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Key value for chemical safety assessment

Effects on fertility

Description of key information

Octabenzone showed no effects on fertility and on offspring in a modified GLP-compliant OECD 422 study and in a four-generation feeding study with rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
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 a modified OECD 422 study, the test substance Octabenzone was administered daily as an aqueous preparation to groups of 12 male and 12 female Wistar rats (F0 animals) by gavage at doses of 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d). Control animals (12 male and 12 female Wistar rats) were dosed daily with the vehicle only (0.5% Carboxymethylcellulose suspension in drinking water + 5 mg/100 mL Tween 80). The duration of treatment covered a 10 weeks pre-mating period in the males, 2 weeks pre-mating in the females, 2 weeks mating period in both sexes, approximately 2 days post-mating in males, and the entire gestation period as well as approximately 30 days of the lactation period (21 days lactation and up to 9 days post-weaning) and 35 days post-mating (for sperm negative females). Analyses confirmed the overall accuracy of the prepared concentrations and the homogeneity of the test substance in the vehicle. The stability of these preparations was demonstrated over a period of 7 days under ambient conditions. No clinical findings were caused by the test substance in the parental animals F0 up to the limit dose of 1000 mg/kg bw/d. Food consumption and body weight (change) of the parental animals showed no treatment-related, adverse changes. In the subsequent investigations including the detailed clinical observation (DCO), the functional observational battery (FOB) and measurement of motor activity (MA) no treatment related, adverse differences to control were observed at any dose level. Regarding clinical pathology, no treatment-related, adverse effects were observed up to 1000 mg/kg bw/d. At PND 13 in male pups of test groups 13 (1000 mg/kg bw/d) T4 levels were significantly lower compared to controls. However, no histopathological correlate or any alteration of the thyroids was found. Therefore, the statistically significant decrease of T4 in male PND 13 pups of test group 13 was regarded as treatment-related but not adverse. Regarding pathology, there were neither treatment-related organ weight changes nor gross lesions. Histopathology of the thyroid glands in F0 parental male animals and PND 13 male pups did not show any relevant morphological changes consistent with functional alterations. All histopathological changes occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment. Under the conditions of this study the test substance had no adverse effects on fertility and reproductive performance of the F0 parental animals of both sexes up to 1000 mg/kg bw/d. Most of the F0 parental animals proved to be fertile. Failure of pregnancy in one high-dose female could not be attributed to the treatment by gross and histopathological examinations of the respective animals of both genders. Mating behavior, conception, implantation and parturition were not influenced. No signs of developmental toxicity were noted in any of the treated groups; numbers of liveborn pups, pup survival and growth were not influenced by the test substance. Clinical examination and sexual maturation of F1 rearing animals showed no treatment-related, adverse findings. Under the conditions of the present OECD 422 combined repeated dose toxicity study with the reproductive/developmental screening test in Wistar rats, the NOAEL (no observed adverse effect level) for general, systemic toxicity of Octabenzone was 1000 mg/kg bw/d. The NOAEL for reproductive performance and fertility of the F0 parental rats and developmental toxicity in the F1 offspring was 1000 mg/kg bw/d.

A four-generation-study in rats with feed application was performed with CD rats. The design of the study followed the guideline of the US Association of Food and Drug Officials of 1959. This procedure is more extensive than that described in OECD testing guideline 416, but reporting information is less detailed. Whereas in the OECD 416 guideline, 20 pregnant females per generation are targeted resulting in overall at least 40 litters, in this study 16 matings per generation were performed resulting in overall 74 and 72 successful matings for control and test group animals, respectively. The study report does not give all individual data that would be required in the OECD 416 testing guideline. The sex ratio is provided per generation (sum of litters). For pup weight, only a range and then an average per generation (sum of litters) is given. Information at the litter level consists of the number of pups born, the number of pups alive on day 5 and the number of pups successfully weaned after culling to 10 animals per dam on day 5. Indices for fertility, gestation, viability and lactation were determined. Historical control data is not provided or discussed.

Young rats were weaned and placed on test to receive control diet or one containing 6000 ppm test substance. Animals were maintained on their respective diets until they were 3-4 months of age when they were mated. For mating, one male and one female were housed together. Females were removed and housed separately while they cast their litters, which were reduced in size to ten pups at day 5. The pups were weaned directly onto the diets which were being fed to their parents. When they were 3 - 4 months of age, they were in turn mated, and the process was repeated with their pups for a total of three generations. The parents of that third generation were mated a second time, and their second litters of pups were raised to maturity and bred to produce a 4th generation. Overall, there were 80 matings of control and 80 matings of test animals. The reproduction and lactation performance, which was evaluated for each generation and for the four generations combined. The test item purity was reported as > 99%. The dietary concentration of 6000 ppm corresponds to an average concentration of 523.9 mg/kg per day for males or 0 and 614.3 mg/kg per day for females which is lower than the limit dose of 1000 mg/kg bw indicated in the OECD testing guideline for the 2-generation study in rats. This is acceptable, as feed application at doses above 1500 ppm were found to cause adverse effects on kidney in rats upon subchronic exposure (Ciba 1967, 1968, Cytec 1965). The following parameters were examined in F1, F2 and F3 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain. Autopsies were performed only on pups from the first mating of F2 animals. The two weakest or smallest male and female pups were used. One male and one female from each litter were autopsied, and portions, of the following organs were fixed in 10% neutral buffered formalin for histopathologic processing and examination: spleen, pancreas, mesenteric lymph node, stomach, ileum, colon, urinary bladder, uterus or prostate, ovary- or testis, seminal vesicle and urethra in males, vagina in females, kidney, adrenal, liver, femur with marrow, pituitary, brain, thyroid (and parathyroid where included), esophagus, trachea, lung, heart, and skeletal muscle. Skeletal examinations were performed from the other animals from these pups (F3a generation).

No test-item related effects were observed on fertility, gestation, viability and lactation indices. No skeletal abnormalities were seen in the control or treated pups. Body weight gain and incidence of gross abnormalities and histopathology findings were not affected. There were no litters consisting of only stillborn pups. Litters which were completely lost until weaning occurred both in the control group (5 of 74 litters) and in the test group (4 of 72 litters). If litters contained pups born dead, their number range from 0 - 6 for control litters and 2 -8 for test group litters. The highest number of dead pups per litter was 7 (of 11) for the control group and 8 (of 14) in the test group. The percentage of litters containing one or more pup born dead was 18 and 34% for control and test group litters, respectively. The incidence of litters for which pup mortality was observed between days 0 and 5 was 24% and 20% for control and test group litters, respectively. For days 5 to weaning, the incidence of litters with pup loss was 12% for control litters and 10% for test group litters. Although no historical control data is available for comparison, the presented values do not give rise of concern for fertility. Pup survival at day 5 and day 21 is better in the test group than in the control group. There are no extreme findings such as litters with complete stillbirth. The total number of litters is almost identical (74 versus 72). The only parameters with a greater range is the incidence of litters with dead pups (18% in control versus 34% in the test group); however this incidence varied between 0 and 40% among the control groups of all matings and is therefore likely to be the normal variation. Overall, no adverse effects were observed at the highest applied dose of 6000 ppm.

Effects on developmental toxicity

Description of key information

In a prenatal developmental toxicity study following OECD 414 the test substance was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. In addition, the available four generation study in rats contains the skeletal investigation of 13 males and 13 females on postnatal day 21. Dams had been exposed to the limit dose of 6000 ppm in the diet. No indication of skeletal malformations was observed.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
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 a GLP-compliant prenatal developmental toxicity study the test substance was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations, their homogeneous distribution and the stability of the test substance in the vehicle. Generally, clinical observations including food consumption and body weight gain revealed no toxicologically relevant difference between the animals receiving 100, 300 or 1000 mg/kg bw/d test material and controls. No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and post-implantation loss. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. In conclusion, under the conditions of this prenatal developmental toxicity study, the oral administration of Octabenzone to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses as high as 1000 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity. The no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is the highest tested dose of 1000 mg/kg bw/d.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for fertility under Regulation (EC) No. 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/218.