Reaction mass of 3-isopropyl-6-methylenecyclohexene and (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohexene and (4S)-1-methyl-4-(prop-1-en-2-yl)cyclohexene

Endpoint summary

Additional information

d-Limonene has a high partition coefficient between blood and air and is easily taken up in the blood at the alveolus (Falk et al., 1990). The net uptake of d-limonene in volunteers exposed to the chemical at concentrations of 450, 225, and 10 mg/m3 for 2 hours during light physical exercise averaged 65% (Falk Filipsson et al., 1993). Orally administered d-limonene is rapidly and almost completely taken up from the gastrointestinal tract in humans as well as in animals (Igimi et al., 1974; Kodama et al., 1976). Infusion of labelled d-limonene into the common bile duct of volunteers revealed that the chemical was very poorly absorbed from the biliary system (Igimi et al., 1991). In shaved mice, the dermal absorption of [3H]d/l-limonene from bathing water was rapid, reaching the maximum level in 10 minutes (von Schäfer & Schäfer, 1982). In one study (one hand exposed to 98% d-limonene for 2 hours), the dermal uptake of d-limonene in humans was reported to be low compared with that by inhalation (Falk et al., 1991); however, quantitative data were not provided. d-Limonene is rapidly distributed to different tissues in the body and is readily metabolized. Clearance from the blood was 1.1 litre/kg body weight per hour in males exposed for 2 hours to d-limonene at 450 mg/m3 (Falk Filipsson et al., 1993). A high oil/blood partition coefficient and a long half-life during the slow elimination phase suggest high affinity to adipose tissues (Falk et al., 1990; Falk Filipsson et al., 1993). In rats, the tissue distribution of radioactivity was initially high in the liver, kidneys, and blood after the oral administration of [14C]d-limonene (Igimi et al., 1974); however, negligible amounts of radioactivity were found after 48 hours. Differences between species regarding the renal disposition and protein binding of d-limonene have been observed. For rats, there is also a sex-related variation (Lehman-McKeeman et al., 1989; Webb et al., 1989). The concentration of d-limonene equivalents was about 3 times higher in male rats than in females, and about 40% was reversibly bound to the male rat specific protein, "2:-globulin (Lehman-McKeeman et al., 1989; Lehman-McKeeman & Caudill, 1992). The biotransformation of d-limonene has been studied in many species, with several possible pathways of metabolism (Figure 1). Metabolic differences between species have been observed with respect to the metabolites present in both plasma and urine. About 25–30% of an oral dose of d-limonene in humans was found in urine as d-limonene-8,9-diol and its glucuronide; about 7–11% was eliminated as perillic acid (4-(1- methylethenyl)-1-cyclohexene-1-carboxylic acid) and its metabolites (Smith et al., 1969; Kodama et al., 1976). d-Limonene-8,9-diol is probably formed via d-limonene- 8,9-epoxide (Kodama et al., 1976; Watabe et al., 1981). In another study, perillic acid was reported to be the principal metabolite in plasma in both rats and humans (Crowell et al., 1992). Other reported pathways of limonene metabolism involve ring hydroxylation and oxidation of the methyl group (Kodama et al., 1976). Following the inhalation exposure of volunteers to d-limonene at 450 mg/m3 for 2 hours, three phases of elimination were observed in the blood, with half-lives of about 3, 33, and 750 minutes, respectively (Falk Filipsson et al., 1993). About 1% of the amount taken up was eliminated unchanged in exhaled air, whereas about 0.003% was eliminated unchanged in the urine. When male volunteers were administered (per os) 1.6 g [14C]d-limonene, 50–80% of the radioactivity was eliminated in the urine within 2 days (Kodama et al., 1976). Limonene has been detected, but not quantified, in breast milk of non-occupationally exposed mothers (Pellizzari et al., 1982).

See complete references in the monograph:

Falk Filipsson, A., 1998. Concise International Chemical Assessment Document 5 - Limonene, 32 p.

Chapitre 7. Comparative kinetics and metabolism in laboratory animals and humans.

Although the metabolism pattern for individual monocyclic terpenes, constituents of dipentene multi-constituant substance, cannot be accurately estimated as such data do not exist, it can be estimated to be similar from the one of d-limonene based on their similar physico-chemical properties:

- limited molecular weight of the monocyclic terpenes isomers : 136.23 g/mol; Molecular Formula, C10H16,

- lipophilic character (e.g. log Kow values between 4.25 and 4.5 mono-substances).

It may be then assumed that all of the substances in this group will be absorbed to some degree.