Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 410 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
BMDL05
DNEL value:
10.3 mg/kg bw/day
Modified dose descriptor starting point:
other: BMDL05 X 8.7 (Actual percent w/w of boric acid available in the substance after hydolysis)
Explanation for the modification of the dose descriptor starting point:

 

Worker-DNELlong-term, dermal, systemic

For risk assessment of borates a dermal absorption of 0.5 % is used as a worst case approach.Dermal absorption is not regarded relevant for the general population, however, it is considered for workers.A Worker-DNELlong-term, dermal, systemicis derived from the oral BMDL0510.3 mg B/kg bw/day. The assessment factors applied are for interspecies variability (5) and intraspecies variability (6). A DNEL of 0.34 mg B/kg bw/day was obtained for workers. A body weight for workers of 70 kg was assumed.

 

Worker-DNELlong-term, dermal, systemic  = (10.3 mg B/kg bw/day)/ (6 x 5)= 0.34 mg B/kg bw/day or1.96 mg boric acid.

The value has been multiplied by a factor of 8.7 based on Boron content as Boric Acid equal to 11,5% w/w in the substance after hydrolysis.

 

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 705 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
60
Dose descriptor starting point:
BMDL05
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.52 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
60
Dose descriptor starting point:
BMDL05
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.52 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
60
Dose descriptor starting point:
BMDL05

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General population DNELlong-term, oral, systemic

With regard to developmental effects limited human data exist. The available data from animal studies are sufficient to conclude that prenatal exposure to boron (specifically boric acid and disodium tetraborates) by the oral route can cause developmental toxicity. Developmental effects were seen in three different mammalian species, rat, mouse and rabbit, with the rat being most sensitive. From the most robust study in rats (Price et al., 1996) the lowest NOAEL = 9.6 mg B/kg bw/day can be derived for reduced foetal body weight per litter, increase in wavy ribs and increased incidence in short rib XIII. Other effects seen at maternally toxic doses were visceral malformations like enlarged ventricles and cardiovascular effects.

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 (Truhaut et al., 1964, Tarasenko, 1972, Krasovskii et al., 1976, Whorton, 1994, Tuccar, 1998 and Sayli, 1998, 2001, 2003;Robbins et al. 2010, Scialli et al. 2010).

In general the need for good epidemiological studies on male and female fertility, as well as on developmental toxicity was clearly identified by several national and international panels (BfR, 2005; EFSA, 2004; Commission Working Group, 2004; WHO, 1998; ECETOC, 1995; US EPA, 2004).

Male infertility was observed in breeding studies in rats, mice and deer mice. The underlying cause for male infertility was identified to be testicular atrophy. A series of studies has been published that provide insight as to the mechanistic nature of the lesion in rats. Good correlation between doses inducing spermatogenic arrest and infertility could be derived. The effects were reversible at lower doses, but no recovery was possible at doses at which germ cell loss was observed. Germinal depletion correlated well with increased plasma levels of FSH. Levels of other hormones, like testosterone and LH were not always affected. A NOAEL of 17.5 mg B/kg bw/day in rats (Weir, 1966a, b) could be derived.

Two 3-generation studies in rats with boric acid and disodium tetraborate decahydrate (Weir, 1966c, d) and a continuous breeding study in mice with boric acid (Fail et al., 1991) further substantiate the effects seen in males.

The NOAEL of 9.6 mg/kg body weight per day is based on the critical developmental effect of decreased fetal body weight in rats. Allen et al. (1996) developed a benchmark dose based on the studies of Heindel et al. (1992), Price, Marr & Myers (1994) and Price et al. (1996a). The benchmark dose is defined as the 95% lower bound on the dose corresponding to a 5% decrease in the mean fetal weight (BMDL05) and was used by the United States Environmental Protection Agency in its re-evaluation (USEPA, 2004) and by WHO in its guideline for boron in drinking water (2009). The BMDL05of 10.3 mg/kg body weight per day as boron is close to the Price et al. (1996a) NOAEL of 9.6 mg/kg body weight per day. The uncertainty factor used by WHO was derived following the methodology of Doursen et al. (1998).

 

The most appropriate TK uncertainty factor for intraspecies variability is based on available data in pregnant humans for variation in glomerular filtration rate (GFR) as a surrogate for the clearance and elimination of B. This choice is most appropriate because the pregnant human is the population associated with B's critical effect. Furthermore, B's elimination is the kinetic area with the most variability, absorption and distribution of B are expected to be very similar among humans and B is not metabolized. Based on division of the mean glomerular filtration rate by the glomerular filtration rate at two standard deviations below the mean to address variability for approximately 95 % of the population, the toxicokinetic component of interspecies variation is 1.8 (compared with the default value for this component of 3.2). As there are insufficient data to serve as a basis for replacement of the default value for the toxicodynamic component of the uncertainty factor for intraspecies variation, the total uncertainty factor for intraspecies variation is 1.8 x 3.2 = 5.76 (rounded to 6). Data are inadequate to determine a different uncertainty factor for interspecies variation; therefore, the default value of 10 is used (Doursen et al., 1998), giving a total uncertainty factor of 60. The appropriate uncertainty factor for other areas of uncertainty, and specifically for database uncertainty, is 1-fold.

The uncertainty factor (UF) of 60 used in derivation of the DNEL is more conservative than UFs previously used by several other national and international panels where UFs ranging from 25 to 30 have been used (IEHR 1995, ECETOC 1995, IPCS 1998, NAS FNB 2000; See Appendix E). 

The default factor of 100 (10 x 10) was used under the Biocidal Products Directive in 2009, and a total UF of 150 for the general population in the Transitional Annex XV dossier in 2009. The default UF of 100 was also recently used by the ECHA Committee for Risk Assessment (RAC) in their opinion on new scientific evidence on the use of boric acid and borates in photographic applications by consumers adopted 29 April 2010. However, the default value was used because of insufficient time for an in-depth assessment of the toxicokinetic data. The RAC acknowledged that the 10 x 10 was an overly conservative and that there was good scientific justification to derogate from the default values. Further the RAC recongnized the UF of 60 used by WHO in deriving its Guidelines for Drinking Water Quality (2002 & 2009) for boron, and that EFSA in 2004 also ustilsed a combined UF of 60 (Minutes of the 10thmeeting of the Committee for Risk Assessment, 16-18 march 2010).

More recently an UF of 60 was used bytheScientific Committee on Health and Environmental Risks (SCHER)2010Derogation on the Drinking Water Directive 98/83/ECfor Boron (SCHER 2010), and theScientific Committee on Consumer Safety(SCCS) 2010 opinion onBoron compounds(SCCS 2010).

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) is developing guidance on the use of assessment (AF) when deriving DNELs (ECETOC 2010).When substance-specific data documenting intra-species variability are available, the use of‘informed’ AF, rather than the default AF provided in the ECHA guidance is proposed. Such data can be toxicokinetic or toxicodynamic data, and demonstrate either the absence of variability between humans, or on the contrary indicate that some parts of the population may require additional consideration (e.g. young children, the elderly).

In the absence of substance-specific data, ECETOC guidance is to deviate from the default AF of 10 (general population) and 5 (workers) as recommended by the ECHA R8 and to use default values of 5 and 3, for workers and the general population respectively. These values have been proposed in the ECETOC guidances (2003, 2010).

In the case where allometric scaling is already applied (systemic effects) , it is proposed to use an overall additional factor covering the total (inter- and intra-species) variability, of 5 for the general population and 3 for the workplace. In the case where local effects in the respiratory tract are of concern, the intraspecies factors of 5 and 3 are considered to also provide coverage for toxicodynamic differences. This is relevant since compared to rats; humans seem to be less susceptible to the toxic local effects in the respiratory tract associated with inhalation of inorganic metal compounds (Oberdörster, 1995; Mauderly, 1997; ILSI, 2000; Nikula et al., 2001; Greim and Ziegler-Skylakakis, 2007).

The basis provided by ECETOC for the use of the reduced AFs includes:

  • both the ECHA guidance (R8) and ECETOC recognise that, when substance- or category-specific information is available, there may be scientific justification for deviating from default AFs
  • statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population
  • It is anticipated that a low variability in response would be seen in human populations exposed to boric acid that does not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.
  • if allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. In the case where local effects in the respiratory tract are of concern, the intraspecies factors of 5 and 3 are considered to also provide coverage for toxicodynamic differences

Although the more conservative AF was used in derivation of the DNEL in this CSR a reevaluation of the appropriate AF to use will be conducted upon final publication of the ECETOC guidelines that may result in a reduction of the AFs as outline by ECETOC guidance.

General population-DNELlong-term, oral, systemic= (10.3 mg B/kg bw/day)/ (6 x 10) = 0.17 mg B/kg bw/day or 0.98 mg/kg boric acid

The value has been multiplied by a factor of 8.7 based on Boron content as Boric Acid equal to 11,5% w/w in the substance after hydrolysis.