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EC number: 235-935-5
CAS number: 13052-09-0
Oral NOAEL is 1000 mg/kg bw/day based on the outcome of the OECD422 study.
Mating performance was unaffected by treatment at 30, 300 or 1000
Fertility was unaffected by treatment at 30, 300 or 1000 mg/kg
Gestation length was unaffected by treatment at 30, 300 or 1000
As previously discussed one female at 1000 mg/kg bw/day was found
dead during late gestation; additionally at this dosage one female was
found to be non-pregnant. For the non-pregnant animal, histopathological
examination revealed a vaginal retention cyst which was deemed to be the
underlying cause for the unsuccessful mating. Two control litters showedpost
partumtotal litter loss but there were no similar losses for treated
groups. The following assessment is generally based on the 8, 10, 10 and
8 litters successfully reared to Day 5 of age for the control, 30, 300
and 1000 mg/kg bw/day dosage groups respectively.
There was no adverse effect of treatment on corpora lutea and
implantation counts, or on subsequent post-natal litter size, sex ratio
or offspring survival at 30, 300 and 1000 mg/kg bw/day.
Group values for total litter weights, offspring body weight and
body weight change, surface righting reflex and a summary incidence of
clinical signs are given in Tables14,17and18. Individual values and
observations are given in Appendices15, 16 and19.
Litter weight and offspring body weight on Day 1 and subsequent
offspring growth to Day 4 of age was unaffected by treatment at 30, 300
and 1000 mg/kg bw/day.
Assessment of surfacing righting ability on Day 1 of age was
unaffected by treatment at 30, 300 and 1000 mg/kg bw/day. The clinical
signs observed for the offspring on this study were typical for the age
observed and neither the incidence or distribution of these signs
indicated any underlying adverse effect on offspring development.
Introduction.The study was designed to investigate
the systemic toxicity and potential adverse effects of the test item on
reproduction (including offspring development) and is compatible with
the requirements of the OECD Guidelines for Testing of Chemicals No. 422
“Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test” (adopted 22 March
This study was also designed to be compatible with the Commission
Regulation (EC) No. 440/2008 of 30 May 2008 laying down test methods
pursuant to Regulation (EC) No. 1907/2006 of the European Parliament and
of the Council on the Registration, Evaluation, Authorisation and
Restriction of Chemicals (REACH).
Methods.The test item was administered by gavage to
three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST
strain rats, for up to sixteen weeks (including an eleven week
pre-pairing phase, pairing, gestation and early lactation for females),
at dose levels of 30, 300 and 1000 mg/kg bw/day. A control group of ten
males and ten females was dosed with vehicle alone (Arachis oil BP).
Clinical signs, behavioural assessments,
body weight change, food and water consumption, oestrous cycles and
opthalmic change were monitored during the study.
Pairing of animals within each dose
group was undertaken on a one male: one female basis within each
treatment group on Day 78 of the study, with females subsequently being
allowed to litter and rear their offspring to Day 5 of lactation.
During the lactation phase, daily
clinical observations were performed on all surviving offspring,
together with assessments of litter size, offspring weights and surface
Extensive functional observations were performed on males from
each dose group during Week 15 and for parental females from each dose
group on Day 4post partum. Haematology
and blood chemistry were evaluated prior to termination on males
(Day 110) and females (Day 4 of lactation) from each dose group. An
opthalmic examination was made for control and high dose animals prior
to treatment and during Week 13 for females and Week 15 for males.
Adult males were terminated on Day 112, followed by the
termination of all surviving females and offspring on Day 5post partum. Any
female which did not produce a pregnancy was terminated on or after Day
25post coitum. All animals were subjected to a gross necropsy
examination with recording of selected organ weight and additionally
sperm analysis for males. Histopathological evaluation of selected
tissues was performed, with enhanced assessment of testes for males.
Mortality.At 1000 mg/kg bw/day, one female was found
dead on Study Day 98 (Day 18 of gestation) without any significant
clinical signs being seen prior to this event. Enlarged adrenals and a
reddened left lung lobe were apparent at necropsy but microscopic
examination did not reveal the aetiology of this death and this death
was considered to be unrelated to treatment.
Clinical Observations.Clinical signs associated with
treatment were confined to increased post dosing salivation for both
sexes at 1000 mg/kg bw/day, and males and one female at 300 mg/kg bw/day.
Behavioural Assessment.No obvious neurological
effects of treatment at 30, 300 or 1000 mg/kg bw/day were apparent.
Functional Performance Tests.There was no consistent
pattern of results that indicated an effect of treatment at 30, 300 or
1000 mg/kg bw/day.
Sensory Reactivity Assessments.Sensory reactivity
assessments to different stimuli did not reveal any effect of treatment
at 30, 300 or 1000 mg/kg bw/day.
Body Weight.There was no adverse effect of treatment
on body weight performance for males or females, including during
gestation and lactation phases at 30, 300 or 1000 mg/kg bw/day.
Food Consumption and Food Conversion Effeciency.There
was no adverse effect of treatment on food consumption and food
conversion efficiency for males or females, including during gestation
and lactation phases, at 30, 300 or 1000 mg/kg bw/day.
Water Consumption.At 1000 mg/kg bw/day, water
consumption for males was slightly higher than control throughout most
of the study.
Ophthalmoscopy.No treatment-related effects were
detected for animals at 1000 mg/kg bw/day.
Oestrous Cycle.There was no adverse effect of
treatment on female oestrous cycles at 30, 300 or 1000 mg/kg bw/day.
Mating.Mating performance was unaffected by
treatment at 30, 300 or 1000 mg/kg bw/day.
Fertility.Fertility was unaffected by treatment at
30, 300 or 1000 mg/kg bw/day.
Gestation Lengths.Gestation length was unaffected by
treatment at 30, 300 or 1000 mg/kg bw/day.
Offspring Litter Size, Sex Ratio and Viability.Corpora
lutea and implantation counts and subsequent post-natal litter size, sex
ratio and offspring survival were unaffected by treatment at 30, 300 and
1000 mg/kg bw/day.
Offspring Growth and Development.Offspring body
weight, litter weight and surface righting ability on Day 1 and
subsequent clinical signs and offspring growth to Day 4 of age were
unaffected by treatment at 30, 300 and 1000 mg/kg bw/day.
Haematology.Males treated with 1000 mg/kg bw/day
showed increased platelet count compared with control. No
toxicologically significant effects were detected for females at this
dosage or either sex at 30 or 300 mg/kg bw/day.
Blood Chemistry.Females at 1000 mg/kg bw/day showed
increased total protein and albumin levels compared to control. No
similar effects were apparent for males at 1000 mg/kg bw/day or either
sex at 30 or 300 mg/kg bw/day.
Necropsy.At 1000 mg/kg bw/day, two adult males
showed mottled kidneys at necropsy examination. There were no other
necropsy findings for adult animals or their offspring that were
considered to be associated with treatment at 30, 300 or 1000 mg/kg
Organ Weights.For both sexes at 1000 mg/kg bw/day
and males at 300 mg/kg bw/day, absolute and body weight relative kidney
weights were statistically significantly higher than control.
For males at 1000 mg/kg bw/day, increased absolute and body weight
relative liver weights also attained statistical significance compared
Sperm Analysis.Assessment of sperm motility values,
morphological assessments and homogenisation-resistant spermatid counts
for males at 1000 mg/kg bw/day did not indicate any effects of treatment.
Histopathology.At 300 and 1000 mg/kg bw/day males
showed adaptive liver changes consisting of centrilobular hepatocellular
hypertrophy; there were no degenerative or inflammatory lesions.
At 300 and 1000 mg/kg bw/day males also showed treatment related
hyaline droplet nephropathy of the kidney, consisting of increased
incidence and severity of hyaline droplets, tubular degeneration,
granulated tubular casts and interstitial inflammatory infiltrate.
For females at 30 mg/kg bw/day and both sexes at 300 and 1000
mg/kg bw/day increased incidence and severity of follicular hypertrophy
was recorded in the thyroid. This finding was considered to be a
secondary effect of increased hepatic metabolism.
There were no abnormal lesions encountered during testicular
spermatogenesis staging for males at 1000 mg/kg bw/day.
Conclusion.The oral administration of
13052-09-0) to rats by gavage, at dose levels of 30, 300 and 1000 mg/kg
bw/day, resulted in treatment related findings in animals of either sex
treated with 30, 300 and 1000 mg/kg bw/day. The effects detected in
females were mainly confined to adaptive microscopic thyroid changes and
there were no findings observed that were considered to represent an
adverse effect of treatment. The ‘No Observed Adverse Effect Level'
(NOAEL) for females was considered to be 1000 mg/kg bw/day.
Kidney effects detected in males at 300 and 1000 mg/kg bw/day
consisted of increased incidence and severity of hyaline droplets,
tubular degeneration, granulated tubular casts and interstitial
inflammatory infiltrate. This nephropathy was deemed to be related to
treatment and to represent an adverse effect of treatment to the
rat. Hyaline droplets were also present for males at 30 mg/kg bw/day
but, occurred in the absence of any degenerative changes and the ‘No
Observed Adverse Effect Level' (NOAEL) for males was therefore
considered to be 30 mg/kg bw/day. However, the kidney changes of hyaline
droplets were consistent with well documented changes that are peculiar
to the male rat in response to treatment with some hydrocarbons. This
effect is, therefore, not indicative of a hazard to human health. In the
context of this study, the remaining kidney findings, consisting of
tubular and/or degeneration, tubular dilation/vacuolation, granulated
tubular casts and interstitial inflammatory infiltrate detected in males
are more likely to be correlated to the same condition as hyaline
droplet accumulation and are, therefore, considered to represent limited
relevance to humans.
Effects excluding the kidney changes detected in males were
confined to adaptive microscopic liver and thyroid changes. These were
considered not to represent an adverse effect of treatment. In terms of
extrapolation to man and risk assessment calculations whereby effects
relating to male rat renal changes are species and sex specific and
therefore are not relevant, a NOAEL for males can be established at 1000
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
K1: The study was performed according to OECD guidelines and GLP.
No adverse effects were reported in an OECD
422 up to 1000 mg/kg/day, the highest dose tested.
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