«Ascorbic acid Evaluation of the effects on reproduction, recommendation for classification Gezondheidsraad Vo o r z i t t e r Health Council of the ...»
Evaluation of the effects on reproduction, recommendation for classification
Gezondheidsraad Vo o r z i t t e r
Health Council of the Netherlands
Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp : Aanbieding advies Ascorbic acid
Uw kenmerk : DGV/MBO/U-932542
Ons kenmerk : U 5653/HS/pg/543-N11
Datum : 17 december 2009
Geachte minister, Graag bied ik u hierbij het advies aan over de effecten van ascorbinezuur op de vruchtbaarheid en het nageslacht; het betreft ook effecten die optreden na blootstelling via de borstvoeding. Dit advies maakt deel uit van een uitgebreide reeks waarin voor de voortplanting giftige stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad, de Subcommissie Classificatie Reproductietoxische stoffen. Het is vervolgens getoetst door de Beraadsgroep Gezondheid en Omgeving van de raad.
Ik heb dit advies vandaag ook ter kennisname toegezonden aan de minister van Volksgezondheid, Welzijn en Sport en de minister van Volkshuisvesting, Ruimtelijke Ordening en Milieu.
Met vriendelijke groet, prof. dr. J.A. Knottnerus Bezoekadres Postadres Parnassusplein 5 Postbus 16052 2 5 11 V X D e n Haag 2500 BB Den Haag Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4 Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3 E - m a i l : h. s t o u t e n @ g r. n l w w w. g r. n l Ascorbic acid Evaluation of the effects on reproduction, recommendation for classification Subcommittee on the Classification of Reproduction Toxic Substances A Committee of the Health Council of the Netherlands
the Minister of Social Affairs and Employment No. 2009/03OSH, The Hague, December 17, 2009 The Health Council of the Netherlands, established in 1902, is an independent scientific advisory body. Its remit is “to advise the government and Parliament on the current level of knowledge with respect to public health issues and health (services) research...” (Section 22, Health Act).
The Health Council receives most requests for advice from the Ministers of Health, Welfare & Sport, Housing, Spatial Planning & the Environment, Social Affairs & Employment, Agriculture, Nature & Food Quality, and Education, Culture & Science. The Council can publish advisory reports on its own initiative. It usually does this in order to ask attention for developments or trends that are thought to be relevant to government policy.
Most Health Council reports areprepared by multidisciplinary committees of Dutch or, sometimes, foreign experts, appointed in a personal capacity. The reports are available to the public.
The Health Council of the Netherlands is a member of the International Network of Agencies for Health Technology Assessment (INAHTA), an international collaboration of organisations engaged with health technology assessment.
I NA HTA This report can be downloaded from www.healthcouncil.nl.
Health Council of the Netherlands. Ascorbic acid; Evaluation of the effects on reproduction, recommendation for classification. The Hague: Health Council of the Netherlands, 2009; publication no. 2009/03OSH.
all rights reserved ISBN: 978-90-5549-784-3 Contents
1 Scope 9
1.1 Background 9
1.2 Committee and procedure 9
1.3 Additional considerations 10
1.4 Labelling for lactation 11
1.5 Data 11
1.6 Presentation of conclusions 12
1.7 Final remark 12 2 Ascorbic acid 13
2.1 Introduction 13
2.2 Human studies 15
2.3 Animal studies 16
2.4 Conclusion 21
A The committee 29 B Directive (93/21/EEC) of the European Community 31 C Experimental animal fertility and developmental toxicity studies 37 6 Ascorbic acid Samenvatting Op verzoek van de minister van Sociale Zaken en Werkgelegenheid beoordeelt de Gezondsheidsraad de effecten op de reproductie van stoffen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De Subcommissie Classificatie Reproductietoxische stoffen van de Commissie Gezondheid en Beroepsmatige Blootstelling aan Stoffen (GBBS) van de raad, hierna aangeduid als de commissie, adviseert een classificatie van reproductietoxische stoffen volgens Richtlijn 93/21/EEC van de Europese Unie. Het voorliggende rapport betreft ascorbinezuur.
De aanbevelingen van de commissie zijn:
• voor effecten op de fertiliteit adviseert de commissie om ascorbinezuur niet te classificeren wegens onvoldoende geschikte gegevens.
• voor effecten op de ontwikkeling adviseert de commissie ascorbinezuur niet te classificeren op basis van onvoldoende geschikte humane gegevens en voldoende dierexperimentele gegevens.
• voor effecten tijdens lactatie adviseert de commissie om ascorbinezuur niet te kenmerken wegens onvoldoende geschikte gegevens.
Samenvatting 7 Executive summary At the request of the Minister of Social Affairs and Employment, the Health Council of the Netherlands evaluates the effects on the reproduction of substances at the workplace. The evaluation and subsequent classification, according to the Directive 93/21/EEC of the European Union, are performed by the Subcommittee on the Classification of Reproduction Toxic Substances of the Dutch Expert Committee on Occupational Safety of the Health Council, hereafter called the committee. In the present report, the committee reviewed ascorbic acid.
The committee’s recommendations are:
• for effects on fertility, the committee recommends not classifying ascorbic acid due to a lack of appropriate data.
• for developmental toxicity, the committee recommends not classifying ascorbic acid due to a lack of appropriate human data and due to sufficient animal data.
• for effects during lactation, the committee recommends not labelling ascorbic acid due to a lack of appropriate data.
As a result of the Dutch regulation on registration of compounds toxic to reproduction that came into force on 1 April 1995, the Minister of Social Affairs and Employment requested the Health Council of the Netherlands to classify compounds toxic to reproduction. The classification is performed by the Health Council's Subcommittee on the Classification of Reproduction Toxic Substances, hereafter called the committee, according to the guidelines of the European Union (Directive 93/21/EEC). The committee’s advice on the classification will be applied by the Ministry of Social Affairs and Employment to extend the existing list of compounds classified as toxic to reproduction (class 1, 2 or 3) or labelled as ‘may cause harm to breastfed babies’ (R64).
1.2 Committee and procedure
The present document contains the classification of ascorbic acid by the Health Council’s Subcommittee on the Classification of Reproduction Toxic Substances. The members of the committee are listed in Annex A. The classification is based on the evaluation of published human and animal studies concerning adverse effects with respect to fertility and development and lactation of the abovementioned compound.
In 2009, the President of the Health Council released a draft of the report for public review. No comments were received.
1.3 Additional considerations The classification of compounds toxic to reproduction on the basis of the Directive 93/21/EEC is ultimately dependent on an integrated assessment of the nature of all parental and developmental effects observed, their specificity and adversity, and the dosages at which the various effects occur. The directive necessarily leaves room for interpretation, dependent on the specific data set under consideration. In the process of using the directive, the committee has agreed upon a number of additional considerations.
• If there is sufficient evidence to establish a causal relationship between human exposure to the substance and impaired fertility or subsequent developmental toxic effects in the progeny, the compound will be classified in category 1, irrespective the general toxic effects (see Annex B, 126.96.36.199 category 1).
• Adverse effects in a reproductive or developmental study, in the absence of data on parental toxicity, occurring at dose levels which cause severe toxicity in other studies, need not necessarily lead to a category 2 classification.
• If, after prenatal exposure, small reversible changes in foetal growth and in skeletal development (e.g. wavy ribs, short rib XIII, incomplete ossification) in offspring occur in a higher incidence than in the control group in the
1.4 Labelling for lactation The recommendation for labelling substances for effects during lactation is also based on Directive 93/21/EEC. The Directive defines that substances which are absorbed by women and may interfere with lactation or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, should be labelled with R64. Unlike the classification of substances for fertility and developmental effects, which is based on a hazard identification only (largely independent of the dosage), the labelling for effects during lactation is based on a risk characterisation and therefore also includes consideration of the level of exposure of the breastfed child.
Consequently, a substance should be labelled for effects during lactation when it is likely that the substance would be present in breast milk in potentially toxic levels. The committee considers a concentration of a compound as potentially toxic to the breastfed child when this concentration is above an exposure limit for the general population, e.g., the acceptable daily intake (ADI).
Literature searches were conducted in the on-line databases Current Contents and Medline, starting from 1966 up to 2006 and by searches on the internet. An additional search performed in PubMed in May 2009 did not result in relevant additional information. Literature was selected primarily on the basis of the text of the abstracts. Publications cited in the selected articles, but not selected during * Organisation for Economic Cooperation and Development
1.6 Presentation of conclusions The classification is given with key effects, species, and references specified. In case a substance is not classified as toxic to reproduction, one of two reasons is
• Lack of appropriate data preclude assessment of the compound for reproductive toxicity.
• Sufficient data show that no classification for toxic to reproduction is indicated.
1.7 Final remark
The classification of compounds is based on hazard evaluation (Niesink et al.,1995)1 only, which is one of a series of elements guiding the risk evaluation process. The committee emphasises that for derivation of health-based occupational exposure limits these classifications should be placed in a wider context.
For a comprehensive risk evaluation, hazard evaluation should be combined with dose-response assessment, human risk characterisation, human exposure assessment, and recommendations of other organisations.