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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
720 mg/kg bw/day
Species:
rat
Additional information

To assess reproductive toxicity results of a subchronic oral toxicity study could be used as the scope of its examinations was extended to cover also effects on reproductive organs (BASF, 2004). The compound was administered to groups of 10 male and 10 female Wistar rats at dietary concentrations of 0, 100, 1,000 and 10,000 ppm for 3 months. These concentrations corresponded to dosages of about 7 and 8 mg/kg bw/day, 72 and 83 mg/kg bw/day or 720 and 801 mg/kg bw/day for males and females, respectively. At necropsy, the reproductive organs of the males (testes, epididymides, prostate gland) and females (ovaries, uterus) were excised and analyzed histopathologically. Also, sperm motility, sperm morphology and sperm head count (cauda epididymis and testis) were examined, which showed no treatment related changes. The weights of the reproductive organs were not influenced by the exposure, except for a significantly increased absolute and relative weight of the testes (+ 12 % and + 18 %) and relative weight of epididymides (+ 11 %) in the high dose males. This could most likely be regarded as a result of the decreased mean terminal body weight in these animals because no histological abnormalities in the sex organs were detected and no histological correlates were obtained for the changes in weights of the testes and epididymides. Considering the normal biological variation of these organ weight parameters together with the reduced terminal body weight of the high dose animals these observations were not regarded as adverse effects.

In addition to the described subchronic study, results of a two-generation study could also be taken for assessment. No adverse effects on reproduction were found, when 8-10 mg/kg bw/day of the structural analogue mixed ionone isomers (CAS 8013-90-9) were administered to the parental rats for 8 months (Sporn, 1963). Thereby, the female rats were studied through 3 reproduction cycles for number of pregnancies, weight and number of offspring, live pups, weight of pups at birth and after 7 and 21 days, and the viability of the pups after birth. The F1 generation (offspring) were allowed to reach maturity and were then treated with 15 mg/kg of ionone prior to being subject to reproductive toxicity testing. As a result, no effects on reproductive parameters and organs were observed in this study. Because of the structural similarities it can be assumed, that also for beta-ionone no effects on the fertility have to be expected.


Short description of key information:
Fertility:
- NOAEL: 720 mg/kg bw/day (male), 801 mg/kg bw/day (female), (OECD 408, rat)

Effects on developmental toxicity

Description of key information
Teratogenicity:
- NOAEL maternal: 100 mg/kg bw/day (OECD 414, rat)
- NOAEL teratogenic: 400 mg/kg bw/day (OECD 414, rat)
- NOAEL maternal: 50 mg/kg bw/day (OECD 414, rabbit)
- NOAEL teratogenic: 50 mg/kg bw/day (OECD 414, rabbit)
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
50 mg/kg bw/day
Species:
rabbit
Additional information

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF AG, 2004). The test substance Beta Ionon R was administered as a solution in olive oil to 25 "time-mated" (mated by breeder) female Wistar rats/group by stomach tube at doses of 25, 100 and 400 mg/kg bw on day 6 through day 19 post coitum (p.c.). On day 20 p.c., all females were sacrificed and assessed by gross pathology including the uterus and the placentae where corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed, and further investigated for any external findings. Thereafter, nearly one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal findings.

As a result, administration of 400 mg/kg bw elicitedsubstance-induced effects on the dams including signs of maternal toxicity like reduced body weight gain (-29%). The dosage of 100 mg/kg bw/day resulted in some substance-related findings (i.e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals. At the low dose (25 mg/kg bw/day) no substance-induced effects on the dams occurred. The test substance had no influence on gestational parameters and did not induce adverse signs of developmental toxicity or teratogenic effects at all dose levels.

Based on these results,the no observed adverse effect level (NOAEL) for maternal toxicity is 100 mg/kg bw/day. The NOAEL for prenatal developmentaltoxicity could be fixedat 400 mg/kg bw/day.

 

The data resulting from two other studies could not be taken into account for assessment, as they show clear deficits in the protocol or given data (Tsutsumi, 1968; Gomes-Carneiro, 2003).

 

Information for prenatal developmental toxicity of Beta Ionon R is available on a second species, i.e. the rabbit. In a study performed according to OECD Guideline 414 and GLP (BASF SE, 2014) 22 female New Zealand White rabbits/group received Beta Ionon R by inclusion in the diet on day 6 through day 29 post coitum (p.c.) at target dose levels of 17, 50 and 200 mg/kg bw/day. On day 29 p.c., all animals were sacrificed and subjected to an external, thoracic and abdominal examination as well as a laparo hysterectomy. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and corrected body weights (changes) were calculated. The fetuses were weighed, examined for external and visceral malformations and developmental variations, and sexed (by internal examination). Soft cephalic tissue examinations were done for approximately half of the fetuses of all groups and skeletal examinations were performed for all fetuses.

Following dietary treatment at 200 mg/kg bw/day, reduced food consumption (absolute and relative to body weight) were noted during the entire treatment period (days 6-29 p.c.), except for the period from days 10-14 p.c. during which temporally recovery towards normal values was noted. In addition, reduced body weights, lower body weight gain and/or body weight loss were recorded. Body weight gain between days 6 and 19 p.c. was only 42 g at 200 mg/kg bw/day, compared to 335 g in controls. Furthermore, several animals had reduced faeces production. Although the latter finding was observed in all groups, including control animals, there was a trend towards a longer period of reduced faeces production following dietary treatment at 200 mg/kg bw/day as compared to the lower dose levels. The treatment did not result in mortality or gross findings at necropsy. No maternal toxicity was observed in the 17 and 50 mg/kg bw/day groups.

Fetal body weights were slightly lower in males and females at 200 mg/kg bw/day, reaching statistical significance for males only. This change was considered to be secondary to the reduced food intake and markedly decreased body weight gain of the dams. No toxicologically relevant effects on viability, litter size or sex ratio were noted up to 200 mg/kg bw/day. There were no fetal morphology findings (external, visceral and skeletal) up to 200 mg/kg bw/day that were considered to be toxicologically relevant. The incidence of unossified metacarpals and/or metatarsals was slightly higher in the fetuses at 200 mg/kg bw/day, reflecting the slightly lower fetal weights observed in this dose group.

Based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Beta Ionon R was established as being 50 mg/kg bw/day.

 

Justification for classification or non-classification

Due to the negative data obtained for evaluating toxicity on fertility and development, no classification is required.