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EC number: 247-148-4
CAS number: 25637-99-4
The following information is presented for this endpoint:Chengelis C. P. (1996). A 28 Day Repeated-Dose Oral Toxicity Study of HBCD in Rats. Report no.: WIL 186004. Report date: 1997-02-13. as amended by,Chengelis C. P. (1998). Addendum to the final report A 28-day repeated dose oral toxicity study of HBCD in rats. Report date: 1998-05-28.Chengelis C.P. (2001). An Oral(Gavage) 90 Day Toxicity Study of HBCD in Rats. Report no.: WIL-186012. Report date: 2001-12-14.van der Ven, L. T. M., Verhoef, A., van de Kuil, T., Slob, W., Leonards, P. E. G., Visser, T. J., Hamers, T., Herlin, M., Håkansson, H., Olausson, H., Piersma, A. H. and Vos, J. G. (2006). A 28-day oral dose toxicity study enhanced to detect endocrine effects of Hexabromocyclododecane in Wistar rats. Toxicological Sciences (2006) Vol. 94(2), pp. 281-292.Chengelis (2001) and Chengelis (1996) as amended by Chengelis (1998) were both awarded reliability scores of 1 according to the criteria of Klimisch et al. (1997) based upon the recognised study guidelines used within the methodologies, the GLP conditions which were in effect throughout the study period and depth of reporting of methodologies, results and substance identification information. Chengelis (2001) was selected as the key study for this endpoint as it is the only sub-chronic study available for the registered subtance, it is also the most recent and reliable study available.Van der Ven et al. (2006) was also conducted according to recognised testing guidelines however information regarding GLP conditions was not reported and so reliability was reduced to a score of 2 in line with criteria set out by Klimisch et al. (1997).
(2001) was selected as the key study for this endpoint. The study was
conducted according to OECD Guideline 408 and EPA OPPTS 870.3100; no
deviations were reported from these guidelines and GLP conditions were
reported throughout the study period. Groups of 7 week old Crl: CD(SD)
IGS BR rats were dosed by gavage for 90 days (daily dosing). The test
material was administered at concentrations of 0, 100, 300 and 1000
mg/kg/day in corn oil. 30 animals (15 male/15 female) were used for each
dose group with an additional 40 animals (20 male/20 female) used for
each satellite group. Satellite groups were dosed at a concentration of
0 and 1000 mg/kg/day in corn oil in an identical manner to the main test
groups. Animals in the main toxicology groups were observed twice daily
throughout the study for mortality and morbidity. Body weights and food
consumption were measured weekly. Blood was collected at study weeks 3
(n=5/sex/group), 13 (n=10/sex/group) and 17 (n=5/sex/group) for
haematology, serum chemistry and hormone (T3, T4 and TSH) measurements.
Urine was collected prior to each necropsy, at study weeks 13 and 17,
for urinalysis. Ocular examinations were performed prior to initiation
of dosing and during study weeks 12 and 15. Functional Observational
Battery and Locomotor Activity evaluations were performed on 5
animals/sex/group prior to initiation of dosing, during the last week of
test article administration (study week 13), and during the recovery
period. An examination of vaginal cytology (for estrus cycle
determinations) was performed on study days 69-90. At each necropsy,
sperm motility/viability, morphology, and number were assessed. Complete
necropsies were performed on all animals. Approximately 40 organs and/or
tissues/animal were collected and preserved. The adrenals, brain,
epididymides, heart, kidneys, liver, ovaries, prostate, spleen, testes,
thymus, thyroids with parathyroids, and uterus with cervix were weighed.
Paraffin sections of tissues stained with hematoxylin and eosin from the
control and 1000 mg/kg/day dose groups and the liver, lungs, prostate
glands and thyroid glands in the 100 and 300 mg/kg/day doses, and gross
lesions from all animals were examined under the light microscope. The
livers of five randomly chosen animals/sex from the control and 1000
mg/kg/day dose groups was examined microscopically using Oil Red O or
periodic acid Schiff s (PAS) reagent for evidence of lipid accumulation
or glycogen accumulation/depletion, respectively. Statistical
comparisons by sex and treatment day were made between the control and
treated animals where indicated (p <0.05).
article-related effect on mortality occurred. Clinical signs were
non-specific, low in incidence, non-dose-related and not related to test
article administration. No test article-related changes occurred in body
weight, food consumption, Functional Observational Battery or Locomotor
Activity. No test article-related effects on hematologic parameters were
noted. No test article-related ocular lesions were detected at the
ophthalmic exams. No test article-related changes were noted on the
estrus cycle as determined by vaginal cytology, or on sperm
motility/viability, morphology, and number. Instances of statistically
significant differences between control and some treatment groups were
detected at study week 13 in the clinical chemistry data, hormone data,
organ weight data and histology findings. They were generally secondary
to the inducing effects on the liver or were otherwise not considered
adverse effects of treatment as discussed further below.
significant (p <0.05 or p <0.01) test article-related clinical chemistry
changes at week 13 include an increase in albumin (all dose levels for
males), total protein (all dose levels for females and 1000 mg/kg/day
for males), globulin (300 and 1000 mg/kg/day for females), and chloride
(all doses for both sexes). In addition, increased gamma
glutamyltransferase levels were noted in the 1000 mg/kg/day group (p
<0.01). Serum thyroxin (T4) levels were decreased at study week 13
compared to the control mean in all male dose groups and the 300 and
1000 mg/kg/day dose females (p <0.05 or p <0.01). There were no
corresponding statistical effects on T3 and TSH. While potentially test
article-related, the changes in serum chemistry parameters were not of
sufficient magnitude to be adverse, occurred in otherwise clinically
normal animals, tended to be within or close to historical control
values, and were not present at the end of the recovery period. The
increases in serum chloride and CGT levels were likely secondary to
hepatic enzyme induction. The changes in serum chloride were considered
to be due to interference with serum chloride measurement secondary to
free bromide in the test article. The
decrease in T4, which was also reversible, was considered secondary to
hepatic enzyme induction, which is known to cause increased metabolism
and clearance of T4 in the rat. The induction of T4 glucoronidation by
HBCDD and cytochrome P450 levels, wa later demonstrated in livers
obtained from rats treated for 28 days with HBCDD.
incidence of observations noted at gross necropsy was low and there was
no evidence of frank organ damage. Liver weights were increased. At week
13, mean liver weights in all dose levels of both sexes (absolute,
relative to bodyweight and relative to brain weight) were increased
compared to the male and female control means (p <0.05 or p <0.01). The increases
in liver weight were considered a result of induction of hepatic enzymes
and as such is considered indicative of toxicity in the absence of frank
organ damage. Increases in mean
weight were noted in the 1000 mg/kg/day group males at the primary
necropsy. However, the increases in prostate weight was not considered
toxicologically meaningful since the increases did not persist to the
recovery period, there were no correlating histological findings and no
change in sperm production. No other changes in organ weights, including
the thyroid, were observed.
histopathologic examination of tissues, relatively mild findings
occurred in both the control and treated groups. Potential test
article-related histological changes were identified in the liver and
thyroid glands but these would not be considered indicative of frank
toxicity. These organs were examined microscopically in all groups at
both necropsies. The liver changes in male rats at the 90-day necropsy
(Study Week 13) were characterized as minimal hepatocellular vacuolation
and occurred in 10% of control males and -50% of the males at 100, 300
and 1000 mg/kg/day. Minimal hepatocellular vacuolation was also detected
in females in the control and test article treated groups without a
clear dose response (3 to 6/10 animals per group) but, mild and moderate
vacuolation was detected in females only in the 300 (1/10) and 1000
mg/kg/day (2/10) dose groups. Minimal to mild hepatocellular hypertrophy
was also detected only in the 1000 mg/kg/day group (5/10) females.
Minimal thyroid follicular cell hypertrophy was detected 1/10, 1/10,
5/10 and 7/10 males in the control, 100, 300 and 1000 mg/kg/day groups,
respectively and in 4/10 and 3/10 females in the 300 and 1000 mg/kg/day
groups, respectively. In addition, mild thyroid follicular hypertrophy
was detected in 4/10 females and 1/10 males in the 1000 mg/kg/day group.
The reversible histologic changes (vacuolation and hypertrophy) are
often found to accompany increased liver weight caused by liver enzyme
induction. At week 17, the liver changes (weight and histology) had at
least partially, if not fully, resolved in all treated groups without
delayed or long-term toxic effects. The histologic changes in the
thyroid had also nearly completely resolved except in the 1000 mg/kg/day
group females, where partial recovery occurred.
detected in the adipose tissue of male and female rats treated with 1000
mg/kg/day for up to 90 days. Isomer-specific analysis showed that the
relative isomer concentrations in adipose tissue at all time points were
alpha>>gamma>beta which is in contrast to the test article composition
(gamma>>alpha>beta). Steady state levels were achieved by study day 27.
Levels in male and female rats were similar at all time points and
declined during the recovery period.
test article-related changes at 100 and 300 mg/kg/day were mild,
reversible and generally secondary to hepatic enzyme induction (which is
an adaptive not a toxic change) and without effect on the clinical
condition of the animals. The additional findings observed at 1000
mg/kg/day (increased gamma glutamyltransferase and additional increases
in the size of the liver and prostate), were also reversible, not
associated with specific target organ damage or diminished function and
were, therefore, probably of limited, if any, toxicological significance.
basis the no-observed-adverse-effect level (NOAEL) of HBCD administered
to Crl: CD®(SD) IGS BR rats by
gavage in corn oil for 90 days is 1000 mg/kg/day.
The EU Risk
Assessment Report (2008) took a more precautionary approach and derived
a LOAEL from this study of 100 mg/kg bw/day based on increased relative
liver weights (18% in males and 24% in females respectively) in this
dose level and changes in thyroid hormone levels (T4 reduction, TSH
The EU Risk Assessment Report used van der Ven et al. (2006) with a BMDL
of 22.9 mg/kg bw/day as the reference dose for liver weight increase.
However, the changes at mid-dose level in this study can also be
considered as adaptive and a NOAEL of 200 mg/kg bw could also be derived.
For the van der Ven et al. study, it needs to be noted that the number
of animals was low and for some parameters only very few animals were
used with causes some doubts regarding the results. The choice of the
CES (critical effect size) levels in this study is not transparent. It
is still to be established which effects are to be judged as adverse.
Given the low amount of animals used per dose group, the deaths that
occurred by misdosing can significantly affect the statistical value of
the study, in particular given the nature of the effects. It is
therefore difficult to address the borderline between physiological and
adverse reactions. In fact the changes in absolute liver weights in both
sexes are rather small at the dose levels investigated (up to 200 mg/kg
bw) and support the enzyme inducing character of the substance. There
was no increase in ALAT in the treated animals indicating no
pathological liver damage. All changes in clinical chemistry and
histopathological parameters observed in this study seem to to be within
the physiological range (corresponding historical data of the laboratory
were not provided) and do not indicate adverse effects up to the highest
dose tested (200 mg/kg bw). A NOAEL of 200 mg/kg bw could be derived
from this study. In our opinion the thyroid effects cannot be considered
as adverse. It should be noted that the levels of T3, the active hormone
were not significantly altered in this study. Furthermore, rats are more
sensitive than man with regard to changes in thyroid hormones. Both rats
and humans have a non-specific low affinity carrier of thyroid hormone
but humans and other primates, as well as dogs, also have a high
affinity binding protein, thyroxin binding globulin (TBG) that
predominantly binds T4. Rats lack TBG and as a consequence the
biological half-life of thyroid hormones in rats is about 10 fold
shorter than humans. Consequently, any interference with thyroxin
metabolism, even a transient one, leads to more rapid depletion of the
hormone in the rat followed by TSH secretion by the pituitary gland to
stimulate the thyroid to synthesise more T3 and T4 (Zbinden (1987) TIPS
8: 511-514; Hard (1998) Environ Health Perspect 106: 427-433; Hill et
al. (1998) Environ Health Perspect 106: 447-457). This would suggest
that the rat is more sensitive than humans to changes in thyroid hormone
levels. Indeed, rodents have been reported to be particularly sensitive
to thyroid enlargement (Zbinden, 1987; Hard, 1998; Hill et al., 1998).
For the overall assessment of the risk to human health, the result of
the two generation study (Ema et al., 2008) will also be considered.
Based upon the results of the key study (Chengelis, 2001), the
registered substance does not meet the criteria for classification
according to 67/548/EEC and EC Regulation 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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