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Administrative data

Description of key information

Repeated dose toxicity (OECD TG 422): NOAEL = 83 mg/kg bw, Target organs were liver and especially kidneys on which the NOAEL is based.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
83 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
OECD 422 guideline study in compliance with GLP, no restrictions, fully adequate for assessment.
System:
urinary
Organ:
kidney

Mode of Action Analysis / Human Relevance Framework

Pinyl Isobutyraldehyde is an aldehyde, which likely oxidises in the gastrointestinal tract into its respective acid. Reduction into the alcohol can also occur as was shown in the bioaccumulation study.

Additional information

Repeated dose/Reproscreen study (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 iso butyraldehyde alpha 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.

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).

Justification for classification or non-classification

Based on the available data, Pinyl Isobutyraldehyde does not need to be classified for repeated dose toxicity in accordance with the criteria outlined in EU CLP (EC no. 1272/2008 and its amendments).