binding to human liver microsomes suggest that the loss of radioactivity in the incubation sample was not due to the binding of 14C-D4 and its metabolite(s) to the microsomal protein. Since D4 is volatile, it is possible that one or more of its metabolites is volatile also, which would make it difficult to quantify. This is one possible explanation
for the lack of proportionality of metabolite formation with incubation time and protein concentration. With human liver microsomes (and possibly liver microsomes from saline-treated rats), the results (lack of proportionality with incubation time and protein concentration) seem to suggest that only a portion of the added D4 is available to be metabolized, which might occur if D4 bound to plastic, formed micelles, or formed a film on the surface of incubation medium. However, the observation that with microsomes from phenobarbital-treated rats caused extensive metabolism of D4 would seem to argue against such an interpretation of assay artefact and may suggest that
microsomal metabolism of D4 in the uninduced system is a complex blend of enzyme action and inhibition. Based on the results of experiments with recombinant human CYP enzymes and polyclonal antibodies, it was concluded that 14C-D4 is primarily metabolized in vitro to M8, and that CYP2B6 and CYP3A4 are largely responsible for its formation.

Applicant's summary and conclusion

Conclusions:
In an in vitro study (reliability score 1) that investigated the metabolism of D4 by human liver microsomes, 14C-D4 was converted by liver microsomes from the phenobarbital-treated rats to at least eight metabolites, designated M1 through M8, based on their retention times. M8 was the major metabolite formed in incubations with human liver microsomes and also in liver microsomes from saline-treated rats, suggesting a similarity in the metabolism of D4 for rats and humans