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Administrative data

Description of key information

A subchronic oral gavage study in rats with the read-across chemical, n-butanol, indicates CNS depression as the critical effect of exposure.  A number of dietary studies with the read-across chemical, terephthalic acid, indicate the urinary tract as the target organ following repeated exposures.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
10.05 mg/m³
Study duration:
subacute
Species:
rat

Additional information

There were no repeated exposure studies conducted with dibutyl terephthalate identified.

Given the rapid and complete metabolic conversion of dibutyl terephthalate, both in vitro and in vivo, to n-butanol and terephthalic acid, it is presumed that the repeated dose toxicity of dibutyl terephthalate is related to formation of these metabolites.

Male and female rats were administered n-butanol daily by gavage at 0, 30, 125 or 500 mg/kg bw/d for either 6 or 13 weeks. Dosing resulted in no significant changes in body weights or body weight gains, organ weights, food consumption, hematology, clinical chemistry or urinalysis. There were no gross or histopathological changes noted in any exposed group. Ataxia and hypoactivity (lasting less than 1 h) were present immediately following dose administration in both sexes at the highest dose level. The NOAEL reported in this study based on CNS effects was 125 mg/kg bw/d.

Several subchronic dietary studies in rats have been conducted with terephthalic acid. At dose levels of 3% for 90 days, terephthalic acid did not produce overt toxicity. Occult blood was found in the urine and crystalluria was seen after 90 days. Kidney weights were increased but no other organs were affected and this change was not thought to be biologically significant. At necropsy, mild to moderate epithelial hyperplasia of the bladder and evidence of chronic cystitis were noted. In a second study, male and female rats exposed to terephthalic acid in the diet for 15 weeks at up to 5% (w/w) displayed no overt signs of toxicity or mortality. Small reductions in body weights, but not food consumption, were seen at the highest dose level. Noteworthy findings were limited primarily to the urinary bladder of high dose males and included a high incidence of bladder stones. Microscopic examinations revealed proliferative changes characterized by thickening of the epithelium, and in some cases, narrowing of the lumen of the bladder. The NOAEL based on bladder effects for this study was 1.6% in the diet and corresponded to 980 mg/kg bw/d for males and 1186 mg/kg bw/d for females. In a third dietary study employing both male and female Wistar and CD rats, animals were exposed for 90 days at concentrations of 0, 0.03, 0.125, 0.5, 2.0 or 5.0%. Toxicity was evident in rats fed diets containing 0.5% and above of terephthalic acid. Chronic inflammatory lesions of the bladder and uethra were present in treated animals with the highest incidence occurring in rats at the 5% dose level. Bladder calculi were also found in rats fed 5% terephthalic acid, with higher incidence in Wistar versus CD rats. Based on body weight reductions, the NOAEL in this study was reported as 0.125%.

Inhalation

Male and female rats were exposed for 6 h/day, 5 days/week over a period of 4 weeks to terephthalic acid dust at concentrations of 1.03, 2.93 or 10.05 mg/m3. No adverse effects were observed in clinical obsersations, body weights or gross pathology findings. Male rats at the highest dose level showed decreased cholinesterase levels. Bilirubin levels were significantly decreased in low dose males and females but slightly increased in females in the high dose group. Plasma glucose levels were slightly increased in low dose males but mildly decreased in the medium and high dose groups. Similar changes were present in female rats. Changes noted above were all reversed in recovery group animals and were considered of minimal toxicological significance. In a functional observational battery (FOB) conducted during the last week of treatment, some (mainly transient) effects were noted in all treatment groups but generally displaying no clear dose-response and considered of low toxicological significance. No significant inflammatory or other lesions were observed in other treated animals.


Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: central nervous system

Justification for classification or non-classification

Based on the toxicological profiles of n-butanol and terephthalic acid, the metabolic products of dibutyl terephthalate, no classification for “Specific Target Organ Toxicity – Repeated Exposure” according to GHS is warranted.