Justification of classification of boron compounds in European Union

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1 Justification of classification of boron compounds in European Union Boguslaw Baranski, Beata Peczkowska Bureau for Chemical Substances 30/34 Dowborczyków Street Lódz, Poland

2 Boric acid and borates Boric acid Boric oxide Disodium octaborate tetrahydrate Disodium tetraborate

3 Toxicokinetics Boric acid is a weak acid with a pk a of 9.2 and exists primarily as the undissociated acid (H3BO3) in aqueous solution at physiological ph, as do the borate salts. Therefore, the toxicity associated with these compounds is expected to be similar based on boron equivalents. Boron oxide will also produce similar effects because it is an anhydride that reacts exothermically with water in the body to form boric acid. Sodium octaborate tetrahydrate is converted into boric acid//borate upon dissolution in water.

4 Toxicokinetics Boron is readily absorbed following oral exposure in both humans and animals (>90%). Estimated human skin absorption is less than 0.3%, but may be higher in damaged skin. Absorption by inhalation assumed to be 100% Boric acid and borate compounds in the body exist primarily as undissociated boric acid, which distributes evenly throughout the soft tissues of the body, but shows some accumulation in bone. More than 90% of an orally administered dose of boron as boric acid is excreted in a short time in both humans and in animals.

5 Intake of boron by humans Typical daily intake via food and drinking water has been estimated to be mg B/kg bw/day, while a "reasonable worst case" estimate came to , mgb/kg bw/d (Austria 2009). Total daily systemic exposure dose (SED) of boron from cosmetic products is estimated to be 1.23 mg per day corresponding to 0.02 mg B/kg bw/day. NOAEL = 9.6 mg B/kg bw/day (developmental effects in rats) Taking into account these possible additional exposures still a sufficient Margin of Safety (> 100) is obtained for the total dose of boron from cosmetics, food and water Source: Opinion of Scientific Committee on Consumer Safety for Directorate General for Health and Consumers, 28 September 2010

6 The available data on toxicokinetics do not indicate major differences between laboratory animals and humans. It is not known whether there are significant differences in the toxicodynamics between humans and laboratory animal models and in the absence of such knowledge it must be assumed that the effects seen in animals could occur in humans. On the basis of toxicokinetic and toxicodynamic considerations it is assumed that the animal data are relevant to humans. Source: Opinion of Scientific Committee on Consumer Safety for Directorate General for Health and Consumers, 28 September 2010

7 History of Classification (1) April January 1999 Sodium Borates and Boric Acid were included in the agenda of EU as for classification Netharlands in April, Denmark in December 1998 and France in January 1999 submitted proposals far classification of sodium borates and boric acid May 2001 Sodium borates and boric acid have been recommended to classified as toxic to reproduction; Category 3 and included in the 29th ATP list 2003 The Risk Assessment studies have been Initiated by Austria April 2004 Removal of sodium borates and boric acid from the proposal of the 29th ATP of the Council Directive 67/548/EEC

8 History of Classification (2) May 2004 DG Environment initiated and Specialised Expert (SE) Group to evaluate whether the available data merit classification of borates or not October 2004 SE recommended sodium borates and boric acid to be classified as Reprotox. Category 2 (R60-61) and sodium perborates as Reprotox. Category 3 (R62) April 2005 Turkey EU technical meeting in Brussels on the Commission s intention to classify boric acid and sodium borates as toxic for reproduction under directive 67/548//EEC August 2005 Sodium borates and boric acid classification have been included in the 30th ATP list of directive 67/548//EEC in Commission Directive 2008/58/EC on 21 August 2008

9 History of Classification (3) June 2010 Scientific Committee on Consumer Safety provides to EC Directorate-General for Health and Safety an opinion on safety of boron compounds taking into account scientific data on which classification has been based May 2012 French Agency for Food, Environmental and Occupational Health & Safety issues an opinion on assessing the need for a revision of classification of boric acid on request of French Directorate General for Labour based on proposal submitted by the European Borates Association in accordance with article 37(6) of the CLP Regulation.

10 Current classification of boron compounds Boron compound: Boric acid (EC No ; CAS No ); Classification According to: Boric acid, crude natural, containing not more than 85 % of H 3 BO 3 calculated on the dry weight (EC No ; CAS No ) CLP Regulation (EC) No 1272/2008 (Table 3.1) Directive 67/548/EEC (Table 3.2) Repr. 1B; H360FD Repr. Cat. 2; R60-61 Diboron trioxide; Boric oxide (EC No ; CAS No ) Repr. 1B; H360FD Repr. Cat. 2; R60-61 Disodium tetraborate, anhydrous; Boric acid, disodium salt (EC No ; CAS No ) Tetraboron disodium heptaoxide, hydrate (EC No ; CAS No ) Orthoboric acid, sodium salt (EC No ; CAS No ) Disodium tetraborate decahydrate; Borax decahydrate (EC No ; CAS No ) Disodium tetraborate pentahydrate; Borax pentahydrate (EC No ; CAS No ) Repr. 1B; H360FD Repr. Cat. 2; R60-61 Repr. 1B; H360FD Repr. Cat. 2; R60-61 Repr. 1B; H360FD Repr. Cat. 2; R60-61

11 Boron substances identified as SVHC Candidate List SVHC Diboron trioxide EC No CAS No Tetraboron disodium heptaoxide, hydrate EC No CAS No Boric acid EC No , CAS No , Disodium tetraborate EC No CAS No , , Date of inclusion Reason for inclusion Toxic for reproduction Cat. 1B (Article 57 c)

12 Species,Strain, no/group Guidline Acute tox oral, animals LD50 [mg/kg bw] result Reference Boric Acid Rat: Sprague Dawley 5/group No specific guidelines were available at the time of this study. LD 50 (m, f)= 3765 mg /kg bw (659 mg B/kg) unclassified Keller, 1962 Weir & Fisher, 1972; Pfeiffer et al., 1945 Disodium Tetraborate Anhydrous Rat: Crl:CD.BR 5/group OECD 401 > 2500 mg (538 mg B)/kg bw males unclassified Denton. (1996). Disodium Tetraborate Pentahydrate Rat: Sprague Dawley 5/group Disodium Tetraborate Decahydrate Rat: Sprague Dawley 5/group US EPA-FIFRA 3305 ( ) mg/kg (489 mg B/kg) Unknown 5560 ( ) mg/kg (628 mg B/kg) unclassified Reagan and Becci (1985a) unclassified Meyding and Foglhian (1961), Criteria: DSD 200 < LD 50 = 2000 Harmful Xn, R 22 CLP 300 < LD 50 = 2000 Acute Tox. 4, H302

13 Acute tox oral, humans Acute human adult quantitative dose response data range from 1.4 to 70 mg B/kg bw. In cases where ingestion was less than 3.7 mg B/kg bw, subjects were asymptomatic. Scientific Committee on Consumer Safety for Directorate General for Health and Consumers, 28 September 2010

14 Skin/eye irritation and sensitisation Boric acid is not irritant to the skin. Some borates are mild eye irritants. Boric acid, disodium tetraborate anhydrous, disodium tetraborate pentahydrate and disodium tetraborate decahydrate are neither skin nor respiratory sensitisers.

15 Boric Acid Repeated dose toxicity: oral Studies in Animals (1) Reference National Toxicology Program (NTP)Technical Report Series No. 324, 1987 duration of study 13 weeks for control and top dose group, 16 weeks for other dose groups Species/Strain Mouse, B6C3F1 10/sex/Group Results At > 142 mg B/kg bw/day: degeneration and atrophy of the seminiferous tubules was observed. At all dose levels extra medullary haematopoiesis of the spleen LO(A)EL > 142mg B/kg bw/day in males 196 mg B/kg bw/day in females NO(A)EL 71 mg B/kg bw/day in males 98 mg B/kg bw/day in females

16 Boric Acid Repeated dose toxicity: oral Studies in Animals (2) Reference Weir, 1962 duration of study 90 days Species/Strain Rat/ Sprague Dawley Treatment: 10/sex/group Results At > 88 mg B/kg bw/day: Reduction bodyweight; clinical signs of toxicity; testicular atrophy At 26 mg B/kg bw/day on male exhibited partial testicular atrophy LO(A)EL 26 mg B/kg bw/day NO(A)EL 8.8 mg B/kg bw/day

17 Repeated dose toxicity In the key 2-year rat feeding study (Weir, 1966) haematological effects and testicular atrophy was observed at the highest doses tested (58.5 mg B/kg bw/day) of both boric acid and disodium tetraborate decahydrate. The NOAEL for the effects of boron was 17.5 mg B/kg bw/day.

18 Mutagenicity/genotoxicity All available in vitro data indicate no mutagenic activity. In addition the only in vivo study on boric acid also indicated no mutagenic activity. Carcinogenicity The studies available in animals were inadequate to ascertain whether boron has the potential to cause cancer. Scientific Committee on Consumer Safety for Directorate General for Health and Consumers, 28 September 2010

19 Species Study type or duration Toxicity for reproduction Reproductive effects - Studies in Animals NOAEL LOAEL Effect at LOAEL Referen ce, 3-, 8 16 / 17.5 / / 58.5 / / ( ), 1966,, 2, 70//, 35// 17.5 / / 58.5 / / ;, 1966,, -1, 40, / / (0) /, 25% (1) (2)., 1991 (, 1990)

20 Toxicity for reproduction Effects on fertility- Studies in Animals (1) Fertility study of Boric Acid in Rats oral diet Reference Weir RJ (1966d) Test type method guideline Predates OECD 3generation 2litter per generation study Species/Strain Rat/Crl:CD Sprague Dawley 8 males 16 females/group Exposure period 14 weeks pretreatment then through three generations Doses 0, 670, 2000 or 6700 ppm boric acid (0, 117, 350 and 1,170 ppm boron) in the diet, equivalent to 0, 34 (5.9), 100 (17.5) and 336 (58.5) mg boric acid (mg B)/kg bw Critical effect Top dose level caused testes atrophy prior to first mating so no litters produced. Infertility in males and females of the high dose when mated with untreated animals. No adverse effects in mid and low dose groups in any generation. NOAEL Parental NOAEL F1 NOAEL F ppm = 100 mg/kg bw boric acid= 17.5 mgb/kg bw for male and female

21 Toxicity for reproduction Effects on fertility- Studies in Animals (2) Fertility Study of Borax in Rats oral diet Reference Weir RJ (1966c) Test type method guideline Predates OECD 3generation 2litter per generation study Species/Strain Rat/Crl:CD Sprague Dawley 8 males 16 females/group Exposure period 14 weeks pretreatment then through three generations Doses 0, 1030, 3080 or ppm borax (0, 117, 350 and 1,170 ppm boron) in the diet, equivalent to 0, 50 (5.9), 155 (17.5) and 518 (58.5) mg borax (mg B)/kg bw respectively Critical effect Top dose level caused testes atrophy prior to first mating so no litters produced. Infertility in males and females of the high dose when mated with untreated animals. No adverse effects in mid and low dose groups in any generation. NOAEL Parental NOAEL F1 NOAEL F2 350 ppm boron in the diet, equivalent to 155 (17.5) mg borax (mg B)/kg bw for male and female

22 Developmental toxicity Exposure to boric acid during pregnancy results in decreased fetal body weight, and fetal cardiovascular and rib malformations in the rat, mouse and rabbit. The rat appears the most sensitive species for developmental toxicity, since the developmental effects were observed at a dose which did not induce any significant maternal toxicity. A NOAEL for pre-natal effects in all three species has been established at 55 mg boric acid/kg bw/day (9.6 mg B/kg bw/day).

23 Studies on humans Several epidemiological studies on fertility effects of borates have been carried out in workers and populations living in areas with high environmental levels of boron.

24 Studies on humans The studies of Truhaut et al., 1964, Tarasenko,1972, Krasovskii et al., 1976, Whorton, 1994, Tuccar, 1998 and Sayli, 1998, 2001, 2003 were available at the time the Commission Working Group of Specialized Experts in the field of Reprotoxicity (Ispra, October 5-6, 2004) was held. The experts came to the conclusion that the epidemiological studies available at that time were of insufficient quality to demonstrate presence or absence of fertility effects.

25 Studies on humans Recently ANSES (France) has reviewed on request of European Borate Association Three studies that investigated reproductive performance and sperm quality in groups of workers in China (Chang 2006, Robbins 2008, Robbins 2010). Five references exploring fertility and sperm quality in groups of workers in Turkey (Sayli 2003, Sayli 2004, Duydu 2011a; Duydu 2011b, Duydu 2011c).

26 Assessment of these new epidemiological studies by ANSES These new studies identified no effect of boric acid on sperm quality or hormone concentrations. However, a potential accumulation of boron in human sperm was identified. Methodological shortcomings and especially the small number of subjects studied have limited the validity of these studies.

27 Conclusion The epidemiological studies in humans are insufficient to demonstrate the absence of an adverse effect on fertility. The available studies do not have a sufficient sample size, do not demonstrate sufficient sensitivity to account for confounders, do not study all the relevant effects and do not provide adequate information about exposures. The relevance for humans of the existing animal data is therefore not put in doubt based on the available human data.

SCIENTIFIC COMMITTEE ON CONSUMER SAFETY

SCIENTIFIC COMMITTEE ON CONSUMER SAFETY Updated, revised request for a scientific opinion following the new classification of some boron compounds as mutagenic and/or toxic to reproduction according to