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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
750 mg/kg bw/day

Additional information

The potential for 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate to cause target organ toxicity following repeated exposure is well understood. Two guideline or equivalent repeat-exposure studies and three lesser studies were available for review. In a study conducted according to USFDA Toxicological Principles for the Safety of Food Ingredients (Redbook 2000), male and female rats were exposed to up to 750 mg/kg bw/day in the diet for 13 weeks. There were no significant treatment-related effects on mortality, clinical signs, body weight and body weight gain, hematology, ophthalmic examination, functional observational battery, or urinalysis parameters. Increases in liver weights and an elevation in cholesterol in both sexes at 750 mg/kg bw/day were suggestive of possible liver involvement but no effects on the liver were observed microscopically. There was also no reported increase in peroxisomal content in any treatment group. The only significant effect, noted only in male rats, was an increase in kidney weights which corresponded to exposure-related increases in the prevalence of hyaline droplets and increased incidence of minimal chronic progressive nephropathy, a common spontaneous lesion in male rats and frequently exacerbated by chemical exposure.

 

In a combined repeat dose and reproductive/developmental toxicity screening study conducted by a method similar to OECD Guideline 422, the test material was administered to male and female rats by oral gavage at dose levels up to 750 mg/kg bw/day for 44 (males) or 40-53 (females) consecutive days. There were no significant treatment-related effects on mortality, clinical signs, body weight and body weight gain, or hematology (evaluated in males only). Except for slight centrilobular swelling (6/11) and hyperplastic foci (1/11) in the livers of some high-dose group males, increases in liver weights (both sexes) and changes in some serum clinical chemistry parameters (evaluated in males only) did not correspond to gross or microscopic liver changes. Basophilic tubules and hyaline degeneration were seen in males in all groups, including controls, but were increased in a dose-related manner in the 150 and 750 mg/kg bw/day groups. Increased kidney weights corresponded to exposure-related increases in the prevalence of hyaline droplets and increased incidence of chronic progressive nephropathy.

 

Three older non-guideline studies were also reviewed. Two studies, in which groups of male and female rats consumed diets containing up to 1% 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate for approximately 100 days, showed no significant treatment-related effects on survival, clinical signs, body weight and body weight gain, feed consumption, hematology, clinical chemistry, organ weights, or gross or microscopic findings in either sex. Although slight increases in liver weights were seen in males and/or females consuming 1% in the diet immediately prior to necropsy, no gross or microscopic abnormalities were observed in either sex for any of the tissues collected. The increase in liver weights was not seen in groups of rats fed the high-dose diet for approximately 50 days and then switched to a control diet for approximately 50 days. There were no significant treatment-related effects on survival, clinical signs, neurological reflexes, body weight and body weight gain, feed consumption, hematology, clinical chemistry, urinalysis, organ weights, or gross or microscopic findings in male or female beagle dogs consuming diets containing up to 1% of the test substance for 90 days. Slight increases in liver and pituitary weights were seen in the 0.35 and 1% dose-groups with no corresponding gross or microscopic changes.

Justification for classification or non-classification

Except for slight increases in liver and pituitary weights in the absence of gross or microscopic changes, no significant treatment-related effects were observed in beagle dogs receiving up to 1% in the diet for approximately 90 days. In rats, slight reversible increases in liver weights and slight changes to certain clinical chemistry parameters suggestive of liver involvement were not considered adverse effects in the absence of significant corresponding gross or microscopic changes. Adverse effects in rats were limited to the kidneys in the male dose groups. The primary treatment-related kidney changes were increases in kidney weights at high doses which corresponded microscopically to dose-related minimal to mild increases in hyaline droplets. Although test substance-related, these findings were not considered adverse because male rats are predisposed to this condition which occurred in controls as well as exposed animals. The morphology, distribution and occurrence of hyaline droplets in the tubular epithelial cells of the proximal tubules of male rats only suggested that the hyaline granules most likely consisted of alpha-2μ-globulin, a spontaneously occurring urinary protein in the adult male rat. A wide range of substances is reported to increase accumulation of this protein in the kidneys of male rats. However, this effect has not been reported to cause human renal toxicity. There was also a slight increased incidence of minimal, chronic progressive nephropathy characterized primarily by basophilic regenerating cortical tubules with thickened basement membranes. The increased incidence of chronic progressive nephropathy in male rats was most likely due to epithelial damage from the presence of hyaline droplets in cortical tubules and not test substance-related toxicity. Chronic progressive nephropathy is present as a spontaneous lesion in rats and is usually less prominent in females than males. Chronic progressive nephropathy has not been reported in humans and was not observed in beagle dogs receiving 1% in the diet for 90 days. Based on a weight-of-the-evidence assessment, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is not classified for “Specific Target Organ Toxicity – Repeated Exposure” according to GHS.