Safety evaluation of certain food additives - ipcs inchem

360 ALKOXY-SUBSTITUTED ALLYLBENZENES
called gutkha, which consists of betel leaf, tobacco, areca nut, catechu (extract of
the Acacia catechu tree) and slaked lime (calcium hydroxide). Spices or sweeteners
are also added to increase palatability (National Cancer Institute, 2002; Nair et al.,
2004). Betel leaves are rich in a number of alkoxy-substituted allylbenzenes, and
daily quid chewing results in chronic exposure to these materials. Betel leaves are
rich in several chemical classes of potential carcinogens, including a number of
alkoxy-substituted allylbenzenes. To assess the exposure to safrole and its potential
relationship to the occurrence of oral and liver cancer among a group of betel quid
chewers in Taiwan, China, the glucuronic acid conjugate of the O-demethylenation
metabolite (1,2-dihydroxy-4-allylbenzene) was evaluated as a biomarker for
exposure. Urine samples collected during the study were treated with glucuronidase
to deconjugate metabolites. To establish the validity of the method,
male Wistar rats were administered 0, 75, 150 or 300 mg safrole/kg bw in corn oil.
Urine samples collected 1 and 2 days post-administration showed a linear dose–
response relationship for the presence of the O-demethylenation metabolite
resulting from opening of the methylene ring. Analysis of the urine of seven betel
quid non-chewers showed that the concentration of the O-demethylenation
metabolite ranged from 0.75 to 17.75 μg/mg creatinine, with a median of 1.64 μg/
mg creatinine. Urine samples of four betel quid chewers contained 1.47–12.16 μg
O-demethylenation metabolite/mg creatinine, with a median of 4.17 μg/mg
creatinine, which was ~2.54 times the mean for non-chewers. The Odemethylenation
metabolite was concluded to be an appropriate biomarker for
exposure to safrole through betel quid chewing (Chang & Ko, 2000).
In a non-representative subset of adult serum samples collected as part of
the Third National Health and Nutrition Examination Survey in the USA (NHANES
III, 1988–1994; National Center for Health Statistics, 1994), the mean serum methyl
eugenol concentration was approximately 24 pg/g serum (whole weight), with
concentrations ranging from