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EC number: 220-246-4
CAS number: 2687-12-9
a combined 28-day repeated dose toxicity study with the
reproduction/developmental toxicity screening test, the test substance
was administered daily to rats at dose levels up to 100 mg eq/kg body
weight/day (OECD 422; Rijcken W., 2017). The parental NOAEL was
established as 33 mg eq/kg body weight/day. The reproductive NOAEL was
established as at least 33 mg eq/kg body weight/day.
substance is classified as reproductive toxicant category 2, according
to the CLP Regulation.
Toxicity to reproduction:
A combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test was performed in
rats, in which male and female rats were exposed up to a dose level of
100 mg/kg body weight/day (OECD 422; Rijcken W., 2017). The vehicle used
was polyethylene glycol 400, and the test solutions were prepared daily
and administered within 3 hours after preparation.
Significant general toxicity was observed at 100 mg eq/kg in both
sexes, most severely in females. Clinical signs of toxicity appeared
after a few days of treatment and included hunched posture,
piloerection, lean appearance, lethargy and rales. Additionally,
salivation (up to moderate degree) occurred after dosing. One female was
found dead in the morning of Day 7. The other animals showed significant
weight loss (on average 10 and 15% of the initial weight in males and
females, respectively). These findings led to the early sacrifice of the
100 mg eq/kg animals (on Day 7 prior to dosing) and adaptation of the
dose volume (from 1 to 5 ml/kg bw) for the Group 1-3 animals from Day 7
onwards. The 100 mg eq/kg animals had macroscopic and microscopic
changes in the esophagus and stomach indicative of local toxicity
resulting from the irritant properties of the test item. Main
macroscopic findings in the esophagus included a thickened wall and grey
white contents which correlated microscopically with erosion/ulceration
of the squamous epithelium, squamous hyperplasia and/or
lymphogranulocytic cell infiltrate. Gastric findings included an
irregular surface of the forestomach at necropsy and histopathological
changes consisting of lymphogranulocytic inflammation, squamous cell
hyperplasia and/or ulceration in the forestomach. Additional macroscopic
findings included distension of the stomach (with gas and
mucous/gelatinous/ foamy contents) and various parts of the intestines
(with gas and gelatinous/foamy contents). The morbidity of the animals
treated at 100 mg eq/kg was considered to have resulted from the local
iritation in the esophagus and stomach.
Body weight loss, and related clinical signs, observed in an
individual female rat at 33 mg eq/kg were likely to be secondary to
local (concentration-dependent) irritant effects of the test item at the
portal of entry. After reduction of the test item concentration in the
dosing formulation (the dose volume was 5-fold increased from Day 7),
the clinical signs disappeared, and body weight gain returned to normal.
At the microscopic level, local irritation by the test item was present
in the form of minimal squamous cell hyperplasia in the forestomach of
females treated at 33 mg eq/kg. Based on its minimal severity this
finding was considered to be non-adverse. Haematological investigation
showed a decrease (by 35%) in the percentage of neutrophils in males
treated at 33 mg eq/kg. Values at 33 mg eq/kg were slightly below the
normal range. In the absence of accompanying changes in total white
blood cells or other types of white blood cells, the decrease in
neutrophils was regarded as non-adverse.
No reproduction toxicity was observed at 11 and 33 mg eq/kg. Higher
prenatal mortality and concurrently reduced post-implantation survival
index were observed at 33 mg eq/kg.
In conclusion, based on these results, the following No Observed
Adverse Effect Levels (NOAELs) were derived:
Parental NOAEL: 33 mg eq/kg in a dose volume of 5 ml/kg.
Reproduction NOAEL: at least 33 mg eq/kg (no data were available
for reproductive performance assessment at 100 mg eq/kg).
Developmental NOAEL: at least 11 mg eq/kg (no data were available
for developmental toxicity assessment at 100 mg eq/kg).
In the combined 28-day repeated dose toxicity study with the
reproduction/developmental toxicity screening test (OECD 422; Rijcken
W., 2017), a developmental NOAEL of at least 11 mg eq/kg was
established. The test substance is known to have an adverse effect on
development, meeting the criteria for classification as reproductive
toxicant category 2. Therefore, no further testing for fertility and
developmental toxicity will be necessary, in accordance with the REACH
Regulation (Annex IX, section 8.7).
In conclusion, based on the results of the OECD 422 study, the following
No Observed Adverse Effect Levels (NOAELs) were derived:
Parental NOAEL: 33 mg eq/kg in a dose volume of 5 ml/kg (based on local
adverse effects in the esophagus and stomach, resulting in moribundity
or death, at 100 mg eq/kg in a dose volume of 1 ml/kg). Dose volume was
increased from 1 to 5 ml/kg from Day 7 onwards.
Reproduction NOAEL: at least 33 mg eq/kg (no data were available for
reproductive performance assessment at 100 mg eq/kg).
Developmental NOAEL: at least 11 mg eq/kg based on higher prenatal
mortality and concurrently reduced post-implantation survival index at
33 mg eq/kg (no data were available for developmental toxicity
assessment at 100 mg eq/kg).
Therefore, the substance is classified as reproductive toxicant category
2, according to the CLP Regulation.
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