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EC number: 603-094-7
CAS number: 125904-11-2
In a two-generation study, groups of 35 male
and female Sprague-Dawley rats were treated daily, by oral gavage, at
dosages of 100, 400 and 1600 mg/kg bw/day. A concurrent vehicle control
group received Mazola corn oil at 5 mL/kg bw. The F0 parent animals were
treated for at least 70 days prior to mating. Treatment continued
throughout all subsequent phases of the study until one day prior to the
scheduled necropsy for each animal. All females were allowed to deliver
and rear their pups to weaning (lactation day 21, culling performed on
lactation day 4). One litter was produced in each generation. Offspring
from the F0 animals (F1 litters) were selected to constitute the F1
generation. The study design for the F1 generation was identical to the
F0 generation; 35 animals per sex were selected for each dose group.
Beginning day 22 post partum, the selcted F1 parent animals were treated
for at least 70 days prior to the pairing and throughout all subsequent
phases of the study until one day prior to the scheduled necropsy for
Decreased male fertility in the F1
generation at 1600 mg/kg bw/day was considered to be a potential effect
of dibromostyrene administration. Although no morphological changes were
observed in the reproductive tract of these males, the mean absolute
testes weight was signficantly reduced. Other reproductive parameters
(gestation length and parturition) were unaffected by treatment in the
F0 and F1 generations at any dose level.
Survival was affected at 1600 mg/kg bw/day;
17 F0 animals (3 males and 14 females) and 2 F1 females died or were
euthanised moribund. Nine of these F0 females died due to an apparent
enhanced toxicity of the test substance due to water deprivation on one
day. Treatment-related clincial signs (primarily salivation, clear
staining around the mouth and/or yellow staining in the urogenital area)
occurred in the F0 and F1 animals at 400 and 1600 mg/kg bw/day. Body
weight gain and/or food cinsumption were inhibited in the 400 mg/kg
bw/day males (F0 and F1 during the 1st week of dosing), 1600 mg/kg
bw/day males (F0 and F1 primarily during the initial one to four weeks
of dosing) and 1600 mg/kg bw/day females (F1 at the end of the gestation
and during the lactation period).
No tretment-related internal findings were
observed in the F0 and F1 parent animals that survived to the scheduled
necropsies. Increased liver weights were apparent in the F0 and F1
generations at 400 and 1600 mg/kg bw/day. Increased weights and
treatment-related microscopic lesions were observed in the kidney at
1600 mg/kg bw/day (F0 and F1); the microscopic lesions consited of
tubular dilatation, nephrosis and/or papillary necrosis. Increased
kidney weights, but no microscopic lesions, were also noted in males at
400 mg/kg bw/day (F0 and F1).
In the F1 and F2 neonates, adverese effects
were apparent at 400 and 1600 mg/kg bw/day. Live litter sizes were
slightly decreased (non-significant) in the 400 mg/kg bw/day F1 pups and
the 1600 mg/kg bw/day F1 and F2 pups. Pup viability was reduced at 400
mg/kg bw/day (F2) and 1600 mg/kg bw/day (F1 and F2). Changes in clinical
condition of the pups (primarily body cool to the touch) were observed
in both generations at 400 and 1600 mg/kg bw/day. Neonatal body weights
were reduced at 400 mg/kg bw/day beginning days 28 (F1) or 21 (F2) post
partum and at 1600 mg/kg bw/day beginning day 1 post partum (F1 and F2).
At 100 mg/kg bw/day, kidney and liver
weights were increased in the F1 males. No other adverse effects were
apparent on the F0, F1 or F2 animals.
The NOAEL for reproductive toxicity was 400
mg/kg bw/day. The NOAEL for neonatal toxicity was 100 mg/kg bw/day. The
NOAEL for parental systemic toxicity was 100 mg/kg bw/day for the F0
generation, and less than 100 mg/kg bw/day for the F1 generation.
The key study for this endpoint, Nemec MD
(1993), was performed in accordance with the current internationally
accepted guideline OECD 416 and in compliance with GLP. The study was
assigned a reliability score of 1 and considered adequate for assesment.
The NOAEL from the study was selected for the assessment of reproductive
toxicity as a protective level against all reported effects.
Short description of key information:
Based on results of the 2-generation study
(Nemec MD (1993)), the NOAEL for reproductive toxicity was 400 mg/kg
bw/day based on possible adverse effect on F1 male fertility observed at
1600 mg/kg bw/day. The NOAEL for neonatal toxicity was 100 mg/kg bw/day
based on decreases in viability indices and pup body weights recorded at
400 and 1600 mg/kg bw/day. The NOAEL for parental systemic toxicity was
100 mg/kg bw/day in the F0 generation, and less than 100 mg/kg bw/day in
the F1 generation.
Justification for selection of Effect on
fertility via oral route:
A single good quality two-generation
reproductive toxicity study was available for the assessment of effects
Treatment of pregnant rats with
dibromostyrene during the organogenesis period at dosages of 100, 400,
800 and 1600 mg/kg bw/day caused both maternal and developmental toxic
effects. Maternal toxicity was slight at the lowest dose level of 100
mg/kg bw/day however, based on the slight decreased body weight gain
during the first 3 days of dosing and a dose-related decrease in food
consumption during the first 6 days of dosing, this dose level was
considered to be a LOAEL. Maternal toxicity increased with increasing
dosages as evidenced by the number of clinical signs and effects on body
weight gains and food consumption. Maternal toxicity was marked at the
highest dose level of 1600 mg/kg bw/day, where 5 dams died and another
one was sacrificed moribund. Related to the degree of maternal toxicity,
effects on foetuses consisted mainly in increases of specific skeletal
variations at 400 mg/kg bw/day and above, and teratogenic effects,
primarily cranio-facial defects, at the highest dose level of 1600 mg/kg
bw/day. The NOAEL for developmental toxicity was 100 mg/kg bw/day.
In a teratogenicity study in rats, groups of
25 presumed pregnant female rats were traeted daily, from day 6 to 15 of
gestation, at dosages of 100, 400, 800 or 1600 mg/kg bw/day. A
concurrent vehicle control group received corn oil alone, at a volume of
5 mL/kg bw.
Maternal toxicity was noted at all dose
level, expressed by reduced body weight gains and reduced food
consumption primarily during the first 3 -6 days of treatment. Clinical
signs, increasing in severity and number of occurences, were noted in
animals dosed at 400 mg/kg bw/day and above. The highest dose level of
1600 mg/kg bw/day was severely toxic to the dams, causing the death of 5
of them and and the sacrifice moribund of another one. Similarly,
developmental toxicity was marked at 1600 mg/kg bw/day, by a decrease in
mean foetal weights and an increase in post-implantation loss. in
addition, deveopmental toxicity was also noted at dosages of 400 mg/kg
bw/day and higher, expressed by external malformations (1600 mg/kg
bw/day dose level) and specific skeletal variations (400 mg/kg bw/day
and higher). Although body weight gain of females dosed at 100 mg/kg
bw/day was only slightly reduced during the first 3 days of dosing, and
food consumption was reduced during the first 6 days of dosing, this
dose level was set as the LOAEL for maternal toxicity. 100 mg/kg bw/day
was NOAEL for deveopmental toxicity.
The Lamb IC (1993) study in rats was
selected as the key study over the study in rabbits (by the same author)
as it provided the lowest NOAEL of the two studies and therefore
conferred a higher level of protection. The rat study was selected as
the key study was conducted to the guideline OECD 414 and in compliance
with GLP. As such, the study was assigned a reliability score of 1 and
considered adequate for assessment.
The supporting study, in rabbits, by Lamb IC
(1993) was conducted in compliance with GLP and according to guideline
OECD 414 and was assigned a reliability score of 1.
Justification for selection of Effect on
developmental toxicity: via oral route:
The study with rats was selected as the key
study as the NOAEL derived in the study was lower than that in the
rabbit study, and was therefore selected on a worst-case basis.
to the criteria in directive 67/548/EEC
and regulation (EC)
No 1272/2008, the substance does not meet the criteria for
classification for reproductive or developmental toxicity.
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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