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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two 2-generation reproductive toxicity studies conducted with structurally similar test substance benzyl C12-16 alkyl dimethyl ammonium chloride are available. Hence, the information requirement for this tonnage band is sufficiently met with the available data
Additional information

In a two-generation study, the read-across substance C12-C16 ADBAC was administered in the diet to male and female Sprague Dawley rats at dose levels of 0, 500, 2,000, 4,000 ppm (purity 49.9%) i.e.,

500 ppm = 16-25 and 24-31 mg/kg bw/day or 8-12.5 and 12-15.5 mg a.i./kg bw/day in males and females;

2,000 ppm = 61-101 and 96-123 mg/kg bw/day or 30.5-50 and 48 to 61.5 mg a.i./kg bw/day in males and females

4,000 ppm = 123-208 and 202-252 mg/kg bw/day or 61-104 and 101-126 mg a.i./kg bw/day in males and females.

Doses were administerd before and through mating and gestation until the end of the lactation period in both F0 and F1 generations. At 2,000 ppm, F0 (males) and F1 parents showed marginally to slightly lower body weight gains and reduced food consumption. Necropsy of parents of both generations revealed dilatation of the caecum in some animals. This was associated with lower liver weights in parental animals of both generations. At 4,000 ppm, in F0 and F1 parents, number of implantation sites and litter size at birth were reduced. The progeny (F2) also showed lower pup weights. Pup weight gain was slightly lower during lactation. Upon necropsy, dilatation of the caecum with faeces was observed in 4/25 males and 2/25 females. Treatment with the test substance had no effect on mating, fertility and behavioural parameters in F0 and F1 parental Sprague-Dawley rats at treatment levels up to 2,000 ppm. No effect was recorded on litter parameters and on pre- and post-natal development of either generation at 2,000 ppm. Consequently, under the experimental conditions of this study, the No Observed Effect Level (NOEL) for parental toxicity was 500 ppm for the male and the female animals. The No Observed Effect Level (NOEL) for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny was 2,000 ppm (i.e., 61 to 101 mg/kg bw/day (nominal) (i.e., equivalent to 30.5 to 50.5 mg a.i./kg bw/day and 96 to 123 mg/kg bw/day (nominal) (i.e., equivalent to 48 to 61.5 mg a.i./kg bw/day for the F0 and F1 generation respectively) (Foulon O, 2008).

In another study, the reproductive/developmental toxicity of the read-across substance C12-C16 ADBAC in rats was evaluated. The test substance was orally administered to Sprague-Dawley CD rats (28/sex/group) at dose levels of 0, 300, 1,000 or 2,000 ppm test substance (i.e., equivalent to 0, 16-31, 51-102, and 100-188 mg/kg bw/day (for males) and 0, 21-32, 67-106 and 139-198 mg/kg bw/day (for females)) in the diet. There was one control group of 28 animals/sex. Following a 10 week pre-breed exposure period, the F0 rats were randomly paired within dose groups for a 3 week mating period to produce the F1 generation. Exposure continued through mating, gestation, parturition and lactation. At weaning, 28 F1 weanling/sex/group were randomly selected and exposed to the same dietary concentration of the test substance as their parents for 10 weeks. After their pre-breed exposure, F1 animals were paired to produce the F2 generation. The animals were observed twice daily and clinical findings, body weights and food consumption were recorded periodically. All F0 and F1 parental animals were necropsied and examined for gross lesions; selected reproductive tissues from the high dose and control groups were examined histologically as were other tissues with gross lesions. Ten F1 and F2 weanlings/sex/dose were randomly selected and necropsied and examined for gross lesions. F0 female body weights and food consumption were reduced at 2,000 ppm during the pre-breeding exposure period. For the pre-breeding period of the F1 parental animals, only slight reductions in body weight gain were observed for males in the high dose group. No other treatment-related effects were observed on any of the reproductive parameters. Based on the results of the study, it can be stated that, dietary administration of the test substance at dose levels of 0, 300, 1,000 and 2,000 ppm for two generations to Sprague-Dawley rats was well tolerated and no sign of reproductive toxicity was observed at any dose level. The NOAEL for both parental generation (P and F1) and offsprings (F1 and F2) was considered to be 1,000 ppm (in diet), equivalent to 51-102 or 41.3-83 mg a.i./kg bw/day in males and 67-106 mg/kg bw/day or 54-86 mg a.i./kg bw/day for female respectively, (Neeper-Bradley TL, 1990).


Short description of key information:
In the most recent two-generation reproduction study, the NOEL for parental toxicity was 500 ppm for the male and the female animals (i.e., 8-12.5 and 12-15.5 mg a.i./kg bw/day in males and females). The NOEL for mating behaviour, fertility and gestation of each generation and for development, growth and survival of each progeny was 2,000 ppm (i.e., 61 to 101 mg/kg bw/day (nominal) or 30.5 to 50.5 mg a.i./kg bw/day and 96 to 123 mg/kg bw/day (nominal) or 48 to 61.5 mg a.i./kg bw/dayfor the F0 and F1 generation, respectively. Further, no reproductive effects were observed in another two-generation reproductive toxicity study conducted in rats up to 2,000 ppm.

Justification for selection of Effect on fertility via oral route:
OECD guideline and GLP compliant study.

Effects on developmental toxicity

Description of key information
No treatment-related maternal or developmental toxicity was observed in rabbits following dermal application up to the highest tested dose of 40 mg a.i./kg bw/day of the test substance during Days 7 to 18 of gestation.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Well-documented study which meets basic scientific principles.
Additional information

Dermal

A guideline study was carried out to assess the effects of the read-across substance C16 TMAC on embryonic and foetal development in New Zealand White rabbits. Twenty mated female rabbits per group were exposed topically (daily for 2 hours) 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. None of these deaths or abortions was considered to be related to the test substance. No treatment-related maternal body weight or food intake effects were noted. The incidence of feotal malformations and genetic and developmental variations in the treated groups was comparable to that of the control group. No other treatment-related effect was noted. Under the conditions of the study, the NOAEL for maternal as well as developmental toxicity was found to be 40 mg a.i./kg bw/day in rabbits (Aldridge D, 1985).


Justification for selection of Effect on developmental toxicity: via dermal route:
Only one study available; comparable to guideline study and in compliance with GLP.

Justification for classification or non-classification

The available data on demonstrates no effects on fertility or development. Therefore, no classification is required according to EC (67/548/EEC) and CLP criteria (EC 1272/2008).