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Key value for chemical safety assessment

Effects on fertility

Additional information

Measurement of fluoride ion production over a range of pH values (1.2 to 9) indicated a hydrolytic half-life time of less than 30 minutes for boron trifluoride. Subsequent analysis of boric acid by titration confirmed the rapidity of the reaction. Consequently, when no data is available, the risk associated to dehydrated boron trifluoride when release into water can be assessed based upon the hazards of its breakdown products in water: boric acid and fluoboric acid.

With regards to boric acid,the preliminary study showed that at each of pH 1.2, 4, 7 and 9 and 50±0.5ºC, less than 10% hydrolysis had occurred after 5 days, equivalent to a half-life of greater than 1 year under environmental conditions (25°C). ThusBoric acid was determined to be hydrolytically stable under acidic, neutral and basic conditions.

With regards to tetrafluoroborate, it is apparent thattetrafluoroborate hydrolyses under environmental conditions, forming boric acid and, predominantly, partially hydrolysed fluoroborate species (i.efluorine and hydronium ions). HF is not expected at significant amounts as it occurs in the systemic circulation only as free ionic or as organically bound fluoride.

In conclusion boric acid is the predominant and most stable breakdown product of boron trifluoride

 

H3BO3

Boric acid is classified R60 and R61, a CMR category 2 according to the directive 67/548/EEC. Indeed several repeated oral exposures of mice, rats and dogs to borates have shown evidence of damage to the testes and repeated oral exposure of pregnant mice, rats and rabbits to borates have shown developmental toxicity. The key studies used in European risk assessment (2007) and for the classification of this substance are as follows:

 

-         Weir RJ Jr, Fisher RS.; Toxicologic studies on borax and boric acid; Toxicol Appl Pharmacol. 1972 Nov;23(3):351-64.

The no-effect-level (NOAEL) in this study is 17 mg Boron/kg bw/day (equivalent to 97 mg/kg bw/day boric acid), based on effects observed in the rat testes during a 3 generation dietary study.

-         Price CJ, Strong PL, Marr MC, Myers CB, Murray FJ.; Developmental toxicity NOAELand postnatal recovery in rats fed boric acid during gestation.; Fundam Appl Toxicol. 1996 Aug;32(2):179-93.

In this study, the NOAEL for developmental effects (reduction in foetal body weight and skeletal malformations) is 9.6 mg Boron/kg bw/day (equivalent to 55 mg/kg bw/day boric acid) in pregnant rats exposed to boric acid from days 0 to 20 of the gestation period.

 

Therefore, the reprotoxicity potential of BF3 has to be considered. Nevertheless, as the substance is very toxic by inhalation (classified R 26) it seems reasonable to consider that the parental toxicity - especially severe respiratory irritation tract - would occur at dose levels well below a predictable reprotoxicity (see below).

 

Extrapolation of the BF3 NOAEC for reproductive effects

 

In order to compare the dose-levels of BF3 that would lead to possible reproductive effects and those leading to severe respiratory tract irritation (studies in rats), boric acid NOAELs were converted into theoretical inhalation NOAECs of BF3:

 

One mole of BF3 is assumed to be transformed into one mole of H3BO3.

Following molecular weights (MW) were used:

MW for Boron: 10.81 g/mol

MW for Fluorine: 19 g/mol

MW for Hydrogen: 1g/mol

MW Oxygen: 16 g/mol

 

One mole of BF3(67.81 g) <-- > one mole of H3BO3(61.51 g)

Then:

97 mg/kg bw/day boric acid <-- > 106.9 mg/kg bw/day BF3

55 mg/kg bw/day boric acid <-- > 60 mg/kg bw/day BF3

 

Considering that NOAELrat x ABSoral/rat = NOAECrat x ABSinh/rat x sRVrat

(SRVrat is the standard respiratory volume for 6 hours duration), then:

NOAEC = (NOAELrat x ABSoral/rat)/ (ABSinh/rat x sRVrat)

 

No data is available for ABSoral/rat and ABS inh/rat; therefore a worst case was used, as proposed in ECHA’s R8 guidance document: ABSoral/rat is 50 % and ABS inh/rat is 100%. SRVrat is 0.29 m3/kg bw

Therefore:

-          virtually BF3NOAEC for effects on fertility = (97 x 50)/(100 x 0.29) = 167.2 mg/m3

-         virtually BF3NOAEC for effects on development = (55 x 50)/(100 x 0.29) = 94.8 mg/m3

 

These concentrations are near those at which mortality or severe respiratory distress were observed in repeated inhalation exposure for 2 weeks (Rusch et al., 1986). In this study, rats exposed to 180 mg/m3of BF3were all dead prior to the sixth exposure. At 66 mg/m3, no mortality occurred but respiratory distress, reduction of mean body weights and increase of lung weights were observed, without any histopathological changes, including no changes in testis.

 

Moreover it should be noted that

- worst case assumption has been made in order to obtain virtually NOAEC for fertility and development, since ABSoral/rat was chosen as twice more than ABSinh/rat.

- the prenatal study with boric acid was done via gavage. This leads to a much higher peak concentration of boric acid in plasma and foetus than after inhalation over 6 hrs.

- BF3,H2O did not show any signs on reproductive organs in the 90-days toxicity study (Rusch, 1986 – equivalent to OECD 413), for levels of 17 mg/m3(highest tested concentration)

 

In conclusion, with BF3exposure, severe parental toxicity would be observed well before effects on fertility and on development. For this reason, any reproductive study with BF3is scientifically unjustified.

 

 

References:

 

ATSDR Toxicological Profile for Fluorides, Hydrogen Fluoride and Fluorine, September 2003

 

Documentations for classification of boric acid:

http://ecb.jrc.ec.europa.eu/documentation/then Classification and labelling/Background documentation to boron

 

Price CJ, Strong PL, Marr MC, Myers CB, Murray FJ.;Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation.; Fundam Appl Toxicol. 1996 Aug;32(2):179-93.

 

Weir RJ Jr,Fisher RS.; Toxicologic studies on borax and boric acid;Toxicol Appl Pharmacol.1972 Nov;23(3):351-64.

 

G.M.Rusch et al., Inhalation toxicity studies with Boron Trifluoride. Toxicol. Apppl. Pharmacol., 83 (1), 69-78, 1986.

 

European Union Risk Assessment Report on Boric Acid (2007)

European Union Risk Assessment Report on HF (2001)

 


Short description of key information:
No experimental study is available. Nevertheless, severe parental toxicity would be observed after exposure to BF3, well before effects on fertility induced by hydrolysis product in human body, boric acid. For this reason, any reproductive study with BF3 is scientifically unjustified.

Effects on developmental toxicity

Description of key information
No experimental study is available. Nevertheless, severe parental toxicity would be observed after exposure to BF3, well before developmental effects induced by hydrolysis product in human body, boric acid. For this reason, any reproductive study with BF3 is scientifically unjustified.
Additional information

See the discussion above in the § fertility.

Justification for classification or non-classification

According to EU directive 67/548/EEC and EU Regulation (EC) N0. 1272/2008 (CLP), the substance is not classified for reproductive effects.

Additional information