Safety evaluation of certain food additives - ipcs inchem

590 SUBSTANCES STRUCTURALLY RELATED TO MENTHOL (addendum)
rat in the 2% dose group died on day 3 of the study as a result of not eating the diet.
At the 2% dose level, there was a significant (P < 0.05) decrease in food intake in
male rats and a significant (P < 0.05) reduction in body weight gains in both sexes.
There were significant changes in a number of serum biochemical values in both
sexes in the 1% and 2% dose groups, probably related to the reduced food intake
at the higher dose levels. Significantly (P < 0.05) higher relative kidney weights were
reported in male rats administered 2% menthyl pyrrolidone carboxylate, but not in
female rats. Significantly (P < 0.05) higher relative liver weights were also reported
in both sexes in the 2% dose group animals, but these changes were not
accompanied by any histological changes. The no-observed-adverse-effect level
(NOAEL) was 0.5% menthyl pyrrolidone carboxylate in the diet, equivalent to 610
and 620 mg/kg bw per day for males and females, respectively (Edwards et al.,
1977a).
In a follow-up study, groups of 4-week-old rats (10 per sex per dose) were
fed 0, 0.07, 0.14, 0.7 or 1.4% menthyl pyrrolidone carboxylate in the diet for 13
weeks. These dietary levels were equivalent to daily intakes of 0, 57, 109, 563 or
1111 mg/kg bw per day for males and 0, 71, 127, 710 or 1388 mg/kg bw per day
for females. Food and water intake and individual body weights were recorded
weekly. At necropsy, haematological, serum biochemical and urine analyses were
conducted. Select organs (e.g. brain, spleen, heart, kidney, liver, adrenals and
testes) were weighed, and tissue samples were prepared for histological evaluation.
Significantly (P < 0.05) reduced body weight gain was reported in female rats fed
the 1.4% diet. Relative kidney and liver weights were significantly increased in male
rats fed the 1.4% and 0.7% diets and in female rats fed the 1.4% diet. Although
histological examination revealed centrilobular hypertrophy in the liver of male rats
fed the 1.4% diet, it was not accompanied by other histopathological changes in the
liver and may be an adaptive response resulting from cytochrome P450 induction.
Males fed the 1.4% diet exhibited increased numbers of hyaline droplets in the
proximal convoluted tubules of the kidneys. This is considered to be related to the
aggregation of -2u-globulin in the renal proximal tubules (National Toxicology
Program, 1990; Lehman-McKeenan & Caudill, 1994) and is a male rat–specific
effect (Bucher et al., 1986; Swenberg et al., 1989). The NOAEL was 0.14% menthyl
pyrrolidone carboxylate in the diet, equivalent to 109 and 127 mg/kg bw per day for
males and females, respectively (Edwards et al., 1977b).
(c) Genotoxicity
(i) 2-(l-Menthoxy)ethanol (No. 1853) and l-Menthyl (R,S)-3-hydroxybutyrate
(No. 1855)
No evidence of mutagenicity was reported in modified bacterial reverse
mutation assays when 2-(l-menthoxy)ethanol (No. 1853) and l-menthyl (R,S)-3hydroxybutyrate
(No. 1855) were incubated with various strains of Salmonella
typhimurium and with Escherichia coli strain WP2uvrA at concentrations up to
10 000 μg/plate, with and without metabolic activation (Sasaki, 2003; Morimoto,
2005) (Table 5).