Two types of deposits, hyaline droplets and eosinophilic bodies, associated with α&lt;sub&gt;2u&lt;/sub&gt;-globulin accumulation in the rat kidney

2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (BTMLP, CAS No. 125304-04-3) is widely used as a liquid ultraviolet absorber that prevents deterioration of synthetic resins and so on.To investigate its toxicological properties and determine the no-observed-adverse-effect level (NOAEL), a 90-day repeated oral toxicological study of BTMLP was conducted in Crl:CD (SD) rats at doses of 0 (vehicle control, corn oil), 100, 300, and 1000 mg/kg/day. There was no observed mortality or abnormal clinical signs related to the treatment of any group. Body weight and food consumption were not affected by BTMLP treatment. In males, significant prolongations of prothrombin time and activated partial thrombin time were observed in the BTMLP-treated groups. Histopathological examination revealed a slight increase of the eosinophilic bodies and hyaline droplets in the renal cortical tubules in the 1000 mg/kg group in males. As mentioned above, the toxic effect of the BTMLP was noted in the blood coagulation system and kidneys only in males. Based on these findings, the NOAEL was judged to be less than 100 mg/kg/day in males and 1000 mg/kg/day in females under this study's condition.

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

A 90-day dose toxicity study of 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol in rats

Kuwagata¹,

Tsuboi²,

Igarashi³

et al. 2023

“…All three hydrocarbons displayed renal toxicity, but only in males. The results of immunohistochemical staining, hyaline droplet or eosinophilic bodies in proximal tubules demonstrated α2u-globulin accumulation, which has been reported to be specific to male rats and cannot be extrapolated to humans (Hamamura et al, 2017;Hard et al, 1993;Nakatsuji, 1996;Swenberg et al, 1989). Consequently, these α2u-globulin nephropathy-related changes were regarded as irrelevant for human health.…”

Section: Discussionmentioning

confidence: 95%

Combined repeated-dose and reproductive/developmental oral toxicity of 3-methylpentane, isooctane, and isononane in rats

Kawashima¹,

Inoue²,

Yoshizaki³

et al. 2020

3-Methylpentane, isooctane, and isononane are acyclic branched saturated hydrocarbons with carbon numbers C6, C8, and C9, respectively. To assess human risk, we conducted a combined repeated-dose and reproductive/developmental oral toxicity studies in rats. [Organization for Economic Co-operation and Development (OECD) Test Guideline 422]. Each hydrocarbon was administered by gavage to rats at three doses (plus a control group). All three chemicals targeted the liver and kidney. An increase in liver weight without hepatic injury was observed as the adaptive response to the chemical treatments. Males treated by each chemical showed α2u-globulin nephropathy, which is a rat-specific finding that bears no human relevance. Reproduction/developmental toxicity parameters showed no treatment-related effects in parents or offspring at any dose for the three chemicals, except for the retardation of offspring bodyweight development which may be a secondary effect of a maternal systemic condition or direct effect on offspring in isononane. No observed adverse effect levels (NOAELs) of repeated toxicity in either sex were determined to be 300 mg/kg/day for 3-methylpentane, 100 mg/kg/day for isooctane, and 250 mg/kg/day for isononane. NOAELs of reproductive/developmental toxicity in parents and offspring were determined to be 1000 mg/kg/day for 3-methylpentane, and 300 mg/kg/day for isooctane. For isononane, NOAELs were determined to be 1000 mg/kg/day for reproduction, and 250 mg/kg/day for offspring development. These results provide new toxicological information and support the category assessment of published reports that evaluate the acyclic branched saturated hydrocarbons as low-toxicity substances.

“…Eosinophilic bodies and hyaline droplets in proximal renal tubules were observed at all the doses but only in males. Considering the male-specific significant increase in the α2 protein ratio and histopathological characteristics, the lesions might be derived from α2-microglobulin, an adult male rat-specific protein (Greaves, 2012;Hamamura et al, 2017). Various chemicals are reported to evoke α2-microglobulin nephropathy, characterized by similar increases in the eosinophilic bodies and hyaline droplets (Dietrich and Swenberg, 1991;Greaves, 2012;Hamamura et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

A 90-day repeated oral dose toxicity study of 2-Butylbenzo[d]isothiazol-3(2H)-one in rats

Kuwagata¹,

Tsuboi²,

Igarashi³

et al. 2023

isothiazol-3(2H)-one (BBIT, CAS No. 4299-07-4) is widely used as an industrial antiseptic and antifungal agent. To investigate its toxicological properties and determine the noobserved-adverse-effect level (NOAEL), a 90-day repeated oral toxicological study of BBIT was conducted in Crl:CD (SD) rats at doses of 0 (vehicle control, corn oil), 30, 90, or 270 mg/kg/day. There was no mortality or abnormal clinical signs related to treatment in any group. Slightly decreased body weight and food consumption were observed in the 270 mg/kg group in females. Increased urine volume and kidney weight, increased liver weight, and thickening of the forestomach mucosa in autopsy were observed in both sexes in the 270 mg/kg group. Histopathological examination revealed that hyperplasia of the squamous epithelium of the forestomach with parakeratosis and/or hyperkeratosis was observed in both sexes in all the BBIT-treated groups. Moreover, centrilobular hypertrophy of hepatocytes was observed in both sexes of the 270 mg/kg group. Similarly, increased depositions of eosinophilic bodies and/or hyaline droplets in the proximal tubules of the kidney were observed among the male in the 270 mg/kg group. Based on the forestomach changes, NOAEL was judged to be less than 30 mg/kg/day in both sexes under this study's conditions.