Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.9 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12.5
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
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:
326 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
BMDL05
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker-DNELacute, inhalation, local

Local effects of borates on the respiratory system have been investigated in animals in four acute inhalation studies (Wnorowski, 1994a, b, 1997) and two Alarie-tests (Krystofiak & Schaper, 1996; Kirkpatrick, 2010). Further, studies in humans were conducted, two small studies (12 probands) under laboratory conditions (Cain et al., 2004, 2008) and three studies on exposed workers (Garabrant et al., 1984, 1985, Wegman et al., 1991). In two studies by Woskie et al. (1994, 1998) the methods used by Wegman et al. (1991) were evaluated and determinants of human susceptibility to the irritant effect of borates were examined.

Borates act as sensory irritants, indicated by the effects observed in humans (i. e. nose, eye and throat irritation; sneezing) and by the results of the Alarie-tests by Kirkpatrick (2010), which demonstrated a depression of the respiratory frequency in mice after exposure to sodium borate. Many of the irritant symptoms (sensory irritation of the nose and throat, cough, phlegm production and broncho-constriction, as evidenced by a decrease in FEV1) are part of the respiratory defense reflex, the function of which is to protect the body from inhaled irritants. This reflex can be triggered by agents that stimulate receptors in the respiratory tract e. g. on the trigeminal nerve (Wegman et al., 1991, Nielsen et al., 2007, Krystofiak & Schaper, 1996; Kirkpatrick, 2010). The actual mechanism, however, has not yet been elucidated.

The relationship between total dust and inhalable dust air sampling results for borates is important in reconstructing measures of past exposures for comparison with current exposures. The samplers designed for the inhalable fraction collect larger dust particles more efficiently than do the total dust samplers so that in dust environments containing large particles the inhalable dust sampler will collect larger proportions of the airborne mass than the total dust sampler. Several studies have demonstrated that the 37-mm total dust sampler equipment under-samples suspended particles by factors ranging from 1.2 to 4.0 compared to the IOM sampler (Culver et al. 1994; Tsai et al. 1995; Werner et al. 1996; Katchen et al. 1998; Teikari et al. 2003). The dust particles associated with borate mining and processing typically have mass median aerodynamic diameters of 10-15 µm (81) and in this environment the IOM sampler collects between 2 and 3 times more mass per unit volume of air than the total dust sampler (Shen et al. 1991; Culver et al. 1994; Katchen et al. 1998). A conversion factor of 2.5 has been suggested for converting “total” personal exposure measures from industries similar to the borate mining and processing facility to equivalent inhalable aerosol exposures (Werner et al. 1996) further supported by paired 37-mm closed face cassette and 25 mm IOM sampling at a borax facility in France (Shen et al. 1991).

A BMDL05of 0.94 mg B/m3can be derived from the study by Wegman et al. (1991) is based on the incidence of any symptom of nose, eye and throat irritation, sneezing, breathlessness and coughing during exposure periods of 15 minutes to disodium tetraborates.A limitation of this study is that the subjects being questioned about irritant responses during their work could see the dust in the air and were able to judge visibly the intensity of their exposure. Much of the dust to which the workers were expsosed was an alkaline dust containing unspecified sodium borates which is capable of some sensory stimulation.Despite certain deficiencies of the study the results of the study allow the derivation of a dose-response curve. Since the number of individuals tested was large enough and as the investigation was carried out in a population of workers no assessment factor is needed to come up for inter-individual variability. A correction factor of 2.5 has to be applied, as the total dust sampler methodology used in this study underestimated the actual exposure levels.

The acute irritant effects which build the basis for the BMDL05of the Wegman-study have been reported by several authors as a consequence of borate exposures. Garabrant et al. (1984 and 1985) who investigated large numbers of borate exposed workers reported dryness of mouth, nose and throat, eye irritation, dry cough, nosebleeds, sore throat, productive cough, shortness of breath, and chest tightness. A NOEC for respiratory irritation of 0.6 mg B/m3based on total dust (IOM equivalent of 1.5 mg B/m3) was derived by Garabrant et al. (1985). Due to several limitations of this study it cannot be used for DNEL derivations, however, the results are useful for the weight of evidence approach.

A NOAEL for irritation from boron of 1.5 mg B/m3(10 mg/m3of sodium tetraborate pentahydrate) among male and female human volunteers under controlled laboratory conditions was derived from Cain et al. (2004). At 10 mg/m3(1.5 mg B/m3) sodium tetraborate pentahydrate increased nasal secretion was observed, but not at 5 mg/m3(0.75 mg B/m3). The increased nasal secretion occurred in the absence of other irritating effects at concentration below that which volunteers considered irritatingand was not seen in subsequent study by Cain et al. 2008. Materials that cause mechanical or chemesthetic sensations in mucosal tissue may produce reflex responses as well, including an increase in secretions and blood flow to the tissue. Since a similar increase in secretion was not observed in the later study, the increase in secretion was likely mechanical in nature due to the increase particle deposition in the nose rather than a chemesthetic response to boron. Similarly, Cain et al. (2008) reported a NOAEL for irritation among human volunteers inhaling boric acid of 1.75 mg B/m3(8.35 mg/m3of disodium octaborate). 

The transitional Annex XV dossier reports that a NOEC of 0.75 mg B/m³ was derived from Cain et al. (2004) with a LOEC of 1.4 mg B/m³ based on increased nasal secretion. However, the increased nasal secretion was likely due to mechanical sensations in the mucosal tissue by the increase particulate diposition in the nose rather than sensory irritation caused by boron. The transitional dossier also reports that a LOEC of 0.44 in a comparable study in 2008. However, the authors of the study clearly state the levels of exposure did not reach the level considered irritating by subjects “…the highest levels studied here lay at the edge of where people would agree that feel in the nose becomes irritating, about 17-18 % carbon dioxide. None of the functions actually reached that concentration, though those for 2.5 mg/m³ calcium oxide and 10 mg/m³ sodium borate came close. ”

A Minimal Risk Level (MRL) has been derived by the Agency for Toxic Substances and Disease Registry (ATSDR) based on the study by Wegman et al. (1991). The value derived in the draft Toxicological Profile for Boron (ATSDR, 2007) appears over-protective, as an assessment factor of 3 for LOEC to NOEC extrapolation and another factor of 10 for intra-species difference was applied. ATSDR failed to correct for the sampling bias that occurs with total-dust monitoring in which the equipment under-samples suspended particles. As a consequence, actual dust levels significantly exceeded those reported. However, the total boron exposure value of 0.44 mg/m3is incorrect since it appears that it includes the background exposure level of 0.02 mg/m3, which when included in the calculation of the mean, gives a lower exposure value than the true exposure level of the exposed group. When the background value is excluded from the calculation, the mean total boron value based on the total dust sample of all exposed groups is 0.52 mg/m3. When this value is corrected by 2.5 for under sampling bias that occurs with total dust sampling, the mean total boron exposure for the exposed group is 1.3 mg/m3.

An airway sensory irritation respiratory depression (RD50) study of sodium tetraborate pentahydrate was conducted in male Swiss-Webster mice based on the ASTM E981-04 (2004) standard test method of estimating sensory irritancy of airborne chemicals. The ASTM E981-04 sensory iritancy test (Alarie assay) has been demonstrated to be a reliable test for estimating sensory irritancy of airborne irritants and RD50s are a basis, at least partially, for OELs by ACGIH (Kuwabara et al. 2007).   The REACH implementation guideline (Chapter R.8) acknowledges the use of the Alarie assay in assessing respiratory irritation. The ASTM standard uses the value of 0.03 x RD50 for estimation of threshold limitvalues (TLV). Alarie et al. (2001) has established that a value of 0.01 x RD50as the concentration where no sensory irritation would be seen in humans.

It was not possible to achieve an RD50 for sodium tetraborate pentahydrate. Based on the results in the mouse sensory irritation model, the RD50 for is greater than 1704 mg/m3(maximum achievable exposure) for sodium tetraborate pentahydrate. Therefore, although the highest achievable concentration was below the RD50 value for sodium tetraborate pentahydrate, based on the high aerosol concentrations achieved with %RD values below 50 %, it is sodium borates have a low potency as sensory irritants. Decreases in respiratory rate less than 12% are graded as no irritation (ASTM E981-04; 2002).The lowest exposure tested of 186 mg/m3sodium tetraborate pentahydrate resulted in a reduced respiration rate of 11% is graded as no irritation.The practical side of these results is that occupational exposure limit of 10 mg/m3total particulates will prevent any sensory irritation in workers.

The ECHA guidelines recommend extrapolating from the RD10 values. However, there is no correlation or extrapolation established for TLVs or human health effects for the RD10. Furthermore RD10 value is below the limit of detection of 12 % for this assay. The RD50 is the relevant value since extrapolation and correlation to humans uses this value.

No study of disodium octaborate tetrahydrate supports the designation as a respiratory irritant. Disodium octaborate tetrahydrate would be less irritating to the nose and throat than sodium tetraborate decahydrate or sodium tetraborate pentahydrate because of its more neutral pH. No threshold limit values (TLV) or occupational exposure limits have been established for disodium octaborate tetrahhydrate. Therefore, disodium octaborate tetrahydrate is not considered a respiratory irritant.

 

Worker-DNELlong-term, inhalation, systemic

This route is not relevant for systemic effects in the general population, but in the occupational setting considerable boron dust concentrations may arise.

No animal studies for the inhalation route are available. Therefore a NOAEC was extrapolated from the oral key study using the BMDL05of 10.3 mg B/kg bw/day. An eight hour workday and an according respiratory volume of 10 m3are assumed. The corrected inhalatory NOAEC of 18.16 mg B/m3was calculated as recommended by Chapter R.8 from the Guidance on IR and CSA using the following equation: 

Corrected Inhalatory NOAEC = oral BMDL5x (1/ sRVrat) x (ABSoral-rat/ ABSinh-rat) x (sRVhuman/ wRV)

Corrected Inhalatory NOAEC = 10.3 mg B/kg bw/day x (1/ 0.38m3/kg/d) x (100 %/ 100 %) x (6.7 m3(8h) / 10 m3(8h))

Corrected Inhalatory NOAEC = 18.16 mg B/m3

sRV: standard Respiratory Volume

ABS: Absorption,

wRV: worker Respiratory Volume

sRVrat= 0,38 m3/day

sRVhuman= 6,7 m3/day (8h);

sRVhuman, moderate work= 10 m3/day (8h)

ABSoral-rat= ABSinh-human= 100 %

Absorption of boric acid and disodium octaborate via the oral route is close to 100 %. Due to the good water solubility of the compounds and studies in animals and humans a realistic worst case assumption of 100 % absorption via the inhalation route is justified. Borates exist predominantly as un-dissociated boric acid in dilute aqueous solution at physiological pH, it is not further metabolized, therefore it can be concluded that the main species in the plasma of mammals is un-dissociated boric acid, and as such can exert its toxic effects in the target organs. The toxicokinetics of boric acid and disodium tetraborates are similar in rats and humans with regard to absorption, distribution, and metabolism. Differences exist for renal clearance, which is approximately 3 times faster in rats compared to humans. The physiological process of renal clearance is affected by the basal metabolic rate. In the above stated formular differences with regard to metabolic rate between rats and humans are considered. The remaining inter-species differences are covered by applying the factor 2.5 for toxicodynamic differences. An additional factor for uncertainties caused by route-to-route extrapolation was considered not necessary.

Worker-DNELlong-term, inhalation, systemic= (18.16 mg B/m3) /(2.5 x 5) =1.45 mg B/m3or 6.9 mg/m³ of disodium octaborate tetrahydrate.

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 or1.6mg/kg bw/day disodium octaborate tetrahydrate

 

External DNEL value = (0.34 mgB/kg bw/day)/0.5% dermal absorption value = 68 mg B/kg bw/day or232.8mg/kg bw/day disodium octaborate tetrahydrate

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
163.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
BMDL05
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.81 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
BMDL05
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.81 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
60
Modified 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 no 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.

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, 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, but they also revealed effects in female animals. The underlying mechanism is, however, much less investigated. Effects observed were infertility in female rats (58.8 mg B/kg bw/day, Weir, 1966c, d) and reduced fertility in female mice (111.3 mg B/kg bw/day, Fail et al. 1991). The continuous breeding study also detected the following effects at the lowest dose at which these effects were investigated: Reduced average dam weight on PND0, reduced average gestational period, significantly reduced adjusted litter weight of F0 females at 111.3 mg B/kg bw/day and reduced oestrus cycle length and significantly reduced adjusted litter weight of F1 females at 26.6 mg B/kg bw/day.

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). 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 UFs 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) developed 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, lower assessment factors were derived based on substance-specific (boron) data used to further refine the toxicokinetic (TK) subfactor. These reduced assessment factors for workers and the general population are presented in the document “Justification for a Reduction of Assessment Factors from Default Values” attached in Section 13 of IUCLID.

 General population-DNELlong-term, oral, systemic= (10.3 mg B/kg bw/day) / (6 x 10) =0.17 mg B/kg bw/day or0.81mg/kg bw/day disodium octaborate tetrahydrate