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EC number: 224-809-5
CAS number: 4500-29-2
The submission substance was tested in a guideline conform reproductive toxicity screening study according to OECD TG 421. No relevant effects on fertility / reproduction or development were observed. The parental NOAEL in this study was 75 mg/kg body weight (based on reduced body weights, inflammatory changes and mortality at higher dose levels evidenced by repeated dose toxicity studies) and the NOAEL for fertility / reproduction was also 75 mg/kg body weight. The submission substance is therefore considered to not exert reproductive toxic (fertility) effects.
Four groups comprised of 10 adult males and 10 non pregnant nulliparous
female rats (Wistar Crl:WI) were dosed daily by oral gavage with 12, 30
and 75 mg/kg body weight per day of the test item at dose volume of 5
mL/kg body weight using sterile water as vehicle. Doses were selected
based on a dose-range finder study. Control animals were treated
identically with the vehicle alone. After 14 days of treatment to both
male and female, animals were paired (1:1) till the evidence of mating
in the form of sperm positive vaginal smears. Males and females were
sacrificed on treatment day 29 and post natal day 4 respectively and
subjected to necropsy.
No test item related clinical signs and mortalities were observed in
both males and females. Body weight development and food consumption was
not affected. Group mean litter weight, total litter weight as well as
male and female litter weight on post natal day 0 and 4 was unaffected.
No treatment related effect was observed on precoital interval and
duration of gestation. Pre and post natal data like group mean number of
corpora lutea, percent preimplantation loss and post implantation loss
remained unaffected due to treatment when compared with controls. No
treatment related effects were observed on reproductive indices like
coagulation index, delivery index, fertility index and viability index
and there were no effects on litter data like number of males and
females, sex ratio and still birth. Survival of pubs from post natal day
0 to 4 remained unaffected and treatment related gross external findings
were not observed.
With regard to organ weights, in males a statistical significant
decrease in absolute right testes weight in LD group and a decrease in
absolute epididymides (right, left and total weight) and relative total
epididymides weight in LD and HD group when compared with the controls
were revealed. However, since no dose relationship was established and
no histopathological changes were observed, no toxicological
significance is attributed to these findings. At necropsy of all male
and female animals, no macroscopic changes were observed and no
treatment-related histopathological findings of reproductive organs were
A detailed qualitative examination of the testes taking into account the
tubular stages of the spermatogenic cycle, revealed no abnormal
In conclusion, the repeated administration of the test item to male
animals for 28 days and female animals for a maximum of 54 days revealed
no significant toxicological findings and mortalities. Reproductive
toxic effects were not revealed. Based on the data, the no observed
adverse effect level (NOAEL) for maternal toxicity was equal or greater
75 mg/kg body weight per day. The no observed effect level (NOEL) for
reproductive toxicity was equal or greater 75 mg/kg body weight per day.
The submission substance was tested for potential reproductive toxicity in a screening assay according to OECD TG 421 following oral administration to rats. Based on toxicity data revealed from a 14 -day repeated oral dose-range-finder toxicity study, 75 mg/kg body weight per day was selected as highest dose level based on reduced body weight gains, generally poor health status, gastrointestinal tract findings and inflammatory effects evidenced by white blood cell counts at a dose level of 125 mg/kg body weight as well as mortalities observed at 500 mg/kg body weight per day. However, the highest dose of 75 mg/kg body weight per day chosen for the reproductive screening study did not affect any relevant biological parameter, neither with regard to parental toxicity nor with respect to reproductive (fertility) toxic effects. Both, the parental NOAEL and the reproductive (fertility) NOAEL in this study was established at 75 mg/kg body weight per day. Likewise, evidence from extensive histopathological evaulation of reproductive organs including pathological sperm staging after repeated administration of the submission substance to rats for exposure periods up to 28 -days have not revealed indications of reproductive / fertility toxic effects. It can therefore be concluded that the submission substance is devoid of reproductive toxic (fertility) potential below doses causing significant maternal toxic effects.
Justification for selection of Effect on fertility via oral route:Guideline study according to GLP with a Klimisch rating 1.
No indications regarding developlental toxicity from an oral reproductive toxicity screening study exist. Likewise, no manifestations of adverse structural or functional changes in reproductive organs were revealed during detailed qualitative examination of the testes including the tubular stages of the spermatogenic cycle.
The developmental toxicity of the registration substance was evaluated in rats in a prenatal developental toxicity study according to OECD 414. The NOAEL for maternal toxicity is 180 mg/kg/day, as the maternal body weight and weight gain, corrected body weight gain and food consumption was unaffected up to 180 mg/kg/day. The NOAEL for developmental toxicity and teratogenicity is 180 mg/kg/day, as fetal resorptions or post implantation loss were comparable to the control, no effects on fetal body weights and further the fetal external, visceral and skeletal examinations revealed no signs of teratogenicity or developmental toxicity up to 180 mg/kg/day..
see attached background materials in "Overall remarks, attachements".
The objective of this study was to evaluate the developmental toxicity of Genamin CH 020 in pregnant female Wistar rats and developing embryos/fetuses consequent to treatment of Genamin CH 020 in pregnant rats by oral gavage from gestation day (GD) 5 to 19. This study was intended to provide a rational basis for risk assessment in humans and to establish a No Observed Adverse Effect Level (NOAEL) for maternal and developmental toxicity in rats.
A total of 96,Day 0 pregnant ratswere randomly divided into different groups according to the study design as follows:
Dosage volume (mL/kg)
No. of Day 0 pregnant rats
The following parameters and endpoints were evaluated in this study: Clinical signs, body weights, body weight gains, food consumption, gross pathology, gravid uterine weights, intrauterine growth and survival,number of corpora lutea, and fetal parameters [sex, weight and anogenital distance, and external, visceral and skeletal observations].Approximately half the number of the fetuses from each litter were examined for visceral malformations and variations and the remaining half were evaluated for skeletal malformations and variations. In addition, from each dam, the thyroid was weighed and subjected to microscopic evaluation. Thyroid hormones levels were determined from the blood samples collected at terminal sacrifie (on GD 20).
Results of the study are summarized below:
· Clinical signs and gross necropsy changes: There were no clinical signs, or mortalities in treated rats at any of the doses tested.
Grossly, at necropsy no abnormalities were detected.
· Maternal Parameters: No treatment-related effects on maternal body weights and food consumption up to the highest tested dose of 180 mg/kg/day. The other maternal parameters comprising of uterine weight, implantations and early and late resorptions, post implantation loss were comparable to vehicle control group up to the high dose of 180 mg/kg/day. Gross evaluation of placenta revealed no remarkable findings.
· Litter Parameters: No treatment-related effects on litter parameters comprising of total number of fetuses, fetal weights, anogenital distance in male and female fetuses, were observed.
· Fetal examination: External, visceral and skeletal examinations revealed no teratogenic effects attributed to the test item.
· Thyroid hormone levels (T3, T4 and TSH), thyroid weights, and thyroid histology were unaffected by treatment.
Based on the above findings, it is concluded that, No Observed Adverse- Effect Level (NOAEL) for
• Maternal toxicity is 180 mg/kg/day as the maternal body weight and weight gain, corrected body weight gain and food consumption was unaffected up to 180 mg/kg/day.
• Fetal developmental toxicity and Teratogenicity is 180 mg/kg/day as fetal resorptions or post implantation loss were comparable to the control, no effects on fetal body weights and further the fetal external, visceral and skeletal examinations revealed no signs of teratogenicity or developmental toxicity up to 180 mg/kg/day.
The reproduction and developmental toxicity potential of the registration substance was investigated in a reproduction/devlopmental toxicity screening study according to OECD 421 and a prenatal developmental toxicity study according to OECD 414. No adverse effects were observed regarding reproduction and developmental toxicity. Based on the available information, the submission substance does not have to be classified for reproduction and developmental toxicity in accordance with the criteria laid down in the EU Classification, Labellling and Packaging Regulation (1272/2008/EC).
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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