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Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity (OECD TG 422): NOAEL > 7200 ppm (corresponding to an actual intake of 246 mg/kg bw/day (highest dose tested)

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Additional information

In the present section the repeated dose, fertility and developmental toxicity is addressed to present the fertility and developmental toxicity in the context of the repeated dose effects and not to duplicate the information.

Repeated dose and Reproductive screening tested in the OECD TG 422

Introduction and Method

Potential toxic effects of the test substance after repeated exposure was investigated in an at least 28 -day repeated dose toxicity study with the combined reproduction/developmental toxicity screening test in rats, performed according to OECD guideline and in accordance with GLP principles. Pinyl isobutyraldehyde was administered by daily oral (dietary admixture) to male and female Wistar Han rats at dose levels of 450, 1800 and 7200 ppm (10 rats/sex/dose level, intended doses were 37.5, 120 and 450 mg/kg bw). A control group of 10 rats/sex was given the vehicle (Basic powdered diet). Males were treated for 31 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were treated during 2 weeks prior to mating, during mating, during post-coitum, and up to the day before necropsy (i.e. on day 13 of lactation for females delivered, on day 25 of gestation for unmated females and on study Day 55 for failed to mate female).

Results

Dietary exposure analysis: Throughout the pre-mating period, the achieved intake of test item was generally lower, at all dose levels, than the theoretical concentrations for males and females (-18 to -31 %). During the gestation period, the achieved test item concentration was close to the nominal concentration at the low and mid dose level, whereas at the high dose level, the decreased achieved concentration ranged from -18 to -32 %. During the lactation period, due to higher food consumption in treated females, the achieved intake of test item was markedly higher than the theoretical concentrations (+31 to + 121 %). In addition, after 24-hour storage in the food hopper at room temperature, a decrease in test item formulation concentration of approximately -20 % was noted when compared with the nominal concentrations. The intake on a mg/kg bw bases was 21, 83 and 246 mg/kg bw using the lower intake for either males or females.

Clinical signs: There was no death or clinical sign during the study. There were decreased mean body weight gains and food consumption at 1800 and 7200 ppm in both sexes up to the end of the gestation period, leading to a relevant lower body weight at 7200 ppm (246 mg/kg bw).

Functional battery observations: There was no obvious effect of treatment on the auditory, pupillary and righting reflexes or open field tests for the males or females at any dose level. Lower gripping strength in treated rats was considered to be the consequence of slightly lower body weights and not a direct effect of the test item.Heamatology, Clinical chemistry and T4 levels: There were no test item-related changes.

Organ weights and histopathological effects: For males and females at 7200 ppm (246 mg/kg bw), test item induced changes in organ weights a.o. increase in relative liver weight up to 25% without showing histopathological changes. At this 7200 ppm, relative kidney weights in males only were increased up to 18%. This increase was associated with tubular degeneration and tubular basophilia for males without hyaline droplets and therefore the effects were not considered to be due to alpha-hydrocarbon nephropathy. This means that this effect has to be taken into account for the derivation of the NOAEL.

Fertility and Developmental toxicity: There were no test item-related effects on mating performance for the males and females or on fertility in any group. There was no effect of treatment in length and regularity of the estrous cycle in any group. There were 7, 9, 9 and 8 females that completed delivery in the control, 450, 1800 and 7200 ppm groups 21, 83 and 246 mg/kg bw), respectively. There were no obvious test item-related effects on the number of implantation, pre-birth loss, litter size, pup viability or body weight. There were no test item-related effects on areola/nipple retention. For none of the examined male pups nipples were observed at PND 13. Anogenital distance (normalized for body weight) in male and female pups was not affected by test item.

Discussion

In view of the instability of the substance, the intake of the substance was lower than anticipated for all doses. The substance may have volatilised and/or degraded due to oxidation of the aldehyde. At 7200 ppm (246 mg/kg bw) slight (maximum -9%) body weight decrease was considered treatment related. Several organ weights were increased e.g. liver, thyroid and kidney. No histopathological effects were seen in most organs but in kidneys tubular effects were seen in males, which could not be attributed to alpha-hydrocarbon nephropathy in absence of hyaline (eosinophilic) droplets. Based on these results and specifically the histopathological effects in the kidneys, the dose of 1800 ppm, corresponding to at least 83 mg/kg bw/day, respectively, was considered as the parental No Observed Adverse Effect Level (NOAEL). For fertility no adverse effects were seen up to the highest dose level (7200 ppm corresponding to an actual intake of 246 mg/kg bw. For developmental toxicity no adverse effects were seen.

Conclusion

Parental NOAEL is 83 mg/kg bw based on actual substance intake from nominal 1800 ppm feed.

For fertility the NOAEL was > 246 mg/kg bw in absence of adverse effects based on actual substance intake from nominal 7200 ppm feed.

Developmental toxicity the NOAEL was > 246 mg/kg bw in absence of adverse effects based on actual substance intake from nominal 7200 ppm feed.

Effects on developmental toxicity

Description of key information

Developmental toxicity (OECD TG 422): NOAEL > 246 mg/kg bw/day (highest dose tested)

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The information is presented in the fertility section.

Mode of Action Analysis / Human Relevance Framework

In absence of fertility and developmental toxicity in the OECD TG 422 the substance does not have a specific mode of action for reproductive toxicity.

Justification for classification or non-classification

Based on the available data and in absence of adverse fertility and developmental toxicity effects Pinyl isobutyraldehyde does not need to be classified for these reproductive toxic effects in accordance with EU CLP (EC no 1272/2008 and its amendments).