Drugs of abuse and tranquilizers in Dutch surface waters, drinking ...

RIVM Report 703719064carcinogenicity was found up to doses of 80 (rat) and 400 (mice) mg/kg bw/d inthe 2-year feeding studies. In a hamster NTP teratology study with dosing(gavage) on gestation days 5 to 13, the NOAEL for codeine-induceddevelopmental toxicity was 10 mg/kg bw, administered twice daily(= 20 mg/kg bw/d); in a NTP mice teratology study with dosing (gavage) ongestation days 6 to 15, the NOAEL was 75 mg/kg bw/d (National ToxicologyProgramme Technical Report Series, 1996).Pharmacologically recommended doses are 1 to 2 mg/kg bw/day for antitussiveeffects lasting all day, and 1.5 to 3 mg/kg bw for analgesic effects(Farmacotherapeutisch kompas). The antitussive and analgesic effects occur atoral doses lower than the levels causing no observed effect in the animal toxicitystudies (lowest NOAEL in animal studies was 15 mg/kg bw/day). Therefore, as astarting point for the provisional ADI, the lowest pharmacologically effectivedose of 1 mg/kg bw is used, to which a safety factor of 100 is applied. This leadsto a provisional ADI of 0.01 mg/kg bw. The provisional drinking-water limit is0.01 mg/kg bw/d /10 * 60 kg bw / 2 L = 0.03 mg/L.MorphineCASnr: 57-27-2Chemical name: Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-,(5alpha,6alpha)-Morphine is an alkaloid of opium and is a phenanthrene derivative. It produces awide spectrum of pharmacologic effects including analgesia, dysphoria,euphoria, somnolence and respiratory depression. It is used in human medicineas an oral narcotic pain reliever when needed for longer periods of time. Theoral dose varies from 30 to 600 mg/day (Baselt, 2004) (0.5 to 10 mg/kg bw/d).No evaluation of morphine is present in the SIR/RIVM database. Morphine hasbeen exhaustively studied but most studies concentrate on abuse, overdose,addiction and treatment of addicts. No suitable toxicological data in thepublished literature were found to derive an ADI. Therefore, a provisional ADI isderived from the lowest pharmacological oral dose level of 0.5 mg/kg bw/d. Tothis level, a safety factor of 100 is applied. This leads to a provisional ADI of0.005 mg/kg bw. The provisional drinking-water limit is (0.005 mg/kg bw/d /10* 60 kg bw / 2 L =) 0.015 mg/L.MethadoneCASnr: 76-99-3Chemical name: 3-Heptanone, 6-(dimethylamino)-4,4-diphenyl-methadoneMethadone possesses many of the pharmacological properties of morphine andis approximately equipotent as an analgesic via different administration routes(including the oral route). Unlike morphine, however, methadone producesmarked sedative effects with repeated administration, as a result of drugaccumulation. The oral bioavailability of methadone is 80% (Baselt, 2004). Noevaluation of methadone is present in the SIR/RIVM database. Methadone is notused as veterinary medicine. It is used in human medicine as maintenancetreatment of former heroin addicts and as an analgesic. The pharmacologicallyrecommended oral dose is 20 mg/day (0.33 mg/kg bw/day) for analgesic effectslasting all day (http://www.drugs.com/dosage/methadone.html). In theliterature, no repeated oral dose toxicity studies were found. Therefore, as astarting point for the provisional ADI, the lowest oral pharmacologically effectivedose is used, to which a safety factor of 100 is applied. This leads to aPage 85 of 90