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Methylphenidate >Ì>Ê/ÝV}ÞÊ*À}À> 1°-°Ê i«>ÀÌiÌÊvÊi>Ì Ê>`ÊÕ>Ê-iÀÛVià iÌiÀÊÀÊ/ iÊ Û>Õ>ÌÊ"vÊ,ÃÃÊ /ÊÕ>Ê,i«À`ÕVÌ NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Methylphenidate August 2005 NIH Publication No. 05 - 4473 TABLE OF CONTENTS Preface..............................................................................................................................................v Abstract.......................................................................................................................................... vii Introduction................................................................................................................................... viii NTP.Brief.on.Methylphenidate.........................................................................................................1 References.........................................................................................................................................6 Appendix.I..NTP-CERHR.Amphetamines.and.Methylphenidate.Expert.Panel. Preface...............................................................................................................................I-1 Expert.Panel.......................................................................................................................I-2 Appendix.II..Expert.Panel.Report.on.Methylphenidate................................................................ II-i Table.of.Contents............................................................................................................ II-iii Abbreviations....................................................................................................................II-v List.of.Tables................................................................................................................. II-viii List.of.Figures...................................................................................................................II-x Preface............................................................................................................................ II-xi Chemistry,.Usage.and.Human.Exposure..........................................................................II-1 General.Toxicology.and.Biologic.Effects.........................................................................II-8 Developmental.Toxicity.Data..........................................................................................II-46 Reproductive.Toxicity.Data...........................................................................................II-122 Summaries.and.Conclusions.........................................................................................II-131 References.....................................................................................................................II-135 Appendix.III..Public.Comments.on.Expert.Panel.Report.on.Methylphenidate No.public.comments.received......................................................................................... III-1 iii [This page intentionally left blank] iv PREFACE The. National. Toxicology. Program. (NTP). chemical. is. hazardous. to. humans.. The. panel. established.the.NTP.Center.for.the.Evaluation. also.identifies.areas.of.uncertainty.and.where. of. Risks. to. Human. Reproduction. (CERHR). additional.data.are.needed..The.CERHR.expert. in.1998..The.CERHR.is.a.publicly.accessible. panels. use. explicit. guidelines. to. evaluate. the. resource.for.information.about.adverse.repro- scientific.literature.and.prepare.the.expert.panel. ductive. and/or. developmental. health. effects. reports..Expert.panel.reports.are.made.public. associated. with. exposure. to. environmental. and.comments.are.solicited.. and/or.occupational.chemicals..The.CERHR.is. located.at.the.National.Institute.of.Environmen- Next,.the.CERHR.prepares.the.NTP-CERHR. tal. Health. Sciences. (NIEHS). of. the. National. monograph..The.NTP-CERHR.monograph.in- Institutes.of.Health.and.Dr..Michael.Shelby.is. cludes.the.NTP.brief.on.the.chemical.evaluated,. the.director.1 the.expert.panel.report,.and.public.comments. on. that. report.. The. goal. of. the. NTP. brief. is. The. CERHR. broadly. solicits. nominations. of. to. provide. the. public,. as. well. as. government. chemicals. for. evaluation. from. the. public. and. health,.regulatory,.and.research.agencies,.with. private.sectors..The.CERHR.follows.a.formal. the. NTP’s. interpretation. of. the. potential. for. process.for.review.and.evaluation.of.nominated. the.chemical.to.adversely.affect.human.repro- chemicals.that.includes.multiple.opportunities. ductive. health. or. children’s. health..The. NTP- for.public.comment..Chemicals.are.selected.for. CERHR.monograph.is.made.publicly.available. evaluation.based.upon.several.factors.including. electronically.on.the.CERHR.web.site.and.in. the.following:. hard.copy.or.CD-ROM.from.the.CERHR. •. potential. for. human. exposure. from. use. and.occurrence.in.the.environment 1.Information.about.the.CERHR.is.available.on.the. •. extent.of.public.concern web.at.<http://cerhr.niehs.nih.gov>.or.by.contact- •. production.volume ing.the.director: •. extent. of. data. from. reproductive. and. NIEHS,.P.O..Box.12233,.MD.EC-32, developmental.toxicity.studies. Research.Triangle.Park,.NC.27709. 919-541-3455.[phone]. The.CERHR.convenes.a.scientific.expert.panel. 919-316-4511.[fax] that.meets.in.a.public.forum.to.review,.discuss,. [email protected].[email]. and. evaluate. the. scientific. literature. on. the. .Information.about.the.NTP.is.available.on.the.web. selected. chemical.. Public. comment. is. invited. at.<http://ntp-server.niehs.nih.gov>.or.by.contact- prior.to.and.during.the.meeting..The.expert.panel. ing.the.NTP.Liaison.and.Scientific.Review.Office. produces.a.report.on.the.chemical’s.reproductive. at.the.NIEHS: and. developmental. toxicities. and. provides. its. [email protected].[email] opinion.of.the.degree.to.which.exposure.to.the. 919-541-0530.[phone] v [This page intentionally left blank] vi ABSTRACT The.National.Toxicology.Program.(NTP).Cen- This. conclusion. is. based. on. studies. showing. ter.for.the.Evaluation.of.Risks.to.Human.Re- that.children.treated.with.therapeutic.doses.of. production.(CERHR).conducted.an.evaluation. methylphenidate. have. no. evidence. of. move- of. the. potential. for. methylphenidate. to. cause. ment. disorders. or. tics. due. to. the. medication.. adverse. effects. on. reproduction. and. develop- Second,.there is minimal concern for meth- ment.in.humans..Methylphenidate.was.selected. ylphenidate-induced growth restriction..This. for.evaluation.because.of.1).widespread.usage. conclusion.is.based.on.growth.restriction.being. in. children,. 2). availability. of. developmental. observed.in.animal.studies.only.at.high.doses. studies. in. children. and. experimental. animals,. of. methylphenidate. using. a. non-therapeutic. and.3).public.concern.about.the.effect.of.this. route. of. exposure..The. effect. on. growth. was. stimulant.on.child.development..Methylpheni- reversible..Finally,.there are insufficient data date.is.a.central.nervous.system.stimulant.ap- to draw conclusions on 1) an association be- proved.by.the.U.S..Food.and.Drug.Administra- tween methylphenidate therapy in pregnant tion.for.the.treatment.of.attention.deficit.hyper- women and pregnancy loss and 2) possible activity.disorder.(ADHD).in.persons.6.years.of. reproductive effects of methylphenidate in age.and.older.and.for.narcolepsy..The.results. humans. NTP-CERHR.monographs.are.trans- of.this.evaluation.on.methylphenidate.are.pub- mitted. to. federal. and. state. agencies,. interest- lished. in. an. NTP-CERHR. monograph. which. ed.parties,.and.the.public.and.are.available.in. includes:.1).the.NTP.Brief,.2).the.Expert.Panel. electronic.PDF.format.on.the.CERHR.web.site. Report.on.the.Reproductive.and.Developmen- <http://cerhr.niehs.nih.gov>.and.in.printed.text. tal.Toxicity.of.Methylphenidate,.and.3).public. or.CD-ROM.from.the.CERHR:. comments.received.on.the.Expert.Panel.Report.. National.Institute.of.. As.stated.in.the.NTP.Brief,.the.NTP.reached. Environmental.Health.Sciences the. following. conclusions. regarding. the. pos- P.O..Box.12233,.MD.EC-32 sible.effects.of.exposure.to.methylphenidate.on. Research.Triangle.Park,.NC.27709 human. development. and. reproduction.. First,. Phone:.919-541-3455 there is negligible concern for methylpheni- Fax:.919-316-4511 date-induced tics and movement disorders. vii INTRODUCTION In.January.2004,.the.CERHR.Core.Committee,. toxicities.of.these.drugs..The.CERHR.Amphet- an.advisory.group.composed.of.representatives. amines.and.Methylphenidate.Expert.Panel.com- from. NTP. member. agencies,. recommended. pleted.its.evaluation.at.a.public.meeting.held.on. amphetamines.and.methylphenidate.for.expert. January.10–12,.2005.in.Alexandria,.VA. panel.review..Methylphenidate.(CAS.RN.113- . 45-1). is. a. central. nervous. system. stimulant. This. monograph. includes. the. NTP. brief. on. used.to.treat.attention.deficit.hyperactivity.dis- methylphenidate,.a.list.of.the.expert.panel.mem- order. and. narcolepsy. in. children. and. adults. bers.(Appendix.I),.the.expert.panel.report.on. and. is. used. off-label. to. treat. depression. and. methylphenidate.(Appendix.II),.and.all.public. patients.with.post-stroke.cognitive.impairment.. comments.received.on.the.expert.panel.report. d,l-Methylphenidate. hydrochloride. (CAS. RN. (Appendix.III)..The.NTP-CERHR.monograph. 298-59-9).is.marketed.under.the.names.of.Rit- is.intended.to.serve.as.a.single,.collective.source.
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