2-ethoxy-1,3-dimethylcyclohexane

Endpoint summary

Description of key information

Based on these results a parental NOAEL for systemic effects of 500 mg/kg bw/d was derived.

Additional information

IFF 05-0293 was administered via oral gavage to male and female Wistar Han rats at doses of 50, 150 and 500 mg/kg bw/d in corn oil (10 rats/sex/dose level) according to OECD 422 Guideline. Concurrent controls (10 rats/sex) received the vehicle. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 40-53 days, i.e. during 2 weeks prior to mating, during mating, during postcoitum, and during at least 4 days of lactation. Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

No mortality or toxicologically related clinical signs were noted. No treatment-related effects on body weight, food consumption, functional behaviour, haematology, and macroscopy were observed.

An adverse histopathological lesion was recorded in the kidneys of males in all treatment groups. In these males, an increased incidence and severity (up to slight) of hyaline droplet accumulation was noted. The hyaline droplet accumulation was considered to likely represent alpha-2u-globulin, a normal protein in male rats which undergoes reabsorption in the proximal cortical tubules. A range of chemicals is known to increase hyaline droplet formation leading ultimately to proximal cortical tubule cell injury as manifested by formation of granular casts and increased tubular basophilia. This male rat specific protein is not present in female rats nor in higher mammals, including man. In this study the increased hyaline droplet accumulation in males was accompanied by indicators of renal tubular damage in the form of granular casts at minimal to slight degree (50 and 500 mg/kg bw/d). This combination of findings was considered to be non-adverse.

Histopathology showed a minimal or slight hepatocellular hypertrophy of the centrilobular areas of the liver for both sexes at 150 and 500 mg/kg bw/d. This histopathological observation was accompanied by higher liver weights in males at 150 mg/kg bw/d (relative weight approximately 17% higher) and in males and females at 500 mg/kg bw/d(relative weight approximately 32% and 15% higher, respectively). These findings occurred without any degenerative histopathological changes or corroborative changes in clinical biochemistry parameters and were therefore considered to be an adaptive, non-adverse finding. Other histopathological changes that were considered to be related to treatment but were considered not adverse in nature were recorded in the adrenal and thyroid glands. Follicular cell hypertrophy as recorded in the thyroid gland of males at 150 and 500 mg/kg bw/d with a minor increase in severity (slight degree) was regarded to be an adaptive change and considered to be non-adverse at the incidences and severities recorded. An increased incidence and severity of vacuolation of the zona glomerulosa of the adrenal glands was seen in females at 500 mg/kg bw/d. Given the slight nature of vacuolation of the zona glomerulosa of the adrenal glands, and absence of any degenerative findings, this was considered to be non-adverse. Additionally, higher adrenal gland weights were present in the opposite sex at 150 and 500 mg/kg bw/d, and were approximately 29% higher at both dose levels. In absence of any morphological support, the higher adrenal gland weight was considered not adverse in nature. Statistically significant changes in clinical biochemistry parameters consisted of higher total protein in males at 50 mg/kg bw/d and higher, higher creatinine and calcium in males at 500 mg/kg bw/d and higher chloride in females at 500 mg/kg bw/d. These changes were considered not toxicologically relevant since no (clear) dose-related trend was noted, changes were generally minor in nature (within the range considered normal for rats of this age and strain), and no apparent relation to morphological lesions described above was seen.

Justification for classification or non-classification

Based on the results of the combined oral repeated dose toxicity study and reproduction/developmental toxicity screening test, the test substance does not have to be classified for repeated dose toxicity in accordance with Regulation (EC) No. 1272/2008.