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 pKa 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.

• 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

Intake of boron by humans

• 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 According to: Boron compound: CLP Regulation (EC) No 1272/2008 (Table 3.1) Directive 67/548/EEC (Table 3.2) Boric acid (EC No 233-139-2; CAS No 10043-35-3); Boric acid, crude natural, containing not more than 85 % of H3BO3 calculated on the dry weight (EC No 234-343-4; CAS No 11113-50-1)

• Repr. 1B; H360FD
• Repr. Cat. 2; R60-61

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

(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)

• Repr. 1B; H360FD
• Repr. Cat. 2; R60-61

Boron substances identified as SVHC – Candidate List SVHC Date of inclusion Reason for inclusion Diboron trioxide

EC No 215-125-8 CAS No 1303-86-2 18-06-2012

Toxic for reproduction

• Cat. 1B

(Article 57 c) Tetraboron disodium heptaoxide, hydrate

EC No 235-541-3 CAS No 12267-73-1

Boric acid

EC No 233-139-2, 234-343-4 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, no/group Guidline LD50 [mg/kg bw] result Reference Boric Acid Rat: Sprague Dawley 5/group No specific guidelines were available at the time of this study. LD50 (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 US EPA-FIFRA 3305 (2403 - 4207) mg/kg (489 mg B/kg) unclassified Reagan and Becci (1985a) Disodium Tetraborate Decahydrate Rat: Sprague Dawley 5/group Unknown 5560 (5150 - 6000) mg/kg (628 mg B/kg) unclassified Meyding and Foglhian (1961), Criteria: DSD 200 < LD50 = 2000 Harmful Xn, R 22 CLP 300 < LD50 = 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)

• 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

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

Boric Acid

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

Toxicity for reproduction

Species Study type or duration NOAEL LOAEL Effect at LOAEL Referen ce

• Reproductive effects - Studies in Animals

Toxicity for reproduction

Effects on fertility- Studies in Animals (1)

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.

Fertility study of Boric Acid in Rats – oral diet

NOAEL Parental NOAEL F1 NOAEL F2 2000 ppm = 100 mg/kg bw boric acid= 17.5 mgB/kg bw for male and female

Toxicity for reproduction

Effects on fertility- Studies in Animals (2)

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 10300 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.

Fertility Study of Borax in Rats – oral diet

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

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).

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.

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

• f fertility effects.

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).

Assessment of these new epidemiological studies by ANSES

• These new studies identified no effect of boric acid
• n 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.

• 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.

Conclusion