title: Safety evaluation and risk assessment of d-Limonene.
abstract: d-Limonene, a major constituent of citrus oils, is a monoterpene widely used as a flavor/fragrance additive in cosmetics, foods, and industrial solvents as it possesses a pleasant lemon-like odor. d-Limonene has been designated as a chemical with low toxicity based upon lethal dose (LD50) and repeated-dose toxicity studies when administered orally to animals. However, skin irritation or sensitizing potential was reported following widespread use of this agent in various consumer products. In experimental animals and humans, oxidation products or metabolites of d-limonene were shown to act as skin irritants. Carcinogenic effects have also been observed in male rats, but the mode of action (MOA) is considered irrelevant for humans as the protein α(2u)-globulin responsible for this effect in rodents is absent in humans. Thus, the liver was identified as a critical target organ following oral administration of d-limonene. Other than the adverse dermal effects noted in humans, other notable toxic effects of d-limonene have not been reported. The reference dose (RfD), the no-observed-adverse-effect level (NOAEL), and the systemic exposure dose (SED) were determined and found to be 2.5 mg/kg/d, 250 mg/kg//d, and 1.48 mg/kg/d, respectively. Consequently, the margin of exposure (MOE = NOAEL/SED) of 169 was derived based upon the data, and the hazard index (HI = SED/RfD) for d-limonene is 0.592. Taking into consideration conservative estimation, d-limonene appears to exert no serious risk for human exposure. Based on adverse effects and risk assessments, d-limonene may be regarded as a safe ingredient. However, the potential occurrence of skin irritation necessitates regulation of this chemical as an ingredient in cosmetics. In conclusion, the use of d-limonene in cosmetics is safe under the current regulatory guidelines for cosmetics.
authors.affiliation: Division of Toxicology, College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Kim
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Kim
authors.forename: Bu Young
authors.initials: BY
authors.lastname: Chung
authors.forename: Du Yeon
authors.initials: du Y
authors.lastname: Bang
authors.forename: Seong Kwang
authors.initials: SK
authors.lastname: Lim
authors.forename: Seul Min
authors.initials: SM
authors.lastname: Choi
authors.forename: Duck Soo
authors.initials: DS
authors.lastname: Lim
authors.forename: Myung Chan
authors.initials: MC
authors.lastname: Cho
authors.forename: Kyungsil
authors.initials: K
authors.lastname: Yoon
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Kyu Bong
authors.initials: KB
authors.lastname: Kim
authors.forename: You Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kwack
authors.forename: Byung-Mu
authors.initials: BM
authors.lastname: Lee
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D053138:Cyclohexenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005421:Flavoring Agents / Q000633:toxicity; D006801:Humans; D000077222:Limonene; D008297:Male; D008452:Maximum Allowable Concentration; D051379:Mice; D051381:Rats; D018570:Risk Assessment / Q000379:methods / Q000592:standards; D013729:Terpenes / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D053138:Cyclohexenes; D005421:Flavoring Agents; D013729:Terpenes; D000077222:Limonene