Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Cross-reference
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Toxic effect type:
concentration-driven

The study does not need to be conducted because pre-natal developmental toxicity studies are available with several read across substances.

Endpoint conclusion:
no study available
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available

Data waiving: The study does not need to be conducted because pre-natal developmental toxicity studies are available with several read across substances. See below section on deveopment toxicity

The available oral and dermal pre-natal development toxicity study with the read across substances in rats and rabbits, indicate no concern for development toxicity.

Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
Guideline compliant study with read across substance
Endpoint conclusion:
no study available
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rabbit
Quality of whole database:
Good quality study with read across substance

Oral: 

Study 1: A study was conducted to determine the developmental toxicity potential of the read across substance, C16 TMAC (purity: 98.5%), using prenatal developmental toxicity oral gavage study in female Sprague Dawley rats, according to the OECD Guideline 414, in compliance with GLP. All animals were administered the read across substance during the gestation period, starting from Day 3 through Day 19 post coitum at the doses of 0, 18.75, 37.5, 75 mg/kg bw/day (25 animals in each group). Body weight, daily clinical signs and food consumption were recorded during the in vivo phase. All females were caesarean-sectioned on Day 20 post coitum and subjected to post-mortem examination. Blood collection for haematology and hormone determination, in association with determination of the thyroid weight from all females was performed on Day 20 post coitum. The number of corpora lutea, implantations, early and late intrauterine deaths, live and dead foetuses, uterus weight, foetal weight and sex were recorded. All foetuses were examined for external abnormalities. The anogenital distance (AGD) in all live foetuses was recorded. Approximately one half of the foetuses in each litter was examined for fixed-visceral and skeletal abnormalities. No animals died during the study. A total of three females were found not pregnant at necropsy: one in the control group, one in the low dose group (18.75 mg/kg bw/day) and one in the mid-dose group (37.5 mg/kg bw/day). One low dose female had unilateral implantation in the left horn and was not pregnant in the right one. The number of females with live foetuses on Day 20 post-coitum was: 24 in the control, low and mid-dose groups and 25 in the high dose group (75 mg/kg bw/day). Piloerection was the treatment-related clinical sign observed in all treated groups with a dose-related incidence. In Group 4 this sign was accompanied by hunched posture in few females. Minor signs, such as hair-loss and damaged ear were sporadically recorded during the study and were considered incidental. The slight statistically significant decreases in body weight observed in females of Group 4 was not considered of toxicological relevance due to the limited magnitude of the change. These changes were considered related to treatment, but not adverse. Statistically significant reduction in food consumption was observed in females of Group 4 starting from Day 6 post coitum through Day 15 post coitum. No differences were recorded on Day 18 post coitum and again a slight decrease was recorded on Day 20 post coitum. This change was considered not relevant because there was a recovery between the start and the end of treatment. The polychromasia observed in all treated groups was considered to be not adverse, even though the relation with the read across substance cannot be excluded. Monocytosis observed in females dosed at 75 mg/kg bw/day was considered to be incidental. The increase of polychromatic cells in the peripheral blood smear even when the reticulocyte count is normal could suggests the premature release of erythroid cells from a marrow that is not hyperactive. Considering that: (a) no haematological findings were observed (e.g. anaemia) (b) no changes were recorded during the in-vivo phase or at post-mortem examination (c) no treatment-related effects were observed in previous studies (https://echa.europa.eu/it/registration-dossier/-/registered-dossier/14219/7/6/2). There were no indications of an effect of the read across substance on the bone marrow or other tissues/organs which could led to an increase of the polychromatic cells, therefore this finding was considered to be not adverse. Due to the dose-relation observed between groups, the relation with the read across substance cannot be definitively excluded. In thyroid hormone determination, no differences between control and treated females were recorded. There was no effect on the thyroid weight at any dose levels, compared to the control group. Statistically significant reductions in terminal body weight, gravid uterus weight and absolute weight gain (terminal body weight minus body weight at Day 0 post coitum minus gravid uterus), seen in females of Group 4, compared to controls were considered not adverse due to the limited magnitude of the change. No differences of toxicological relevance were noted in litter data and sex ratio. Statistically significant differences were noted in AGD of male foetuses of mid and high dose groups and in female foetuses of low and mid-dose groups, compared to the control. Considering that the AGD reflects the prenatal androgenic exposure, with values physiologically higher in males than in females, the increase observed in male foetuses represents a trend towards masculinisation (increase in AGD of males) and is not considered an adverse effect (i.e. decrease in AGD of males, suggesting feminisation). The same applies to the decrease observed in females, that also represents a trend towards feminisation (reduction in AGD of females) and is not considered an adverse effect (i.e. an increase in AGD of females, suggesting masculinisation). Thus, these differences were considered incidental and non-adverse effects. Furthermore, the AGD values were within the range of laboratory historical control data. At post-mortem, no treatment-related macroscopic changes were noted at low, medium and high dose. In microscopic examination, no treatment-related changes were noted in thyroid gland of females at low, medium and high dose. In external examination, small foetuses (<2.7 g) were present both in control and treated groups without a dose-relationship. One foetus in the mid-dose group had alterations classified as malformations: imperforate anus and absence of tail. These findings was considered unrelated to the read across substance. In skeletal examination, malformations were detected in control and in treated groups without dose-relationship, in terms of foetuses and litters affected. The major and minor alterations detected at skeletal examination were considered incidental since they were quantitatively similar between groups or occurred in small foetuses (<2.7 g). In visceral examination, malformations were observed in one foetus of Group 3 and in one foetus of Group 4 (extremely enlarged ureter in association with kidney pelvic dilatation extreme). These findings were considered incidental since they were seen in single foetuses from different litters without a dose relationship, therefore a treatment-related effect is unlikely. The other alterations (anomalies and variations) recorded were noted both in control and treated groups, with a similar incidence. Overall, the study investigator concluded that the dosage of 75 mg/kg bw/day read across substance induced slight maternal toxicity without adverse effects on pregnancy and developmental outcome. The dosages of 37.5 mg/kg bw/day and 18.75 mg/kg bw/day were well tolerated. The NOAEL for maternal toxicity could be considered at 75 mg/kg bw/day. No differences of toxicological relevance were observed between control and treated groups in the foetal development. The major and minor alterations noted at external, skeletal and visceral examinations of foetuses were considered incidental and not treatment-related since they were quantitatively similar between control and treated groups with an absence of dose-related response. Under the study conditions, the NOAEL for maternal and developmental toxicity was determined to be 75 mg/kg bw/day (Liberati, 2020). Based on the results of the read across study, similar absence of development effects can be expected for the test substance.

Study 2: A study was conducted to determine the teratogenicity of read across substance, C12-14 TMAC (35% active in dobanol 45E7), according to the method comparable to OECD 414. Based on the results of a range-finding study, thirteen or 14 mated female rabbits per group were exposed to the read across substance orally at doses of 0, 2, 8 and 24 mg/kg bw/day (i.e., 0.35, 1.4 and 8.4 mg a.i./kg bw/day) during gestation period 6 to 18. The control group was treated with deionized water only. Animals were observed daily for signs of toxicity. Body weights were taken every three days during pregnancy. Food consumption was measured daily. All surviving dams were sacrificed at study termination on gestation Day 29 using sodium pentobarbital. An examination of the uterus, including the number corpora lutea, implantations, and resorptions was conducted. Uteri from females that appeared non-gravid were placed in 10% ammonium sulfide solution for confirmation of pregnancy. At sacrifice fetuses were weighed and examined externally for defects. Sex determination also was conducted on each fetus. Two thirds of the fetuses were examined for skeletal and 1/3 were examined for visceral abnormalities. No significant maternal or fetal effects related to treatment were observed at the tested doses. Under study conditions, the NOAEL of read across substance for maternal and embryotoxic effects/teratogenicty was determined to be 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day) (TRS (HPV), 2001). Based on the results of the read across study, similar absence of development effects can be expected for the test substance.

Dermal:

Study 1: A study was conducted to determine the developmental toxicity / teratogenicity of the read across substance, C16 TMAC (25% active in water), according to a method similar to OECD Guideline 414, in compliance with GLP. This experiment was performed in New Zealand White rabbits. Twenty mated female rabbits per group were exposed topically (daily for 2 h) from Days 7 to 18 of gestation at concentrations of 0, 0.5, 1.0, or 2.0% (equivalent to 0, 10, 20 and 40 mg a.i./kg bw/day, respectively). The control group was treated with deionised water only. Clinical condition and reactions to treatment were recorded at least once daily. Body weights were recorded on Days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29 of gestation. All surviving females were sacrificed on Day 29 of gestation and the foetuses were removed by caesarean section. At necropsy the females were examined macroscopically. Live foetuses were weighed, sexed and were examined for visceral and skeletal abnormalities. Two control animals, one intermediate and one high dose died during the study. Two of the rabbits that died, aborted prior to death (one control and one intermediate dose). Two additional abortions occurred, one each in the intermediate and high dose groups. Deaths or abortions were not considered to be related to the read across substance. No treatment-related maternal body weight or food intake effects were noted. The incidence of foetal malformations, as well as genetic and developmental variations in the treated groups was comparable to that of the control group. No other treatment-related effects were noted. Under the study conditions, the NOAEL of the read across substance for maternal as well as developmental toxicity was established at 40 mg a.i./kg bw/day in rabbits (TRS (HPV), 2001). Based on the results of the read across study, similar absence of development effects can be expected for the test substance.

Study 2: A study was conducted to determine the developmental toxicity of the read across substance, C18 TMAC (98.8% purity), according to a method similar to OECD Guideline 414. Pregnant rats were exposed dermally to the test substance from Day 6 to Day 15 of gestation. Volumes of 0.5 mL were applied on shaved skin. The concentrations of the read across substance ranged from 0.0 to 2.5% (i.e., corresponding to 0, 18, 30 and 50 mg/kg bw/day). Signs of systemic reaction and local reaction of the exposed area of skin were assessed on a daily basis. Body weights were recorded on Days 1, 3, 6, 10, 17, and 20 of pregnancy. Food and water consumption were measured at regular intervals throughout the study. On Day 20 of pregnancy, congenital abnormalities and macroscopic pathological changes in maternal organs as well as in ovaries and uteri (number of corpora lutea, number/distribution of live young and embryo/foetal deaths (early and late, stages of implantation)) and post implantation loss were evaluated. Litter weights (from which the mean pup weight was calculated), foetal abnormalities (external and internal), and sex determination were also recorded on Gestation Day 20. Under the study conditions, a dermal application of the read across substance did not induce toxic effects on dams or foetuses, except for a local irritation (erythema and oedema) on the skin of pregnant animals. The maternal NOAELs (systemic and local) were therefore established at 50 and 18 mg/kg bw/day, respectively. The developmental NOAEL was determined at 50 mg/kg bw/day (Palmer, 1983). Based on the results of the read across study, similar absence of development effects can be expected for the test substance.

Overall, based on the available oral and dermal pre-natal development toxicity studies with the test and/or read across substances in rats and rabbits, indicate no concern for development toxicity. Furthermore, in line with the biocides assessment report, the maternal NOAELs from the pre-natal studies have not been considered further for risk assessment.

Based on the results of the read across pre-natal development toxicity studies in rats and rabbits, the test substance does not warrant a classification according to the EU CLP criteria (Regulation 1272/2008/EC)

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

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