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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the key study for toxicity to reproduction, the effects of Bemotrizinol on reproductive functions of male and female animals and early embryonic development were assessed (Nihon Bioresearch 100721, 2002). Bemotrizinol was administered orally by gavage at dosage levels of 100, 300, and 1000 mg/kg in PEG 400 to male rats daily before mating and throughout the mating period and to female rats daily before mating and throughout the mating period up to the early stages (day 7) of pregnancy.

No effects of Bemotrizinol were noted concerning general signs, body weight, food consumption, or necropsy findings in either sex of the parental animals. Loose stool and salivation were noted in both sexes in the groups treated with Bemotrizinol, but these findings were also noted similarly in the control group. No effects of Bemotrizinol were noted in male organ weights or sperm analysis pararneters as well as in the number of estrous cases, days until copulation after pairing, the copulation index or the fertility index.

Furthermore, Bemotrizinol did not affect the number of corpora lutea, number of implantation sites, the implantation rate, number of pre-implantation losses, pre-implantation loss rate, number of dead embryos (number of post-implantation losses), dead embryo rate (post-implantation loss rate), or number of live embryos.

From the above results, it is concluded that the no observed adverse effect level of Bemotrizinol is at or above 1000 mg/kg for general toxicity in dams, for reproductive functions of parent animals, and for early embryonic development.

 

In a key study assessing the effects of Bemotrizinol on reproductive functions of dams and on growth of offspring (F1) up to the stage of F2 fetuses, Bemotrizinol was administered orally at dosage levels of 100, 300, and 1000 mg/kg by gavage to female (P) rats daily from Day 7 of pregnancy to 21 days after delivery (Nihon Bioresearch 300721, 2002). 

Regarding the dams, no dead dams, moribund dams, dams which aborted, or dams which delivered prematurely were noted in any group. Loose stool and salivation were noted in the groups treated with Bemotrizinol, but these findings were also noted in the control group. Therefore, It was considered, that both of these findings were caused by the vehicle (PEG400). Low food consumption was noted in the 300 and 1000 mg/kg groups 1 day after delivery, but this finding was a change within the background data. Furthermore, no significant changes in food consumption were noted on any other day of measurement, and no effects of the test article were noted in body weight or body weight gain. Thus, It was considered, that the low food consumption was not a Bemotrizinol related effect. Further, treatment with Bemotrizinol did not result in any necropsy findings. Regarding the reproductive functions of the dams, no effects of Bemotrizinol were noted in the gestation length, number of implantation scars, gestation index, delivery conditions or nursing conditions.

Regarding the reproductive functions of the offspring (F1), no effects of Bemotrizinol were noted in the number of estrous cases, copulation index, days until copulation after pairing, fertility index, number of corpora lutes, or number of implantation sites.

Overall, no effects of Bemotrizinol were noted in the dams or offspring even at 1000 mg/kg. Accordingly, it is concluded that the no observed adverse effect level of Bemotrizinol is at least 1000 mg/kg for general toxicity in dams, for reproductive functions of dams, and for pre- and postnatal development of embryos and offspring (see “Effects on developmental toxicity”).

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In the key study for developmental toxicity in rabbits, timed-mated female Hra:(NZW)SPF rabbits were randomly assigned to four dosage groups, 20 rabbits per dosage group (Charles River Discovery 203-014, 2005). Bemotrizinol and/or vehicle, 0.5% (w/v) carboxymethylcellulose in 0.1% (w/v) aqueous Tween® 80, were administered once daily on days 6 through 19 of gestation (DGs 6 through 19) at dosages of 0 (Vehicle), 100, 300 and 1000 mg/kg/day.

No deaths were caused by Bemotrizinol. One doe in the 1000 mg/kg/day dosage group was sacrificed on day 19 of gestation (DG 19) due to its moribund condition as the result of an intubation accident. All other rabbits survived until scheduled Caesarean-sectioning. All clinical and necropsy observations were considered unrelated to Bemotrizinol. Body weights/gains, gravid uterine weights and absolute/relative feed consumption values were unaffected by dosages of Bemotrizinol as high as 1000 mg/kg bw/d. No Caesarian-sectioning or litter parameters were affected by dosages up to 1000 mg/kg bw/d, nor were any gross external, soft tissue, or skeletal fetal alterations (malformations or variations) caused by Bemotrizinol up to 1000 mg/kg bw/d. Therefore the maternal NOAEL is at least 1000 mg/kg bw/d. There were no adverse effects on embryo-fetal development as evaluated in this study, and based on these data, Bemotrizinol is not to be identified as a developmental toxicant.

In the key study for developmental toxicity in rats, Bemotrizinol was administered orally by gavage, once daily, from day 6 through to day 17 post coitum at dose levels of 100, 300 and 1000 mg/kg body weight/day to pregnant Wistar rats (RCC 681491, 1998).

Up to and including a dose level of 1000 mg/kg body weight/day, administration of Bemotrizinol did not influence the development of dams, embryos or fetuses. Based on these results, the NOAEL (no-observable adverse effect level) for the maternal and fetal organisms was considered to be 1000 mg/kg body weight/day. Under the conditions described for this study, Bemotrizinol did not reveal any teratogenic potential up to and including the highest dose level of 1000 mg/kg body weight/day.

In the study assessing the effects of Bemotrizinol on reproductive functions of dams and on growth of offspring (F1) up to the stage of F2 fetuses, Bemotrizinol was administered orally at dosage levels of 100, 300, and 1000 mg/kg by gavage to female (P) rats daily from Day 7 of pregnancy to 21 days after delivery (Nihon Bioresearch 300721, 2002). 

Regarding the dams, no dead dams, moribund dams, dams which aborted, or dams which delivered prematurely were noted in any group. Loose stool and salivation were noted in the groups treated with Bemotrizinol, but these findings were also noted in the control group. Therefore, it was considered, that both of these findings were caused by the vehicle (PEG400). Low food consumption was noted in the 300 and 1000 mg/kg groups 1 day after delivery, but this finding was a change within the background data. Furthermore, no significant changes in food consumption were noted on any other day of measurement, and no effects of the test article were noted in body weight or body weight gain. Thus, it was considered, that the low food consumption was not a Bemotrizinol related effect. Further, treatment with Bemotrizinol did not result in any necropsy findings. Regarding the reproductive functions of the dams, no effects of Bemotrizinol were noted in the gestation length, number of implantation scars, gestation index, delivery conditions or nursing conditions.

Regarding the offspring (F1), no effects of Bemotrizinol were noted in the number of offspring, sex ratio, number of stillbirths, birth index, viability index 4 days after birth, weaning index, incidence of external abnormalities, general signs, body weight, morphological differentiation, reflex functions, motor coordination, emotionality, necropsy findings, or organ weights. In the examination for learning ability, low error values (selected, backing, intra-zone and total error) were noted in the females in the 300 and 1000 mg/kg groups. However, it was concluded, that learning ability was not affected by Bemotrizinol, since the changes were not suggesting any learning ability impairment.

Regarding the reproductive functions of the offspring (F1), no effects of Bemotrizinol were noted in the number of estrous cases, copulation index, days until copulation after pairing, fertility index, number of corpora lutes or number of implantation sites.

Regarding the fetuses (F2), no effects of Bemotrizinol were noted in the implantation rate, number of pre-implantation losses / rate, number of post-implantation losses / rate, number of live fetuses, sex ratio of live fetuses, fetal body weight of either sex, incidence of external abnormalities or incidence of placental abnormalities.

Overall, no effects of Bemotrizinol were noted in the dams or offspring even at 1000 mg/kg. Accordingly, it is concluded that the no observed adverse effect level of Bemotrizinol is at least 1000 mg/kg for general toxicity in dams, for reproductive functions of dams, and for pre- and postnatal development of embryos and offspring.

Toxicity to reproduction: other studies

Additional information

Interaction of Bemotrizinol with androgenic (AR) and estrogenic (ER) receptors has been evaluated in in vitro studies using AR and ER from rat prostate and uteri cytosols, respectively.

In the in vitro AR study, rat prostate cytosols of 8 week-old male Alpk: APfSD rats were incubated with Bemotrizinol (5x10^-10 to 5x10^-4 M) in the presence of 3H-R1881 for 17h at 4°C and the receptor-ligand complex was determined in a Liquid Scintillation Analyser (CTL 2001; 024530). Bemotrizinol did not have any effect in the androgen competitive binding assay.

In the in vitro ER study, uterus cytosols from 15 immature (21-25 day-old) female Alpk: APfSD rats were incubated with Bemotrizinol (5x10^-10 to 5x10^-4 M) in the presence of 3H-E2 at 4°C overnight (17h) and the receptor-ligand complex was determined in a Liquid Scintillation Analyser (CTL 2001; 024529). Bemotrizinol did not have any effect in the estrogen competitive binding assay.

Thus, an interaction between Bemotrizinol and the androgen or the estrogen receptor can be excluded under the chosen testing conditions in vitro.

In an Uterotrophic Assay using 10 immature female Alpk:APrSD (Wistar derived) rats (20-21 days of age at the start of the study), Bemotrizinol was applied via subcutaneous injection of 0 (vehicle control), 250, 500 or 1000 mg/kg bw/d in Arachis oil once a day for 3 consecutive days (CTL 2002; ZR1601). As a positive control, one group of rats received a single oral dose of 0.4 mg 17ß-estradiol benzoate/kg bw once a day for 3 consecutive days.

No adverse clinical signs were observed and no effects on bodyweights or uterine wet (blotted) weights were found at any tested dose.

As expected, in the positive control group the blotted uterus weights and the uterus weights adjusted for bodyweight were significantly increased in comparison with the control group, demonstrating a positive uterotrophic response.

Overall, Bemotrizinol did not show any uterotrophic effect under the chosen testing conditions and confirm the absence of any estrogen receptor interaction as already indicated in vitro.

Justification for classification or non-classification

The present data on reproductive toxicity do not fulfill the criteria laid down in regulation (EU) 1272/2008, and therefore, a non-classification is warranted.

Additional information

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