Review of toxicological assessment of d-limonene, a food and cosmetics additive.

R-(+)-limonene (d-limonene) is a commonly used flavor additive in food, beverages and fragrances for its pleasant lemon-like odor. Considering its increasing applications, it's necessary to understand toxicological effects and risk associated with its use. R-(+)-limonene is rapidly absorbed in experimental animals and human beings following oral administration. In humans, it gets distributed to liver, kidney, and blood resulting in the formation of metabolites like perillic acid, dihydroperillic acid, limonene-1,8-diol and limonene-1,2 diol. Important toxic effects primarily reported in rodents are severe hyaline droplet nephrotoxicity (only in male rats due to specific protein α2u-globulin; however, this effect isn't valid for humans), hepatotoxicity and neurotoxicity. R-(+)-limonene does not show genotoxic, immunotoxic and carcinogenic effects. Substantial data is available about limonene's stability after treatment with thermal and non-thermal food processing techniques; however, information about toxicity of metabolites formed and their safe scientific limits is not available. In addition, toxicity of limonene degradation products formed during storage of citrus juices isn't known. Based on all available toxicological considerations, R-(+)-limonene can be categorized as low toxic additive. More detailed studies are required to better understand interaction of limonene with modern food processing techniques as well as degradation products generated and toxicity arising from such products.