For definition of Groups, see Preamble Evaluation.
VOL.: 73 (1999) (p. 307)
Chem. Abstr. No.:
Chem. Abstr. Name: (R)-1-Methyl-4-(1-methylethenyl)cyclohexene
5.1 Exposure data
d-Limonene is a terpene which occurs naturally in citrus and a variety of other plants. Exposure occurs from its presence in foods and its use as a solvent. It is being evaluated in clinical trials for use as a cancer chemotherapeutic agent.
5.2 Human carcinogenicity data
No data were available to the Working Group.
5.3 Animal carcinogenicity data
d-Limonene was tested for carcinogenicity by oral gavage in mice and rats and in several two-stage experiments with multi-organ carcinogens. It significantly increased the incidence of renal tubular tumours (adenomas and carcinomas) and induced atypical renal tubular hyperplasia in male rats, which normally synthesize a 2u-globulin in the liver, but not in female rats or in mice of either sex. It consistently enhanced the incidences of renal tubular tumours and atypical renal tubular hyperplasia initiated by carcinogens in two-stage carcinogenesis assays in male rats of a strain conventionally used in bioassays, but not in a strain that lacks hepatic synthesis of a 2u-globulin.
d-Limonene was tested as a cancer-preventive agent in other experimental models with known carcinogens. It inhibited lung carcinogenesis in mice, preneoplastic stages of colon carcinogenesis in rats and pancreatic carcinogenesis in hamsters.
5.4 Other relevant data
d-Limonene is metabolized in humans and experimental animals to a variety of metabolites, including perillic acid and d-limonene-1,2-diol. d-Limonene causes a male rat-specific nephrotoxicity resulting from accumulation of the male rat-specific protein a 2u-globulin. d-Limonene-1,2-epoxide binds reversibly to a 2u-globulin. d-Limonene causes sustained cell proliferation in renal proximal tubular cells, and the dose–response relationships for tumour outcome, enhanced cell proliferation and other histopathological end-points typical of a 2u-globulin nephropathy are similar. Female rats, male rats of strains that do not express this protein and other species are not susceptible to the nephrotoxic action of d-limonene.
Developmental toxicity in the form of delayed prenatal growth has been observed in mice, rats and rabbits exposed to d-limonene during gestation. Skeletal anomalies have also been observed in the fetuses of exposed mice and rabbits.
The few available data indicate that d-limonene and its 1,2-epoxide metabolite are not genotoxic.
There is inadequate evidence in humans for the carcinogenicity of d-limonene.
There is sufficient evidence in experimental animals for the carcinogenicity of d-limonene.
In making its overall evaluation of the carcinogenicity to humans of d-limonene, the Working Group concluded that d-limonene produces renal tubular tumours in male rats by a non-DNA-reactive mechanism, through an a 2u-globulin-associated response. Therefore, the mechanism by which d-limonene increases the incidence of renal tubular tumours in male rats is not relevant to humans.
d-Limonene is not classifiable as to its carcinogenicity to humans (Group 3).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Vol. 56 (1993)
See Also: Toxicological Abbreviations Limonene, d- (IARC Summary & Evaluation, Volume 56, 1993)