SVHC-32 硼酸 Boric Acid publication(R 生殖毒性)

BORIC ACID SVHC SUPPORT DOCUMENT 1 Substance name: Boric acid EC number: 233-139-2 (234-343-4) CAS number: 10043-35-3 (11113-50-1) MEMBER STATE COMMITTEE DRAFT SUPPORT DOCUMENT FOR IDENTIFICATION OF BORIC ACID AS A SUBSTANCE OF VERY HIGH CONCERN BECAUSE OF ITS CMR PROPERTIES Adopted on 9 June 2010 BORIC ACID SVHC SUPPORT DOCUMENT 2 CONTENTS JUSTIFICATION .........................................................................................................................................................5 1 IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES .................................5 1.1 Name and other identifiers of the substance ...................................................................................................5 1.2 Composition of the substance .........................................................................................................................5 1.3 Physico-chemical properties ...........................................................................................................................6 2 MANUFACTURE AND USES..............................................................................................................................8 3 CLASSIFICATION AND LABELLING ...............................................................................................................8 3.1 Classification According to the first ATP to Regulation (EC) No 1272/2008................................................8 3.2 Self classification(s) .......................................................................................................................................8 4 ENVIRONMENTAL FATE PROPERTIES...........................................................................................................9 5 HUMAN HEALTH HAZARD ASSESSMENT.....................................................................................................10 6 HUMAN HEALTH HAZARD ASSESSMENT OF PHYSICO-CHEMICAL PROPERTIES ..............................10 7 ENVIRONMENTAL HAZARD ASSESSMENT ..................................................................................................10 8 PBT, VPVB AND EQUIVALENT LEVEL OF CONCERN ASSESSMENT.......................................................10 9 REFERENCES........................................................................................................................................................11 10 ABBREVIATIONS ................................................................................................................................................13 ANNEX 1 .....................................................................................................................................................................14 Repeated dose toxicity .....................................................................................................................................14 Repeated dose toxicity: oral …………………………………………………………………………………….14 Other relevant information ………………………………………………………………………………………18 Summary and discussion of repeated dose toxicity:……………………………………………………………..18 Toxicity for reproduction ................................................................................................................................ 18 Effects on fertility …………………………………………………………………………………………….…19 Developmental toxicity ………………………………………………………………………………………….23 Human data ………………………………………………………………………………………………………26 Other relevant information ………………………………………………………………………………………26 Summary and discussion of reproductive toxicity……………………………………………………………….26 BORIC ACID SVHC SUPPORT DOCUMENT 3 TABLES Table 1: Summary of physico- chemical properties.................................................................................................6 Table 2: Summary of toxicokinetics of boric acid (taken from ECHA (2008a) with minor modifications) ......14 Table 3: Key repeat dose toxicity studies performed with boric acid (adopted from ECHA, 2008a) .................17 Table 4: Key fertility studies for boric acid (adopted from ECHA (2008)) ...........................................................21 Table 5: key developmental studies with boric acid (adopted from ECHA (2008a))............................................24 BORIC ACID SVHC SUPPORT DOCUMENT 4 Substance Name: Boric acid EC Number: 233-139-2 / 234-343-4 CAS number: 10043-35-3 / 11113-50-1 • Boric acid is identified as a substance meeting the criteria of Article 57 (c) of Regulation (EC) 1907/2006 (REACH) owing to its classification as toxic for reproduction (category 2)1. Summary of how the substance meets the CMR2 (Cat 1 or 2), PBT3 or vPvB4 criteria, or is considered to be a substance of an equivalent level of concern Pursuant to the first ATP to Regulation (EC) No 1272/2008 (Commission Regulation (EC) No 790/20095) as of 1 December 2010, boric acid will be listed in Table 3.2 (the list of harmonised classification and labelling of hazardous substances from Annex I to Directive 67/548/EEC) of Annex VI, part 3, of Regulation (EC) No 1272/20086 as toxic to reproduction category 27, R60-61 (May impair fertility. May cause harm to the unborn child). Therefore, this classification of the substance in Commission Regulation (EC) No 790/2009 shows that the substance meets the criteria for classification as toxic for reproduction in accordance with Article 57 (c) of REACH. Registration number(s) of the substance or of substances containing the substance: 1 Category in accordance with Annex I to Council Directive 67/548/EEC 2 CMR means carcinogenic, mutagenic or toxic for reproduction 3 PBT means persistent, bioaccumulative and toxic 4 vPvB means very persistent and very bioaccumulative 5 Commission Regulation (EC) No 790/2009 of 10 August 2009 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (1st ATP) 6 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. 7 This corresponds to a classification as toxic to reproduction 1B in Annex VI, part 3, Table 3.1 of Regulation (EC) No 1272/2008 (list of harmonised classification and labelling of hazardous substances) as amended by the 1st ATP to (EC) No 1272/2008. BORIC ACID SVHC SUPPORT DOCUMENT 5 JUSTIFICATION 1 IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES 1.1 Name and other identifiers of the substance Chemical Name: Boric acid EC Name: Boric acid CAS Number: 10043-35-3 / 11113-50-1 IUPAC Name: Boric acid 1.2 Composition of the substance Chemical Name: Boric acid EC Number: 233-139-2 / 234-343-4 CAS Number: 10043-35-3 / 11113-50-1 IUPAC Name: Boric acid Molecular Formula: BH3O3 Structural Formula: Molecular Weight: 61.83 g/mol Typical concentration (% w/w): > 99 % w/w Concentration range (% w/w): 95 – 100 % w/w BORIC ACID SVHC SUPPORT DOCUMENT 6 1.3 Physico-chemical properties Table 1: Summary of physico- chemical properties REACH ref Annex, § Property IUCLID section Value [enter comment/reference or delete column] VII, 7.1 Physical state at 20°C and 101.3 kPa 4.1 solid Merck, 1983 VII, 7.2 Melting/freezing point 1) 4.2 No melting point can be defined in the range 25- 1000°C due to the decomposition of the substance. Cordia et al., 2003a VII, 7.3 Boiling point 4.3 not required (due to the decomposition of the substance) VII, 7.5 Vapour pressure 4.6 not required (due to the decomposition of the substance) VII, 7.7 Water solubility 2) 4.8 49.20 ± 0.35 g/l at 20 ± 0.5°C (Cordia, 2003) 47.2 g/l at 20°C (Mellor, 1980) Cordia et al., 2003a Mellor, 1980 VII, 7.8 Partition coefficient n- octanol/water (log value) 3) 4.7 partition coefficient -1.09 ± 0.16 (22± 1°C) Cordia et al., 2003a IX, 7.16 Dissociation constant 4) 4.21 Boric acid is a Lewis acid (hydroxide ion acceptor) rather than a Brønsted acid (proton donator). For this purpose the formula for boric acid is best written as B(OH)3. pKa = 9.0 at 25°C for boric acid in dilute solutions only (B ≤ 0.025 M). At higher boron concentrations, polynuclear complexes are formed and several dissociation/formation constants apply. Ingri, 1963 VII, 7.4 Relative Density 4.4 D423 = 1.489 ± 0.006 Cordia et al., 2003a VII, 7.6 Surface Tension 5) 4.10 not applicable Thermal stability 6) 4.19 Boric acid is stable up to approximately 75°C. Cordia et al., 2003b 1) If heated above 100°C water is lost and boric acid converts initially to metaboric acid (HBO2) and on further heating forms boric oxide (B2O3). 2) The difference between the determined water solubility (Cordia et al., 2003a) and the literature value (Mellor, 1980) could be explained by the fact that the two protocol methods used in each case were different. BORIC ACID SVHC SUPPORT DOCUMENT 7 3) Although not required as this is an inorganic substance, an end point has been derived in Cordia et al., 2003a. 4) At low boron concentrations (B ≤ 0.025 M) the following equilibrium is found B(OH)3 + 2H2O ↔ [B(OH)4]- + H3O+ pKa = 9.0 at 25 °C Although at these concentrations, boric acid exists as undissociated boric acid B(OH)3 at pH < 5, whereas at pH > 12.5 the metaborate ion -[B(OH)4]- - becomes the main species in solution. Both species are present at pH 5-12.5 at concentrations B ≤ 0.025 M. At higher boron concentrations (B > 0.025 M) an equilibrium is formed between B(OH)3, polynuclear complexes of B3O3(OH)4-, B4O5(OH)42-, B3O3(OH)52-, B5O6(OH)4- and B(OH)4-. In short: B(OH)3 ↔ polynuclear anions ↔ B(OH)4-. Again, at pH<5, boron is mainly present at B(OH)3 and in alkaline solution at pH>12.5, boron is mainly present as B(OH)4-. At in between values (pH 5-12) polynuclear anions are found as well as B(OH)3 and B(OH)4-. The dissociation constant depends upon temperature, ionic strength and presence of group I metal ions (Na, K, Cs). In the presence of metal ions (e.g. Na, Mg, Ca) ionpair complexes are formed, which further reduce the undissociated boric acid concentration: Mn+ + B(OH)4- ↔ MB(OH)4(n-1)+ These ion pair complexes are expected to be present in solutions of disodium tetraborate, disodium octaborate and buffered solutions of boric acid and boric oxide. 5) Surface tension is not expected for inorganic substances. 6) It dehydrates on further heating to form metaboric acid and then boric oxide: B(OH)3→ HBO2+ H2O (Temperature range 120 to 180°C) HBO2→ 0.5 B2O3+ H2O (Temperature range 180 to ~400°C). Boric oxide and metaboric acid will convert to boric acid on contact with water or on exposure to moist air. Rapid heating to ~250°C may cause boric acid to form a highly viscous liquid whose composition lies between HBO2and B2O3. Under these conditions, a small quantity of boric acid can evaporate with the evolved water vapour. This will be visible as white fumes of condensed boric acid as the gas cools. BORIC ACID SVHC SUPPORT DOCUMENT 8 2 MANUFACTURE AND USES Not relevant for this type of dossier. 3 CLASSIFICATION AND LABELLING 3.1 Classification According to the first ATP to Regulation (EC) No 1272/2008 Pursuant to the first ATP to Regulation (EC) No 1272/2008 (Commission Regulation (EC) No 790/2009) as of 1 December 2010, boric acid will be listed in Table 3.1 (list of harmonised classification and labelling of hazardous substances) of Annex VI, part 3, of Regulation (EC) No 1272/20088 as follows: Index Number: 005-007-00-2 Repr. 1B H360FD (May damage fertility. May damage the unborn child.) Specific Concentration limits: Repr. 1B; H360FD: C ≥ 5.5 % According to the first ATP to Regulation (EC) No 1272/2008, the corresponding classification in Annex VI, part 3, Table 3.2 of this Regulation (EC) No 1272/2008 (list of harmonised classification and labelling of hazardous substances from Annex I to Directive 67/548/EEC) will be as follows: Index Number: 005-007-00-2 Repr. Cat. 2; R60-61 (May impair fertility. May cause harm to the unborn child) Specific Concentration limits: Repr. Cat. 2; R60-61: C ≥ 5.5 % 3.2 Self classification(s) None 8 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. BORIC ACID SVHC SUPPORT DOCUMENT 9 4 ENVIRONMENTAL FATE PROPERTIES Since this is a dossier targeted to the identification of Boric acid as a CMR substance, environmental fate properties have not been considered. BORIC ACID SVHC SUPPORT DOCUMENT 10 5 HUMAN HEALTH HAZARD ASSESSMENT Information on hazard to human health relevant for the assessment as to whether boric acid meets criteria of Article 57 of the REACH-Regulation is provided in section 3 of this report (classification information). Supplementary information on the toxicological properties of boric acid, which could be relevant for risk assessment, comparative assessment of alternative substances, or for priority setting in the context of recommending substances for the ‘Authorisation List’ (Annex XIV of the REACH Regulation) can be found in Annex 1 to this report. 6 HUMAN HEALTH HAZARD ASSESSMENT OF PHYSICO-CHEMICAL PROPERTIES Not relevant for this type of dossier. 7 ENVIRONMENTAL HAZARD ASSESSMENT Not relevant for this type of dossier 8 PBT, VPVB AND EQUIVALENT LEVEL OF CONCERN ASSESSMENT Not relevant for this type of dossier. BORIC ACID SVHC SUPPORT DOCUMENT 11 9 REFERENCES Aleman CL, Mas RM, Rodeiro I, Noa M, Hernandez C, Menendez R and Gamez R, 1998, Reference database of the main physiological parameters in Sprague-Dawley rats from 6 to 32 months. Laboratory Animals 32: 457-466. Commission Directive 2002/72/EC of 6 August 2002 relating to plastic materials and articles intended to come into contact with foodstuffs (OJ L 220/58, 15/8/2002, p.18) Commission Regulation (EC) No 790/2009 of 10 August 2009 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (OJ L 235/1, 5/9/2009) Council Directive 76/768/EEC of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products (OJ L262, 27/9/1976, p169) Cordia JA, Bal EA, Mak WA and Wils ERJ, 2003a, Determination of some physico-chemical properties of Optibor EP. Rijswijk, The Netherlands: TNO Prins Maurits Laboratory, report PML 2002-C42rr, GLP, Unpublished, confidential data provided by Borax Europe Limited. Cordia JA, Bal EA, Mak WA and Wils ERJ, 2003b, Determination of some physico-chemical properties of Neobor. Rijswijk, The Netherlands: TNO Prins Maurits Laboratory, report PML 2002-C41rr to C43rr, GLP, Unpublished, confidential data provided by Borax Europe Limited. Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing of biocidal products on the market (OJ L123/1, 24/4/1998, p.1) European Chemicals Agency (ECHA) 2008a: Annex XV transitional reports. Boric acid http://echa.europa.eu/doc/trd_substances/boric_acid/ann_xv_trd/trd_austria_boric_acid.pdf Fail PA, George JD, Sauls HR, Dennis SW, Seely JC, 1989, Effects of boric acid on reproduction and fertility of rodents Adv Contracept Delivery Syst. 1989; 5: 186-96 Fail PA, George JD, Seely JC, Grizzle TB and Heindel JJ, 1991, Reproductive toxicity of boric acid in Swiss (CD-1) mice: assessment using the continuous breeding protocol. Fund. Appl. Toxicol. 17: 225- 239. Grella P, Tambuscio B and Suma V, 1976, Boric acid and poisoning during pregnancy: Description of one case. Acta Anaestesiol. Ital. 27: 745-748 (in Italian). Heindel JJ, Price CJ, Field EA, Marr MC Myers CB, Morrissey RE and Schwetz BA, 1992, Developmental toxicity of boric acid in mice and rats. Fund. Appl. Toxicol. 18: 266-272. Ingri N, 1963, Equilibrium studies of polyanions containing BIII, SiIV, GeIV and VV. Sven. Kem. Tidskr. 75(4): 199-230. Ku WW, Chapin RE, Wine RN and Gladen BC, 1993, Testicular toxicity of boric acid (BA): Relationship of dose to lesion development and recovery in the F344 rat. Reprod. Toxicol. 7: 305-319. Matsuzawa T, Nakata M, Goto I, and Tsushima M, 1981, Dietary deprivation induces fetal loss and abortion in rabbits, Toxicology, 22, 255-259 Mellor's Comprehensive Treatise on Inorganic & Theoretical Chemistry, Volume V Boron, Part A: Boron-Oxygen Compounds, 1980, Longman London and New York, ISBN 0-582-46277-0 Merck Index, 10th edition, Windholz, M. (ed.), 1983, Rahway N.J. USA BORIC ACID SVHC SUPPORT DOCUMENT 12 Moore JA and an Expert Scientific Committee, 1997, An assessment of boric acid and borax using the IEHR evaluative process for assessing human developmental and reproductive toxicity of agents. Repro. Toxicol. 11: 123-160 and NTIS Technical Report PB96-156005, March, 1995. NTP (National Toxicology Program), 1987, Toxicology and carcinogenesis studies of boric acid (CAS No. 10043-35-3) in B6C3F1 mice. National Toxicology Program, US Department of Health and Human Services, National Institute of Health (Technical Report Series No. 324). NTP (National Toxicology Program), 1990, Final report on the Reproductive Toxicity of Boric Acid (CAS NO. 10043-35-3) in CD-1 Swiss Mice. National Toxicology Program, NTP Report # 90-150 Parker JA, Macgregor JA and Schroeder RE, 1986, Diet restriction during gestation in NZW rabbits does not adversely affect fetal outcome, Teratology, 33, 71C Price CJ, Strong PL, Marr MC, Myers CB and Murray FJ, 1996a, Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation. Fund. Appl. Toxicol. 32: 179- 193. Price CJ, Marr MC, Myers CB, Seely JC, Heindel JJ and Schwetz BA, 1996b, The Developmental Toxicity of Boric Acid in Rabbits, Fund. Appl. Toxicol. 34: 176-187. Robbins, WA, Wei, F, Elashoff, DA, Wu, G, Xun, L, and Jia, J (2008), Y:X sperm ratio in boron- exposed men. J. Androl 29