Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
publication
Title:
Subacute effects of the brominated flame retardants hexabromocyclododecane and tetrabromobisphenol A on hepatic cytochrome P450 levels in rats.
Author:
Germer, S., Piersma, A.H., van der Ven, L., Kamyschnikow, A., Fery, Y., Schmitz, H.-J. & Schrenk, D.
Year:
2006
Bibliographic source:
Toxicology (2006) Vol. 218, pp. 229-236

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Juvenile/young male and female Wistar rats were treated orally with various doses via the feed (TBBPA) or by gavage (HBCD). After 28 days of treatment the animals were sacrificed and hepatic mRNA and microsomes were isolated.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
Dose range: 0, 0.3, 1, 3, 10, 30, 100 & 200 mg/kg b.w.
No. of animals per sex per dose:
10 (5 male/5 female)
Control animals:
yes, concurrent vehicle

Results and discussion

Preliminary studies:
not reported.

Any other information on results incl. tables

The brominated flame retardant HBCDD was given to juvenile/young WU (CPB) rats of both sexes daily by gavage. After 28 days, animals were sacrificed and livers were removed for further analysis. HBCDD led to a significant induction of PROD activity in male rats at 10 and 100 mg/kg body weight per day, and of LBD activity in female rats at 10, 30 and 200 mg/kg body weight per day. At 30 mg/kg body weight per day PROD activity in males seemed to be slightly, but not significantly increased. LBD activity in microsomes from females also seemed to be increased at 100 mg/kg body weight per day. However, the effect was not statistically significant. No trends were observed for any of the other activities including EROD activity. HBCDD was an effective inducer of CYP2B1 mRNA in females, and a weaker but significant inducer in males. The standard deviation shown for the effect on CYP2B1 mRNA in females at the highest dose reflects the high variability of this response on the transcript level. Nevertheless, pronounced induction was observed in all animals of the corresponding group, while the degree of induction was variable. Induction of CYP3A1/3A3 mRNAs was also much more pronounced in females than in male animals and reached significance at a dose level of 3 mg/kg body weight per day. In males significant but much lower induction was observed at 30 mg/kg body weight per day and above. Analysis of AhR-regulated CYP1A2 mRNA did not reveal any significant effects. Fig. 5 shows the results of Western blot analysis of CYP enzymes in liver microsomes from HBCDD-treated rats. It was found that HBCDD led to a dose-dependent significant induction of CYP2B1/2B2 in females and a trend for induction in males. Furthermore, CYP3A1 protein was induced in females at a daily dose of 3 mg/kg body weight and above, in males at 30 mg/kg body weight and above, the effect in females being much stronger than in males. No effects on the levels of CYP1A1/1A2 were observed.

Applicant's summary and conclusion

Conclusions:
HBCD was found to act as an inducer of CYP2B1/2B2 mRNA in rats of both sexes. In contrast to males, HBCD acted as a highly effective inducer in females at the highest dose level only. However, no effects on PROD activity, indicative for induction of CYP2B1/2B2 function were detected in females. It is noteworthy that all female rats in this dose group showed markedly increased CYP2B1/2B2 mRNA levels, the high standard deviation being due to the fact that the extend of induction was highly variable. A possible explanation for the discrepancy between the effects on CYP2B1/2B2 mRNA and the lack of PROD induction may be that high levels of HBCD sufficient to induce CYP2B1/2B2 mRNA may inhibit PROD activity. Furthermore, a dose-dependent increase in immunodetectable CYP2B1 protein in females confirms the notion that HBCD is a ‘phenobarbital’-type inducer of drug metabolism in rats. A consistent dose–response was found for induction of PXR-regulated CYP3A1/3A3 mRNA. Here, the lowest effective dose was 3.0 mg/kg body weight per day in females. In females, the inducing effect was much more pronounced than in males which is in agreement with the female-predominant expression of CYP3A1 in rats (Thangavel et al., 2004). Our findings indicate that CYP3A1/3A3 induction is a major effect of HBCD and seems to be among the most sensitive effects of these compounds in higher animals reported so far. In humans, PXR regulated CYP3A enzymes, most notably CYP3A4, and CAR-regulated CYP2B enzymes, most notably human CYP2B6, metabolize a broad spectrum of drugs (Maurel, 1996; Ekins and Wrighton, 1999). In rats both CYP3A1 and CYP2B1 catalyse the hydroxylation of testosterone in the liver (Elias and Gwinup, 1980). As a consequence, phenobarbital-type induction may increase hepatic androgen metabolism, e.g. during male development, and could result in androgenic deficiency, reproductive failure and demasculinization.