Justification of classification of boron compounds in European - PowerPoint PPT Presentation

Justification of classification of boron compounds in European Union Boguslaw Baranski, Beata Peczkowska Bureau for Chemical Substances 30/34 Dowborczyków Street 90-019 Lódz, Poland

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

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.

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.

Intake of boron by humans Typical daily intake via food and drinking water has been estimated • to be 0.038 – 0.046 mg B/kg bw/day, while a "reasonable worst case" estimate came to 0.058 – 0.066, 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

• 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

History of Classification (1) • April 1998- 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

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

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.

Current classification of boron compounds Classification CLP Regulation Directive According to: (EC) No 67/548/EEC 1272/2008 (Table 3.2) Boron compound: (Table 3.1) Boric acid (EC No 233-139-2; CAS No 10043-35-3); Repr. 1B; H360FD Repr. Cat. 2; R60-61 Boric acid, crude natural , containing not more than 85 % of H 3 BO 3 calculated on the dry weight (EC No 234-343-4; CAS No 11113-50-1) Diboron trioxide; Boric oxide (EC No 215-125-8; CAS No 1303-86-2) Repr. 1B; H360FD Repr. Cat. 2; R60-61 Disodium tetraborate, anhydrous; Boric acid, disodium salt Repr. 1B; H360FD Repr. Cat. 2; R60-61 (EC No 215-540-4; CAS No 1330-43-4) Tetraboron disodium heptaoxide, hydrate (EC No 235-541-3; CAS No 12267-73-1) Orthoboric acid, sodium salt (EC No 237-560-2; CAS No 13840-56-7) Repr. 1B; H360FD Repr. Cat. 2; R60-61 Disodium tetraborate decahydrate; Borax decahydrate (EC No 215-540-4; CAS No 1303-96-4) Repr. 1B; H360FD Repr. Cat. 2; R60-61 Disodium tetraborate pentahydrate; Borax pentahydrate (EC No 215-540-4; CAS No 12179-04-3)

Boron substances identified as SVHC – Candidate List Date of Reason for SVHC inclusion inclusion Diboron trioxide EC No 215-125-8 CAS No 1303-86-2 Tetraboron disodium heptaoxide, hydrate EC No 235-541-3 Toxic for CAS No 12267-73-1 reproduction 18-06-2012 Boric acid Cat. 1B EC No 233-139-2, 234-343-4 (Article 57 c) CAS No 10043-35-3, 11113-50-1 Disodium tetraborate EC No 215-540-4 CAS No 1303-96-4, 1330-43-4, 12179-04-3

Acute tox – oral, animals Species,Strain, Guidline LD50 result Reference no/group [mg/kg bw] Boric Acid Rat: Sprague No specific LD 50 (m, f)= 3765 mg /kg unclassified Keller, 1962 Dawley guidelines were bw Weir & Fisher, 1972; 5/group available at the ( 659 mg B/kg ) Pfeiffer et al., 1945 time of this study. Disodium Tetraborate Anhydrous Rat: Crl:CD.BR OECD 401 > 2500 mg unclassified Denton. (1996). 5/group ( 538 mg B)/kg bw males Disodium Tetraborate Pentahydrate Rat: Sprague US EPA-FIFRA 3305 (2403 - 4207) unclassified Reagan and Becci Dawley mg/kg ( 489 mg B/kg ) (1985a) 5/group Disodium Tetraborate Decahydrate Rat: Sprague Unknown 5560 (5150 - 6000) unclassified Meyding and Dawley mg/kg Foglhian (1961), 5/group ( 628 mg B/kg ) Criteria: DSD 200 < LD 50 = 2000 Harmful Xn, R 22 CLP 300 < LD 50 = 2000 Acute Tox. 4, H302

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

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.

Repeated dose toxicity: oral Studies in Animals (1) Boric Acid • 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

Repeated dose toxicity: oral Studies in Animals (2) Boric Acid • 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

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.

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