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

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RIVM Report 703719064Appendix H Provisional drinking water limitsToxicological limits for party drugs in drinkingwater sourcesAdvice requested by: Drs. N.G.F.M. van der Aa (RIVM/IMG)Date requested: 17-03-2010Date advice: 19-07-2010Date of revision1: 16-11-2010Advice preparation: Dr B.M. van de Ven (RIVM/SIR)Advice review: Ing. P.J.C.M. Janssen (RIVM/SIR)Project no. RIVM: M/703719/10/BBPORS no.: 12658MethodIn the present document, provisional toxicological limits for party drugs indrinking-water sources are determined, to be used within RIVM projectM/703719/10/BB: exploring measurements in drinking water (sources). Limitderivation is based on allocation of 10% of the ADI (acceptable daily intake) orthe MRL (maximum residue limit) for milk determined for veterinary medicinesto drinking water. In the calculation, an average bodyweight of 60 kg and adrinking water intake of 2 litres/day are assumed. For drugs not used as aveterinary medicine, the SIR/SEC database was searched to determine if anexisting ADI was available. When no ADI was available from this database, alimited literature search was performed in Toxnet (queries using the name of thedrug and the words ‘toxicity’ and ‘review’). Abstracts were screened for ADIs ortoxicologically relevant data. If no ADI or MRL was available, a provisionaldrinking-water limit was determined from the lowest pharmacological effectivedose and a safety factor of 100, an average body weight of 60 kg and aconsumption of 2 litres of drinking water per day.Although it is known that some drugs interact at pharmacologically effectivedoses, no information was available on their possible interaction at the level ofthe proposed drinking-water limits. Therefore, no attempt was made todetermine drinking-water limits for combinations of drugs. Only for drugsbelonging to the same chemical group that are known to have the samemechanism of action a drinking water limit was derived for the whole group.BenzoylecgonineCASnr: 519-09-5Chemical name:(1R,2R,3S,5S)-3-(Benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acidBenzoylecgonine is a (O-demethylated) metabolite of cocaine, not used as adrug itself but found in blood and urine after cocaine use. No evaluation ofbenzoylecgonine is present in the SIR/RIVM database. No ADI or oraltoxicological information was found. Only some comparative toxicological studieshave been performed in order to assess whether cocaine metabolites are moreor less toxic then cocaine itself. In a study of Morishima et al., it was determinedthat doses of benzoylecgonine necessary to produce mild neurobehavioralPage 81 of 90
RIVM Report 703719064changes in rat after intravenous administration, were 30-fold higher than thosefor cocaine and that benzoylecgonine was not lethal, even at doses 100 timesgreater than those of cocaine (Morishima et al., 1999). Infusion withbenzoylecgonine resulted in later onset of convulsions and respiratory andcirculatory arrest in rats than after infusion with cocaine (Metz and Virag, 1995).Furthermore, in vitro, benzoylecgonine inhibited the development of embryos toblasocysts only at higher concentrations than did cocaine (Kaufmann andArmant, 1992). These results indicate that benzoylecgonine is less toxic thancocaine. Based on this conclusion, the provisional drinking-water limit forcocaine of 0.02 mg/L (see below) will be safe for benzoylecgonine as well.Therefore, a provisional drinking-water limit for benzoylecgonine is proposed of0.02 mg/L.CocaineCASnr: 50-36-2Synonym: BenzoylmethylecgonineChemical name:Methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acidCocaine is a strong central nervous system stimulant that induces euphoriceffects. No evaluation of cocaine is present in the SIR/RIVM database. Cocaine isnot used as a veterinary drug. It is used in human medicine but only as topicalanaesthetic for ophthalmological procedures and for membranes of the nose andthroat (Baselt, 2004). Typical use levels for addicts to cocaine are not providedin literature. In the IPCS monograph on cocaine it is mentioned that “thetherapeutic use rate” is 1 to 3 mg/kg bw (IPCS), without specification of theroute of administration. In a study which investigates “low doses of oralcocaine”, levels of 50 mg/ person were used (0.8 mg/kg bw/d) (Epstein et al.,1999). The effects of cocaine have been exhaustively investigated but moststudies concentrate on abuse, overdose, addiction and treatment of addicts. Nosuitable toxicological data are available for the derivation of an ADI. Therefore, aprovisional ADI is derived from the lowest known oral pharmacological dose levelof 0.8 mg/kg bw/day, using a safety factor of 100. This leads to a provisionalADI of 0.008 mg/kg bw. Allocating 10% of this ADI to drinking-water, aprovisional drinking-water limit is derived of 0.02 mg/L (0.008 mg/kg bw/d /10* 60 kg bw / 2 L).NorcocaineCASnr: 18717-72-1Chemical name: Methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-azabicyclo[3.2.1]octane-2-carboxylic acidNorcocaine is a (N-demethylated) metabolite of cocaine, not used as a drugitself but found in blood and urine after cocaine use. No evaluation of norcocaineis present in the SIR/RIVM database. No ADI or oral toxicological informationwas found. Only a few comparative toxicological studies have been performed inorder to assess whether cocaine metabolites are more or less toxic than cocaineitself. In a study of Morishima et al., it was determined that doses of norcocainenecessary to produce toxic effects were smaller than those of cocaine whenadministered systemically to rats (Morishima et al., 1999). In another study,norcocaine infusion resulted in earlier onset of convulsions and respiratory arrestin conscious rats than with cocaine. Onset of circulatory arrest was also earlierwith norcocaine (Metz and Virag, 1995). Cocaine was found to producePage 82 of 90
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Page 90 and 91: RIVM Report 703719064ReferencesAmio
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