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EC number: 254-996-9
CAS number: 40601-76-1
Results from an OECD 421 reproductive/developmental toxicity screening
study in rats
This study was designed to screen for potential adverse
effect on reproduction including embryo/foetal development in the rat
following OECD TG 421 and under GLP conditions.
The test material was administered by dietary admixture
to three groups, each of ten male and ten female rats, for up to 54
consecutive days at dietary concentrations of 1000, 10000 and 20000 ppm
(equivalent to mean achieved dosages of 64, 651, 1294 and 77, 782 and
1558 mg/kg bw/day for males and females, respectively). A further group
of animals served as control. Following 14 days of dosing, male and
female rats were paired within their dose groups to produce litters. On
Day 5 post partum, all surviving animals were euthanised and examined
macroscopically. Clinical signs, bodyweight development and food and
water consumption were monitored during the study. Offspring development
and growth was also monitored. All animals were subjected to a gross
necropsy examination and histopathological evaluation of selected
tissues from control and high dose parental males and females was
For adults, there were no treatment-related deaths during the study. At
10000 ppm and 20000 ppm, adverse signs of irritancy were observed in
males and females. There were no treatment-related effects on body
weight, food consumption or water consumption. Mating performance and
fertility were not adversely affected by the treatment. No
treatement-related effects were observed for organ weights or necropsy
At 20000 ppm there was in increase in post implantation loss which was
not statistically significant compared to controls but was of
toxicological significant because of the intragroup variation in
individual post implantation loss values. At 10000 ppm there was also a
high post implantation loss but this was due to a single female with a
total litter loss in utero.
For offspring, at 20000 ppm, there was a slightly lower mean litter size
at birth compared to control values but this was not statistically
significant. Offspring viability between birth and day 4 of lactation
was comparable to control values. For all other observations, there were
no treatment-related effects observed.
Administration of the test material to male and female rats throughout
maturation, gestation and lactation phrases of reproduction resulted in
signs of test material irritancy at 10000 and 20000 ppm. The irritancy
was considered to be an adverse effect due to its degree of severity.
Therefore, the NOEL for adults was 1000 ppm (66 -74 mg/kg). The NOAEL
for effects on fertility was 10000 ppm (782 mg/kg; due to increased post
implantation loss and a consequential decrease in mean litter size at
birth at 20000 ppm). The NOEL for developmental toxicity/teratogenicity
was 20000 ppm (1294 -1558 mg/kg).
OECD 421 reproduction/developmental toxicity screening test was
conducted in Sprague-Dawley rats by dietary administration at nominal
dose levels of 0, 1000, 10000 or 20000 ppm. Toxicologically significant
but statistically insignificant post-implantation losses were reported
at the two highest dose levels. Signs of irritation were also present at
the two highest dose levels. The NOAEL for parental (P1) reproductive
effects was set at 782 mg/kg bw/d (10000 ppm, females) level based on
increased but statistically insignificant post-implantation losses. The
NOEL for parental effects was set at 64 mg/kg bw/d (1000 ppm, males)
based on irritaton.
dietary repeated dose toxicity studies conducted in both rats and dogs,
no histopathologically significant effects on reproductive tissues were
Short description of key information:
Results from an OECD 421 reproductive/developmental toxicity
screening study in rats
Justification for selection of Effect on fertility via oral route:
A well conducted OECD 421 Guideline study conducted in the rat
The test item was administered daily by oral gavage to pregnant rats from gestation day (GD)-5 up to and including GD20 according to the OECD Test Guideline 414 (June 2018) and following GLP principles.
There was no test item effect on maternal body weight, body weight gain, maternal corrected body weight and body weight gain, and on food intake up to and including 1000 mg/kg bw/day.There were no toxicologically significant differences, or test item related-changes in the reproductive parameters examined up to and including 1000 mg/kg bw/day.
There were no test item effects on the external, visceral and/or skeletal development of foetuses in the study.
In this study, from the observations made in the dams and their foetuses, there were no changes on embryos or foetuses. The following no-observed-adverse-effect (NOAEL) levels were derived:
NOAEL maternal toxicity: 1000 mg/kg bw/dayNOAEL embryotoxicity: 1000 mg/kg bw/dayNOAEL foetotoxicity: 1000 mg/kg bw/dayNOAEL teratogenecity: 1000 mg/kg bw/day
See tables available in the attached background document.
The purpose of this study was to investigate the effects of the test item on embryo-fetal development in rats when administered orally from Gestation Day (GD) 5 up to and including GD 20 and to characterize the dose-response relationship of any observed toxicity according to the OECD TG 414 and following GLP.
One hundred (100) mated female rats were randomly assigned to 4 groups with 25 animals in the control and treatment groups. Animals were administered the test item at dose levels of 0 (control formulation, 1% (w/v) CMC-Na in purified water), 100, 300, and 1000 mg/kg/day by oral gavage once daily from GD 5 to 20. The dose volume was 10 mL/kg. At initiation of mating, male and female rats were approximately 10 to 11 weeks of age and the male animal body weights were 315.35 to 414.25 g and the female animals were 190.53 to 258.47 g. Females were nulliparous and non-pregnant before cohabitation.
The study animals were observed daily for mortality and clinical signs, and measured for body weight and food consumption during this study. On GD 21, all study animals were necropsied and examined for gross pathology, organ weights, and histopathology (control and high dose groups). Blood samples were collected to conduct thyroid stimulating hormone (TSH) and thyroid hormones T3 and T4 analysis from all study animals at the scheduled necropsy. The ovaries and uteri were examined for determination of litter data. Uteri without visible implantation were placed in ammonium sulfide solution for detection of early resorptions. The placenta of live fetuses was examined macroscopically. All the live fetuses were weighed and examined for external abnormalities; their crown-lump lengths were measured and sexes were determined. Approximately 1/2 of the live fetuses in each litter were fixed with modified Davidson’s fixative for soft tissue examination and the remaining fetuses were stained with Alcian Blue Solution and Alizarin Red Solution for subsequent skeletal examination. The visceral and skeletal examination of fetuses was conducted for the high dose and control groups.
The concentrations of the test item in dosing formulations (which were used to dose) were within 101% to 105% of nominal values. Homogeneity analysis of the low and high-dose formulations was performed. The concentrations of the top, middle and bottom of samples (in dosing formulation which were used to dose) were within 100% to 106% of nominal values. The relative standard deviations (RSD) of top, middle, and bottom of samples were within 0.4% to 3%.
All animals survived to the scheduled necropsy. There were 23/25, 25/25, 19/25, and 23/25 pregnant animals in 0, 100, 300, and 1000 mg/kg/day, respectively.
There were no test item-related changes in the clinical signs, body weights, body weight changes, gravid uterine weight, food consumption, gross pathology, organ weights, and histopathology of the dams.
There were no test item-related changes in litter data (number of corpora lutea, implantation sites, live fetuses, fetal death, dead fetuses, resorptions, pre‑ and post- implantation loss, fetal weight and fetal crown-rump length), sex ratio, placental examination, the anogenital distance or fetal structure (visceral and skeletal examinations).
There was no test item-related changes observed in this study for thryoid hormones (T3, T4, and TSH).
In conclusion, administration of the test item to pregnant female rats once daily during the period of organogenesis (from Gestation Day 5 to 20) by oral gavage at dosages of 0, 100, 300, and 1000 mg/kg/day was well tolerated and did not result in any treatment-related mortality, and any adverse effects in clinical signs, body weight, food consumption, and pathology. No test item-related embryo-fetal developmental toxicity was noted at any dose level. The No-Observed-Adverse-Effect-Level (NOAEL) for all was considered to be 1000 mg/kg/day (the highest dose tested).
There were no significant developmental or teratogenic effects noted in offspring in an OECD 414 study. The NOAEL for developmental effects in this study was reported as 1000 mg/kg bw/day, the highest dose level tested.
Justification for selection of Effect on developmental toxicity: via oral route: A well conducted OECD 414 Guideline study conducted in the rat
Minimal but statistically insignificant reproductive effects were noted in an OECD 421 study in rats as post-implantation losses. These effects were not seen in the OECD 414 conducted subsequently. No significant effects were reported in reproductive tissues from chronic toxicity testing in either rats or dogs. Based on these findings, no classification of the test material for reproductive effects is warranted.
Based on negative finding for developmental effects in an OECD 414 study in rats, no classification of the test material for developmental toxicity is warranted.
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