A 13-week Subchronic Toxicity Study Of 2-(l-menthoxy)ethanol in F344 Rats Ⅱ

Results

In-life parameters, hematology, and serum biochemistry No significant clinical signs were noted throughout the experimental period, and all animals survived until the scheduled necropsy. Furthermore, no significant differences in body weight and daily food intake were observed in male and female rats (Fig. 1A and B).

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Hematology and serum biochemistry data are shown in Tables 1 and 2, respectively. Hematological analyses revealed significantly decreased HGB, HCT, MCV, and MCH and increased PLT in male rats administered 250 mg/kg BW/day 2-(l-menthoxy)ethanol (Table 1). In serum biochemistry, significant increases in TP, T-Chol, and Ca and decreases in Bil and ALP were noted in males of the 250 mg/kg group (Table 2). A significant increase in Cre and a decrease in A/G were noted in males of the 60 and 250 mg/kg groups. In females, a significant increase in Ca and a decrease in ALP were recorded in the 60 and 250 mg/ kg groups, whereas elevated T-Chol and reduced A/G, Bil, TG, AST, and ALT were detected in the 250 mg/kg group. Although a significant increase in TG and a decrease in Cl were observed in males administered 60 mg/kg, the lack of any dose relationship suggested that these differences were not associated with exposure to the test substance.

Organ weights 

Data for organ weights are summarized in Table 3. Ab

solute and relative liver weights were significantly increased in both sexes of the 250 mg/kg group (Table 3). A significant increase in relative liver weights was observed in males of the 60 mg/kg group. In males, absolute and relative kidney weights were significantly increased in the 60 and 250 mg/ kg groups. In the male 250 mg/kg group, significant increases in absolute and relative weights of adrenal glands and relative weights of spleen and testes were noted.

Histopathology and immunohistochemistry 

Data for histopathological and immunohistochemical findings are summarized in Tables 4 and 5, respectively. Histopathological findings revealed that the frequency of accumulation of eosinophilic granules (Fig. 2A–D), basophilic tubules, and hyaline cast, as well as focal interstitial inflammation in the kidney, were significantly increased in all-male treatment groups when compared with the control group (Table 4). Based on immunohistochemical analyses, male rats treated with the test substance presented an increase in α2u-globulin immunoreactivity in epithelial cells of proximal tubules, demonstrating a clear dose-dependency (Fig. 2E–H) (Table 5).

At necropsy, one male rat in the 250 mg/kg group showed severe enlargement of the right kidney owing to a histologically characteristic nephroblastoma. Although nephroblastoma is uncommon in most rat strains9, this case was considered incidental, as no other animals presented similar lesions. In addition, in oral carcinogenicity studies, the incidence of spontaneous nephroblastoma in male F344/DuCrlCrlj rats reportedly ranged between 0–2.0%10. Although several lesions were sporadically detected in other organs, no significant treatment-dependent alterations in the incidence of these lesions were apparent.

Fig. 1. Body weight (A) and daily food intake (B) data for male (closed symbols) and female (open symbols) F344 rats treated with the indicated dose of 2-(l-menthoxy)ethanol for 13 weeks. Each group was composed of 10 animals. The error bars represent the standard deviation for experimental groups.

Table 1. Hematology Data for F344 Rats Treated with 2-(l-menthoxy)ethanol for 13 weeks