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Administrative data

Description of key information

The analogue chemical, dimyrcetol, has been tested for repeated dose toxicity in rats by sub-acute (14-day) sub-chronic (90-day) oral gavage administration.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
500 mg/kg bw/day
Study duration:

Additional information

The repeated dose toxicity of the analogue chemical, dimyrcetol, has been determined in sub-acute and subchronic oral gavage studies in rats. In a 14-day range-finding oral gavage study conducted prior to a 90-day sub-chronic study, rats (3 males and 3 females per treatment group) were treated at 0 (control) and 1000 mg/kg bwt/day. All animals displayed increased salivation 10 minutes following dosing. Body weights of male rats were slightly reduced on day 14. At necropsy, males displayed pale kidneys. No such effects were noted in female rats. Based on slightly decreased body weights in male rats, 1000 mg/kg bwt/day was assigned as the LOAEL in this study. In a 90-day oral gavage study, rats were treated with dimyrcetol at dose levels of 0, 10, 50, 500 or 1000 mg/kg bwt/day. Body weights in males were decreased at the highest dose level but not significantly. Significant reductions in body weight gains, most evident at the highest dose level but not at all time points measured, occurred in both males and females at levels of 500 and 1000 mg/kg bwt/day. Diuresis was evident as increases in urine volumes (statistically significant only for females at the highest dose level) and decreased albumin/globulin ratios. In male rats, nephropathy (consistent with alpha-2u-globulin accumulation) was present at all dose levels. Evidence for this consisted of observations of increased incidence or severity of basophilic tubules and/or granular accumulations of eosinophilic material indicative of alpha-2u-globulin accumulation following staining with Mallory’s Heidenhain stain. Animals of either sex treated with 1000 mg/kg/day and females treated with 500 mg/kg/day showed statistically significant reductions in activated partial thromboplastim time (APPT). Week 13 assessments revealed reductions in hemoglobin, hematocrit, and erythrocyte counts for females treated with 1000 mg/kg/day, with the effect on erythrocyte count also extending into the female 500 mg/kg/day dose group. The effect on platelet count continued into Week 13 assessments and extended into the male 50 mg/kg/day dose group. No similar effects were noted in females treated with 50 mg/kg/day or animals of either sex treated with 10 mg/kg/day. Adrenal and thymus weights were significantly increased for all groups of dosed males. Although statistically significant, increased weights were not associated with any reported histopathological changes. The histopathological changes associated with alpha-2u-globulin deposition were not considered relevant to human hazard and were not used in the hazard evaluation process. A NOAEL value of 10 mg/kg bwt/day was assigned to this study by the authors and was based on the hematological effects seen in male rats. An expert review of the hematological findings from this study concluded that based on the minimal nature of the effects observed, with most values falling within historical control ranges, diyrcetol did not produce any treatment-related hematological effects. In addition, the expert review also concluded that the suggested possibility of bone-marrow hypoplasia in male rats in this study was a misinterpretation, and that when all data were considered, and lacking a similar effect in female rats, the bone marrow was not considered to be a target tissue in this study. Of additional concern in this study were reduced spermatid counts at the highest dose level noted in the testes of male rats, with no similar reductions in the cauda epididymis. No histopathological changes were associated with the reduced spermatid counts. Due to questions concerning the methodology used to determine spermatid counts, and because only the highest dose level was assayed in this study, no further conclusions can be drawn concerning the significance of these findings. Body weight changes, most pronounced at the highest dose level tested, are suggestive of a general systemic effect for dimyrcetol. In the absence of a well-defined mode-of action for dimyrcetol; the lack of chronic toxicity information; and the possibility that long-term diuresis may represent an adverse effect: a NOAEL value of 500 mg/kg bwt/day value was assigned to this study and was used for the derivation of DNEL values. It is not possible to state if any of the effects observed in studies with dimyrcetol were due to the presence of the formate ester.

Please refer to Section 13 of this IUCLID for read-across documentation and rationale for the selection of analogue chemicals to dihydromyrcenol.

Justification for classification or non-classification

Based on the results for analogue chemical, dimyrcetol, dihydromyrcenol would not be rated for repeated dose effects. Male-rat specific kidney effects associated with alpha-2u-globulin accumulation were observed in a 90 -day oral gavage study in rats at all administered dose levels in male rats. These effects were discounted for purposes of human health hazard assessment. Hematological effects were observed in male and female rats; however, changes observed were minimal in nature, with most values falling within historical control ranges. Based on a separate expert review of the hematological findings from this 90 -day study, the hematological changes were not considered to be treatment related. Other body and organ weight changes noted were not associated with any observed pathological findings and were thus not of a severe nature and not indicative of serious damage of toxicological significance. For the purpose of human hazard assessment, a NOAEL value of 500 mg/kg bwt/day was assigned based on the presence of diuresis, representing a potential long-term adverse effect. Under the EU DSD classification system (EU Directive 67/548/EEC), the test material would not be rated as R48 (Danger of serious damage to health by prolonged exposure). Similarly, the test material would not be rated for Specific Target Organ Toxicity (repeated exposure) under the EU CLP Regulation (EU Regulation 1272/2008) or UN-GHS.