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EC number: 211-989-5
CAS number: 732-26-3
Table 1: Mean Body Weights (g)
Time of Measurement
Dose Group (mg/kg)
Day 1, Week 1
Day 8, Week 2
Day 15, Week 3
Dunnett-test based on pooled variance significant at 5 % (*) or 1 % (**)
2: Summary of Macroscopic Findings
Group 23 mg/kg
Group 310 mg/kg
Group 430 mg/kg
END OF TREATMENT
Animals without findings
LiverAccentuated lobular patternEnlarged
Preputial glandsReduced in size
Thyroid glandReduced in size
Mesenteric lymph nDiscolouration
Table 3: Selected Organ/Body Weight Ratio and Organ
Body Weight (g)
Liver weight (g)
Liver/bw ratio (%)
*/** Dunnett-test based on pooled variance significant at
5 % (*) or 1 % (**) level
The repeated dose toxicity of the test material was investigated in a
combined repeated dose toxicity study with the reproduction /
developmental toxicity screening test conducted in accordance with the
standardised guidelines OECD 422 and US EPA OPPTS 870.3650 under GLP
Based on the results of a 10-day dose range finding study, the dose
levels for this study were selected to be 3, 10 and 30 mg/kg.
The test material, formulated in corn oil, was administered daily by
oral gavage to SPF-bred Wistar Han rats. One control group and three
treated groups were tested, each consisting of 10 males and 10 females.
Males were exposed for 29 days, i.e. 2 weeks prior to mating, during
mating, and up to termination. Females were exposed for 41 to 56 days,
i.e. during 2 weeks prior to mating, during mating, during post-coitum,
and during at least 4 days of lactation.
The following observations and examinations were evaluated: mortality /
viability, clinical signs (daily), functional observations and locomotor
activity (end of treatment), body weight and food consumption (at least
at weekly intervals), clinical pathology (end of treatment), macroscopy
at termination, organ weights and histopathology on a selection of
tissues. Reproduction/developmental parameters were also evaluated.
Formulations were analysed once during the study to assess accuracy,
homogeneity and stability. Analysis showed that the formulations were
prepared accurately and homogenously, and were stable for at least 6
hours at room temperature.
Histopathological examination showed hepatocellular hypertrophy up to
moderate degree in both sexes at 10 and 30 mg/kg. This was supported at
necropsy by enlargement and/or accentuated lobular pattern of the liver
for some animals at 30 mg/kg. At 30 mg/kg, hepatocellular necrosis was
present in a single male and a single female at minimal degree.
Additionally, higher liver weights (absolute and/or relative to body
weights) were recorded at 10 and 30 mg/kg; relative liver weights were
increased 39 and 63 % in males and females at 30 mg/kg, respectively,
and 21 % in females at 10 mg/kg. The higher liver weights in females at
10 and 30 mg/kg along with the combined occurrence of hepatocellular
hypertrophy with necrosis at 30 mg/kg were considered to be adverse in
Mucosal hypertrophy of the cecum in males treated at 10 and 30 mg/kg was
noted up to a slight degree only and occurred in absence of any other
indicators of toxicity in this organ. This histopathological lesion was
therefore not considered adverse in nature.
Decreased splenic haematopoiesis was observed in females treated at 10
and 30 mg/kg, which occurred along with lower reticulocyte counts.
However, red blood cell counts showed an increase rather than a decrease
at this dose level. Also, since there were no other indicators of
toxicity in the spleen, these changes were not considered to represent
an adverse effect on red blood cell turn over.
At 30 mg/kg, other changes in blood of females that were considered to
be related to treatment consisted of lower relative neutrophil counts,
higher relative lymphocyte counts, lower mean corpuscular volume and
mean corpuscular haemoglobin, higher total protein, albumin, calcium,
cholesterol, potassium and glucose and lower urea and total bilirubin.
Higher potassium and lower total bilirubin were also noted for males at
At 10 mg/kg, changes in blood consisted of lower mean corpuscular volume
and mean corpuscular haemoglobin in females, lower total bilirubin in
males and females, and higher cholesterol in females. In the absence of
any concurrent morphological lesions, and given the slight nature of
these changes (i.e. within or just outside the range considered normal
for rats of this age and strain), these were not considered adverse in
Females at 10 and 30 mg/kg showed lower food consumption during the
lactation period, as well as notable weight loss during lactation
ranging from 4 to 9 % of Day 1 lactation values. The lower maternal food
intake and body weight gain and mean pup body weight gain appeared
unrelated on an individual animal basis. Also, these changes were not
accompanied by supportive clinical signs or inadequate maternal care. As
such, these changes in food intake and body weight gain during lactation
were considered not adverse in nature.
No toxicologically relevant clinical signs or changes in functional
observation parameters were noted.
No toxicologically relevant changes in reproductive parameters were
With regard to developmental effects, at 30 mg/kg, the mean number of
living pups at first litter check appeared slightly lower than controls.
Also, an increased postnatal loss and lower viability index was noted at
10 and 30 mg/kg. At 10 mg/kg, a total of 3 dams showed postnatal loss.
At 30 mg/kg, a total of 5 dams showed postnatal loss. The
significance of these findings is not clear at this stage and are
proposed to be further investigated
Mean pup body weights for both sexes combined on Day 4 of lactation were
approximately 16 and 20 % lower than the control mean at 10 and 30
mg/kg, respectively. Although there were no other developmental changes
noted for these pups (macroscopy and clinical signs), the magnitude of
changes in pup body weight was considered to represent an adverse effect
on pup development. No apparent relationship could be found between
maternal food intake and mean pup body weight gain on an individual
Under the conditions of the study, the repeated dose NOAEL was
determined to be 3 mg/kg (based on higher liver weights at 10 and 30
mg/kg, with hepatocellular hypertrophy and necrosis at 30 mg/kg).
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