Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22.4 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
4.74
Modified dose descriptor starting point:
NOAEC
Value:
106 mg/m³
Explanation for the modification of the dose descriptor starting point:
BMD established for boric acid (59 mg/kg bw, equivalent to boron of 10.3 mg/kg bw) based on developmental oral studies in rats was used (Allen et al., 1996).
AF for dose response relationship:
1
Justification:
Dose response differencies in two studies are covered by the derived BMD (Allen et al., 1996)
AF for differences in duration of exposure:
1
Justification:
developmental study
AF for interspecies differences (allometric scaling):
1
Justification:
not required in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
1
Justification:
A factor for interspecies differences for toxicodynamik is set to 1 because humans are not more sensitive to the effects of boric acid than laboratory animals.
AF for intraspecies differences:
4.7
Justification:
The intraspecies factor for toxicokinetic variability can be reduced for workers to a data-derived value of 1.5 (Maier et al. 2014) based on variability in GFR in populations after excluding preeclamptic women (Dunlop, 1981; Krutzén et al., 1992; Sturgiss et al., 1996). A factor of 3.16 was used to account for variability in human toxicodynamics (US EPA, 2004).
AF for the quality of the whole database:
1
Justification:
default; numerous studies available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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:
1 585 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):
19
Modified dose descriptor starting point:
NOAEL
Value:
30 117 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
BMD established for boric acid (59 mg/kg bw, equivalent to boron of 10.3 mg/kg bw) based on developmental oral studies in rats was used (Allen et al., 1996).
AF for dose response relationship:
1
Justification:
Dose response differencies in two studies are covered by the derived BMD (Allen et al., 1996)
AF for differences in duration of exposure:
1
Justification:
developmental study
AF for interspecies differences (allometric scaling):
4
Justification:
The calculated clearance rate difference (3-fold) between rats and humans for boron is similar to the default allometric scaling factor of 4 (TK).
AF for other interspecies differences:
1
Justification:
A factor for interspecies differences for toxicodynamik (TD) is set to 1 because humans are not more sensitive to the effects of boric acid than laboratory animals.
AF for intraspecies differences:
4.7
Justification:
The intraspecies factor for toxicokinetic variability can be reduced for workers to a data-derived value of 1.5 (Maier et al. 2014) based on variability in GFR in populations after excluding preeclamptic women (Dunlop, 1981; Krutzén et al., 1992; Sturgiss et al., 1996). A factor of 3.16 was used to account for variability in human toxicodynamics (US EPA, 2004).
AF for the quality of the whole database:
1
Justification:
default; numerous studies available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with ECHA REACH “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (2012).

Available dose descriptors:

Zinc borate is not acutely toxic by oral and dermal routes of exposure because the LD50values are > 5000 mg/kg (Kreuzmann, 1990a,b). The read-across substance diboron tetrazinc heptaoxide monohydrate was practically non-toxic if administered to treated animals by inhalation (LC50 > 4.5 mg/L exceeded the limit dose; Blagden, 1996). The substance is also not irritating or sensitising to skin (Kreuzmann, 1990c, d). Therefore, no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures local effects for dermal route need to be derived.

Localized inflammation occurred in the rat lung in inhalation studies of zinc borate and zinc oxide(Randazzo 2014;Placke et al. 1990). Since the inflammation appeared to be reversible and was considered to be due to particle lung overload that is observed primarily in rats caused by the slightly soluble zinc hydroxide and zinc oxide particles (please refer to No STOT-RE classification (section "Repeated dose toxicity"), no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures (local effects for inhalation routes) need to be derived.

 

The critical endpoint for zinc borate was determined to be fetal body weight changes and fetal skeletal developmental variations (higher mean litter proportions of reduced ossification of the 13th rib[s], sternebra[e] nos. 5 and/or 6 unossified, 7th cervical ribs, and 25 presacral vertebrae and lower mean litter proportions of 14th rudimentary rib[s]) (Edwards 2014). There were no test substance-related malformations noted at any dosage level. Based on these results, a dosage level of 100 mg/kg/day was considered to be the LOAEL for embryo/fetal development when zinc borate 2335 was administered orally by gavage to inbred Crl:CD(SD) rats. Mean combined fetal weights in the 100 mg/kg/day groups were 5.4% lower than the control group. Since a NOAEL was not determined in this study and the developmental affects appear to correlate with the boron content, the 95% lower confidence limit of the benchmark dose for 5% reduction of fetal body weight for boron (BMD = 10.3 mg B/kg/day based on BMD of 59 mg/kg bw for boric acid) (Allen et al. 1996) was used for derivation of the DNELs. Moreover, systemic toxicity of inhaled zinc borate is considered also to be mediated by boric acid because of hydrolysis of zinc borate in lungs (for the detailed explanation see the sections “Bioavailability” and “Inhalation absorption” below). Therefore, the use of BMD for the DNEL derivation is considered to be justified.

 

The systemic DNELs for inhalation and dermal routes can be derived by route-to-route extrapolation applying appropriate assessment factors.

 

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because a No-Observed-Effect-Level could not be established from the relevant studies.

 

Modification of the starting point:

 

From all available data on zinc borate is clear that the substance exerts its effects by a threshold mode of action. Thus, DNELs can be calculated for the threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

Bioavailability (absorption):

Zinc borates are sparingly soluble salts. Hydrolysis under high dilution conditions leads to zinc hydroxide via zinc oxide and boric acid formation. Zinc hydroxide and zinc oxide solubility is low under neutral and basic conditions. This leads to a situation where zinc borate hydrolyses to zinc hydroxide, zinc oxide and boric acid at neutral pH quicker than it solubilises. Therefore, it can be assumed that at physiological conditions and neutral and lower pH zinc borate will be hydrolysed to boric acid, zinc oxide and zinc hydroxide. Hydrolysis and the rate of hydrolysis depend on the initial loading and time. At a loading of 5% (5g/100ml) zinc borate hydrolysis equilibrium may take 1-2 months, while at 1 g/l hydrolysis is complete after 5 days. At 50 mg/l hydrolysis and solubility is complete (Schubert et al., 2003). At pH 4 hydrolysis is complete.

Zinc Borate heptahydrate breaks down as follows:

2ZnO∙3B2O3∙3.5H2O + 3.5H2O + 4H+↔ 6H3BO3+ 2Zn2+

2Zn2++ 4OH-↔ 2Zn(OH)2

____________________________________________________________

Overall equation

2ZnO∙3B2O3∙3.5H2O + 7.5H2O ↔ 2Zn(OH)2+ 6H3BO3

The relative zinc oxide and boric oxide % are as follows:

Zinc borate heptahydrate:

Zinc oxide = 37.45% (30.09% Zn)

B2O3= 48.05% (14.94% B)

Water = 14.5%

Zinc borate hydrate:

Zinc oxide = 78.79% (63.31% Zn)

B2O3= 16.85% (5.23% B)

Water = 4.36%

Zinc Borate, Anhydrous

Zinc oxide = 45%

B2O3= 55% (17.1% B)

 

Based on such a chemical behavior, and since the critical toxicity endpoints appear to correlate with boron dose levels, substantial human and animal data on absorption of inorganic borate compounds are used to assess the absorption rates by oral, dermal and inhalation routes of exposure. 

 

Furthermore, zinc homeostasis in mammals is highly regulated. The body maintains constant tissue levels of zinc with varying intakes by adjusting gastrointestinal zinc absorption and intestinal endogenous zinc excretion.

Studies show that homeostatic control mechanisms limit the amount of zinc absorption and tissue uptake in laboratory animals. Studies in rats demonstrate a capacity to maintain a relatively constant content of zinc in the whole body while dietary zinc intakes vary by as much as 10-fold (King et al. 2000).

 

Oral absorption:

Intestinal absorption of soluble zinc compounds is considered to be 20 % (see CSR for zinc oxide), while absorption of borates amounts to nearly 100 % (see CSR for boric acid). Furthermore, the results of the ADME study in rats conducted with zinc borate show that oral absorption was significant (Muzzio and Johnson, 2010). Therefore, oral absorption of boron is set to 100 % (worst-case) for the purposes of hazard assessment (DNEL derivation). The oral absorption of boron is considered to be the same in animals and in humans (worst-case). Because of the homeostatic control of zinc, the amount of zinc absorbed and bioavailable after repeated oral dosing of zinc borate is likely limited. 

Dermal absorption:

No significant dermal absorption is expected for zinc borate. Under neutral and slight lower pH, which is the case for skin, zinc borate can be considered to hydrolyze to zinc hydroxide and boric acid. Absorption of borates and zinc compounds via the skin is very low (0.2% for borates and less than 2% for zinc compounds; see CSRs for zinc oxide and boric acid). Due to the physical appearance of zinc borate as a dust, a default value of 0.2 % of boron is considered to represent realistic case for dermal absorption. The value was established for borate compounds based on in vitro and in vivo studies in animals and in humans (Wester et al. 1998).

Inhalation absorption

Zinc borates are “sparingly soluble salts”. Hydrolysis under high dilution conditions leads to zinc hydroxide via zinc oxide and boric acid formation. Zinc hydroxide and zinc oxide solubility is low under neutral and basic conditions. This leads to a situation where zinc borate hydrolyses to zinc hydroxide, zinc oxide and boric acid at neutral pH quicker than it solubilizes. Therefore, it can be assumed that at physiological conditions and neutral and lower pH zinc borate will be hydrolyzed to boric acid, zinc oxide and zinc hydroxide. Therefore it can be assumed that the boron (as boric acid) is absorbed leaving the slightly soluble zinc oxide and zinc hydroxide. The zinc oxide and zinc hydroxide is likely associated with the “lung overload effects” observed in the inhalation studies with ZnO and ZnB in rats (Placke et al., 1990; Randazzo 2014). In this regards, the use of ZnO equivalents presented above to extrapolate boron safe levels to zinc borate is justified.

The absorption of the boric acid hydrolysis fraction by inhalation route is assumed to be 100% as worst case scenario. Limited absorption of zinc was observed in a 90-day inhalation study of ZnO at air concentrations ranging from 1 to 200 mg/m3(Placke et al. 1990). No statistically significant increases in plasma zinc levels were observed at any exposure level compared to the control group, although some tissue levels were slightly higher at the highest exposure concentrations.

Regarding inhalation absorption of the slightly soluble zinc hydroxide and zinc oxide, data on bioavailability of soluble and insoluble zinc compounds have been taken into account. The bioavailability of insoluble ZnO is about 60% of the bioavailability of the soluble forms (Prasadet al., 1993). Once translocated to the gastrointestinal tract, uptake will be in accordance with oral uptake kinetics. Hence, for the part of the material deposited in head and tracheobronchial region that is cleared to the gastrointestinal tract, the oral absorption figures 20% for soluble zinc compounds and 12% (20 x 0.6) for slightly soluble and insoluble zinc compounds can be estimated. Slightly soluble and insoluble zinc compounds (zinc oxide, zinc phosphate and zinc metal) inhalation absorption is at maximum considered to be 20%. Therefore, inhalation absorption of slightly soluble zinc hydroxide and zinc oxide is considered to be similar with that established for insoluble zinc compounds in humans. This is supported by the findings in the study by Oberdörster et al., (1980), where the dissolution half-life of 1mm diameter zinc oxide particles in the deep lung was approximately 6 hrs. Since most of the particles of zinc borate in these areas will have a diameter >1mm, the dissolution half-lives for these larger particles will be longer, and the absorption will also be less. Based on this knowledge, the total inhalation absorption factor for the slightly soluble zinc hydroxide and zinc oxide will be 0.12 (resulting from GI tract) + 0.20 (resulting from the part deposited in the head region) = 0.32 (32%).

Based on this information, the inhalation absorption of zinc borate is considered to be mediated by the absorption of boric acid and therefore 100 % is taken for the DNEL calculation.

Route-to-route extrapolation:

Since reversible localized inflammation occurred in the rat lung associated with particle overload caused by the slightly soluble zinc hydroxide and zinc oxide particles in inhalation studies of zinc borate and zinc oxide, and not considered relevant to humans, oral-to-inhalation extrapolation based on boron is performed to obtain long-term inhalation NOAEC for systemic effects. The following formula was used:

Corrected inhalatory NOAEC = oral BMD x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is the standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Oral-to-dermal extrapolation is performed to obtain dermal NOAEL for systemic effects. The following formula was used (as described in the Example B.5 of the Appendix R.8 -2, ECHA REACH Guidance R.8):

Corrected dermal NOAEL = oral BMD x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ABSderm-human) = oral BMD x (ABSoral-rat/ABSderm-human).

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38 m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat BMD from oral studies of borates in rats was used to assess inhalation exposure in humans. The standard respiratory volumes in rats for an 8 hour exposure is 0.38 m³/kg/day. Standard respiratory volumes for workers under normal conditions and by light activity are 6.7 and 10 m³, respectively.

Applying of assessment factors and calculation of DNELs:

Assessment Factors for Workers

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data. For zinc borate, the value for individual assessment factors was based on substance-specific (boron) information to further refine the toxicokinetic (TK) subfactor. The examination of species differences in boron distribution to extravascular fluids and renal elimination served as the basis for the replacement of the default value for interspecies TK subfactor, while critical intraspecies evaluation of the human inter-individual variation of underlying renal clearance mechanism (glomerular filtration rate) served as the basis upon which to replace the default value for the intraspecies TK component (Maier et al. 2014). Because of data available on the mode or mechanism of action for boron (Hox genes, HDAC inhibitors, and protective effect of intrinsically higher zinc levels in humans) show that humans are not more sensitive than laboratory animals. Therefore, the default values for the interspecies toxicodynamic component is reduced to 1. Because no data are available to inform on intraspecies toxicodynamic variability in humans, the more protective default factor of 3.16 is applied (ECHA REACH Guidance Appendix R.8-3).

Interspecies differences:

Based on the results of the 90-day oral and developmental toxicity studies, the primary driver for adverse effects for zinc borate appears to be boric acid formed when zinc borate hydrolyses to zinc hydroxide and boric acid upon ingestion. Boron is not metabolized and is eliminated from the body primarily via the urine. 

Dourson et al. (1998) initially calculated a mean clearance rate for boron of approximately 4-fold higher in rats than humans. However, when a subset of the data with greater confidence was used, a 3-fold difference was estimated. Since the calculated clearance rate difference (3-fold) difference between rats and humans for boron is similar to the default allometric scaling factor of 4, the more protective factor of 4 for interspecies differences in toxicokinetics was used (ECHA REACH guidance R.8, table R. 8-3). A factor of 1 was applied for remaining differences based on data showing that humans are not more sensitive to the effects of boric acid than laboratory animals.

In accordance with ECHA guidelines, no allometric scaling factor was applied when the oral BMD was used for the derivation of inhalation long-term DNEL (ECHA REACH guidance R.8, table R. 8-4).

Intraspecies differences:

The data-derived toxicokinetic adjustment factor for boron for human variability was calculated in the US EPA (2004) assessment from data on the variability in glomerular filtration rate (GFR) during pregnancy; GFR was identified as the primary determinant of boron clearance rates. The US EPA (2004) modified the sigma method (Dourson et al., 1998) to calculate the lower bound of risk at 3 standard deviations (SD) with the goal of ensuring adequate coverage of preeclamptic women (the sensitive subpopulation), resulting in an intraspecies (i.e., human variability) toxicokinetic adjustment factor of 2 (see assessment factors for general public below). However, the intraspecies factor for toxicokinetic variability can be reduced for workers to a data-derived value of 1.5 (Maier et al. 2014) based on variability in GFR in populations after excluding preeclamptic women (Dunlop, 1981; Krutzén et al., 1992; Sturgiss et al., 1996). The results from these three studies were averaged to increase the sample size and therefore better reflect the overall population distribution, including median response and variability. Because the worker DNEL is intended to protect working populations, it is not appropriate to include preeclamptic women, since they would not likely be represented in the work place. Of the total workforce, pregnant women represent a relatively small percentage of total workers. Women with preeclampsia represent an even smaller subset of this population; overall incidence of preeclampsia is estimated at roughly 3%, or less, of total pregnancies. Women diagnosed with mild preeclampsia are given outpatient, and sometimes inpatient; treatment including blood pressure measurements, laboratory monitoring, and physician visits twice weekly and generally, bed rest. Women with preeclampsia are, therefore, unlikely to be working during this period of sensitivity. Although it is possible that a pregnant woman with preeclampsia could be found in an occupational setting, specifically if the woman had not been receiving prenatal care, the percentage of the working population, under such circumstances, would be very small. Additionally, working populations are more homogenous than general populations, so increasing the lower bound to 3 SDs instead of 2 is unnecessary for an occupational assessment, especially when preeclamptic women are excluded (Maier et al. 2014). Moreover, the GFR values for preeclamptic women are approximately 2 SD below those of healthy women (Krutzén et al., 1992), indicating that using the sigma-method with 2 SD, at most, is adequate. As with the general population, the more protective default factor of 3.16 was used to account for variability in human toxicodynamics.

Extrapolation of duration:

An assessment factor of 1 was applied for duration of exposure (developmental toxicity).

Quality of whole data base:

A default assessment factor of 1 was used since numerous data are available for zinc and borates compounds.

Issues related to dose response:

A default assessment factor of 1 was used since there was a clear dose response in the developmental toxicity and 90-day study.

Composite Factor for Workers

This composite factor for workers was calculated by multiplying the subfactors of 4 (oral and dermal routes) for interspecies differences in toxicokinetics (based on data for boron clearance rates in rats versus humans), a value of 1 for remaining interspecies differences in toxicodynamics, a value of 1.5 for variability in human toxicokinetics (based on data on human variability in glomerular filtration rate), and the default factor of 3.16 to account for variability in human toxicodynamics. Oral and dermal routes: 4 x 1 x 1.5 x 3.16 = 19. Inhalation route: 1 x 1 x 1.5 x 3.16 = 4.74.

Calculation of end-point specific DNELs for workers:

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat BMD of 10.3 mg B/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC= oral BMD x (1/sRVrat) x (ABSoral-rat/ABSinhal-human) x (6.7 m³/10 m³)

                            = 10.3 mg B/kg bw x (1/0.38 m³/kg/day) x (100 %/100 %) x (6.7/10)

                            = 18.2 mg B/m³

                            = 18.2/0.1494 = 122 mg ZB 2335/m³

                            = 18.2/0.171 = 106 mg ZB anhydrous/m³

 

DNEL for Zinc borate heptahydrate (ZB 2335) = 122 mg/m³/4.74 = 25.7 mg/m³

DNEL for Zn borate anhydrous = 106 mg/m³/4.74 = 22.4 mg/m³

Assessment factors are:

1 – Remaining interspecies (TD) differences , 1.5 – intraspecies TK, 3.16 – intraspecies TD, 1 – study duration (developmental Toxicity), 1 – dose response, 1 – quality of data base. The total AF amounts to 4.74.

 

Long-term exposure – systemic effects (dermal DNEL):

For the oral rat BMD of 10.3 mg B/kg bw the following conversion was necessary:

Dermal NOAEL = oral BMD x (ABSoral-rat/ABSderm-human) = 10.3 x (100 %/0.2 %) = 5150 mg B/kg bw

DNEL for Boron = 5150 mg B/kg bw/19 = 271 mg B/kg bw.

DNEL for Zinc borate heptahydrate (ZB 2335) = 5150 mg B/kg bw/0.1494 = 34,471 mg ZB 2335/kg bw/19 =1814 mg/kg bw.

DNEL for Zn borate anhydrous = 5150 mg B/kg bw/0.171 = 30,117 mg ZB Anhydrous/kg bw /19 =1585 mg /kg bw.

Assessment factors are: 4 – interspecies (TK), 1 – remaining interspecies differences (TD), 1.5 – intraspecies TK, 3.16 – intraspecies TD, 1 – study duration (developmental study), 1 – dose response, 1 – quality of data base. The total AF amounts to 19.

 

Selected Worker DNELs

 

DNEL systemic inhalation – Zinc borate heptahydrate (ZB 2335) = 25.7 mg/m³

DNEL systemic inhalation – Zinc borate anhydrous = 22.4 mg/m³

DNEL systemic dermal (long-term) – Zinc borate heptahydrate (ZB 2335) = 1814 mg/kg bw

DNEL systemic dermal (long-term) – Zinc borate anhydrous = 1585 mg/kg bw

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
6.32
Modified dose descriptor starting point:
NOAEC
Value:
52.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
BMD established for boric acid (59 mg/kg bw, equivalent to boron of 10.3 mg/kg bw) based on developmental oral studies in rats was used (Allen et al., 1996).
AF for dose response relationship:
1
Justification:
Dose response differencies in two studies are covered by the derived BMD (Allen et al., 1996)
AF for differences in duration of exposure:
1
Justification:
developmental study
AF for interspecies differences (allometric scaling):
1
Justification:
not required in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
1
Justification:
A factor for interspecies differences for toxicodynamik is set to 1 because humans are not more sensitive to the effects of boric acid than laboratory animals.
AF for intraspecies differences:
6.3
Justification:
The data-derived toxicokinetic adjustment factor of 2 for boron for human variability covering preeclamptic women was calculated in the US EPA assessment (2004). The more protective default factor of 3.16 was used to account for variability in human toxicodynamics (US EPA 2004).
AF for the quality of the whole database:
1
Justification:
default; numerous studies available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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:
1 205 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):
25
Modified dose descriptor starting point:
NOAEL
Value:
30 117 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
BMD established for boric acid (59 mg/kg bw, equivalent to boron of 10.3 mg/kg bw) based on developmental oral studies in rats was used (Allen et al., 1996).
AF for dose response relationship:
1
Justification:
Dose response differencies in two studies are covered by the derived BMD (Allen et al., 1996)
AF for differences in duration of exposure:
1
Justification:
developmental study
AF for interspecies differences (allometric scaling):
4
Justification:
The calculated clearance rate difference (3-fold) between rats and humans for boron is similar to the default allometric scaling factor of 4 (TK).
AF for other interspecies differences:
1
Justification:
A factor for interspecies differences for toxicodynamik (TD) is set to 1 because humans are not more sensitive to the effects of boric acid than laboratory animals.
AF for intraspecies differences:
6.3
Justification:
The data-derived toxicokinetic adjustment factor of 2 for boron for human variability covering preeclamptic women was calculated in the US EPA assessment (2004). The more protective default factor of 3.16 was used to account for variability in human toxicodynamics (US EPA 2004).
AF for the quality of the whole database:
1
Justification:
default; numerous studies available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 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):
25
Modified dose descriptor starting point:
NOAEL
Value:
60.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Route-to-route extrapolation is not applicable (oral study and oral route of exposure)
AF for dose response relationship:
1
Justification:
Dose response differencies in two studies are covered by the derived BMD (Allen et al., 1996)
AF for differences in duration of exposure:
1
Justification:
developmental study
AF for interspecies differences (allometric scaling):
4
Justification:
The calculated clearance rate difference (3-fold) between rats and humans for boron is similar to the default allometric scaling factor of 4 (TK).
AF for other interspecies differences:
1
Justification:
A factor for interspecies differences for toxicodynamik (TD) is set to 1 because humans are not more sensitive to the effects of boric acid than laboratory animals.
AF for intraspecies differences:
6.3
Justification:
The data-derived toxicokinetic adjustment factor of 2 for boron for human variability covering preeclamptic women was calculated in the US EPA assessment (2004). The more protective default factor of 3.16 was used to account for variability in human toxicodynamics (US EPA 2004).
AF for the quality of the whole database:
1
Justification:
default; numerous studies available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.15 m³/kg bw/day for rats was used to convert oral BMD into inhalation NOAEC.

Applying of assessment factors and calculation of DNELs:

Assessment Factors the General Population

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data. For zinc borate, the value for individual assessment factors was based on substance-specific (boron) information to further refine the toxicokinetic (TK) subfactor.The examination of species differences in boron distribution to extravascular fluids and renal elimination served as the basis for the replacement of the default value for interspecies TK subfactor, while critical intraspecies evaluation of the human inter-individual variation of underlying renal clearance mechanism (glomerular filtration rate) served as the basis upon which to replace the default value for the intraspecies TK component (Maier et al. 2014). Because of data available on the mode or mechanism of action for boron (Hox genes, HDAC inhibitors, and protective effect of intrinsically higher zinc levels in humans) show that humans are not more sensitive than laboratory animals. Therefore, the default values for the interspecies toxicodynamic component is reduced to 1. Because no data are available to inform on intraspecies toxicodynamic variability in humans, the more protective default factor of 3.16 is applied (ECHAREACH Guidance Appendix R.8-3).

Interspecies differences: 

The assessment factor of 4 for interspecies differences in toxicokinetics and a factor of 1 was applied for remaining differences as described for workers are also applied to general public.

Intraspecies differences:

The data-derived toxicokinetic adjustment factor for boron for human variability was calculated in the US EPA (2004) assessment from data on the variability in glomerular filtration rate (GFR) during pregnancy; GFR was identified as the primary determinant of boron clearance rates. The US EPA (2004) modified the sigma method (Dourson et al., 1998) to calculate the lower bound of risk at 3 standard deviations (SD) with the goal of ensuring adequate coverage of preeclamptic women (the sensitive subpopulation), resulting in an intraspecies (i.e., human variability) toxicokinetic adjustment factor of 2. The sigma method is a term used for statistical methods using multiple standard deviations to establish acceptable lower bounds. The more protective default factor of 3.16 was used to account for variability in human toxicodynamics.

Extrapolation of duration:

An assessment factor of 1 was applied for duration of exposure (developmental toxicity).

Quality of whole data base:

A default assessment factor of 1 was used since numerous data are available for zinc and borates compounds.

Issues related to dose response:

A default assessment factor of 1 was used since there was a clear dose response in the developmental toxicity and 90-day study.

Composite Factor for General Population

This composite factor was calculated by multiplying the subfactors of 4 for interspecies differences in toxicokinetics (based on data for boron clearance rates in rats versus humans), a value of 1 for remaining interspecies differences in toxicodynamics, a value of 2.0 for variability in human toxicokinetics (based on data on human variability in glomerular filtration rate), and the default factor of 3.16 to account for variability in human toxicodynamics. Oral and dermal routes: 4 x 1 x 2 x 3.16 = 25. Inhalation route: 1 x 1 x 2 x 3.16= 6.32.

Calculation of endpoint-specific DNEL for general population

Long-term exposure - systemic effects (inhalation):

The oral BMD for boron of 10.3 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat BMD x (1/1.15 m³/kg bw/day) x (ABSoral-rat/ABSinhal-human), where 1.15 is the standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 10.3 mg B/kg bw x (1/1.15 m³/kg/day) x (100 %/100 %) = 8.96 mg B/m³

DNEL for Boron = 8.96 mg B/m³/6.32 = 1.42 mg B/m³.

DNEL for Zinc borate heptahydrate (ZB2335) = 8.96 mg B/m³/0.1494 = 59.95 mg ZB2335/m³/6.32 = 9.49 mg/m³.

DNEL for Zinc borate anhydrous = 8.96 mg B/m³/0.171 = 52.38 mg ZB Anhydrous/m³ /6.32 = 8.29 mg/m³.

Assessment factors are: 1 – remaining interspecies differences (TD), 2 – intraspecies TK,3.16 – intraspecies TD, 1 – study duration (developmental toxicity), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 6.32.

Long-term exposure - systemic effects (dermal):

For the oral rat BMD for boron of 10.3 mg B/kg bw the following conversion was necessary:

Dermal NOAEL = oral BMD x (ABSoral-rat/ABSdermal-rat) x (ABSdermal-rat/ABSdermal-human) = 100 x (100 %/0.2 %) = 5150 mg/kg bw

 

DNEL for Boron = 5150 mg B/kg bw/25 = 206 mg B/kg bw.

DNEL for Zinc borate heptahydrate (ZB 2335) = 5150 mg B/kg bw/0.1494 = 34,471mg ZB 2335/kg bw/25 = 1379 mg/kg bw.

DNEL for Zinc borate anhydrous = 5150 mg B/kg bw/0.171 = 30,117 mg ZB Anhydrous/kg bw/25 = 1205 mg/kg bw.

 

Assessment factors are: 4 – interspecies TK, 1 – remaining interspecies differences (TD), 2 – intraspecies TK, 3.16 – intraspecies TD, 1 – study duration (developmental toxicity study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

Long-term exposure - systemic effects (oral):

The oral BMD of 10.3 mg B/kg bw had not to be converted.

The oral BMD of 10.3 mg B/kg bw was not modified for differences in absorption by oral route in rats and in humans since: oral absorptionrat= oral absorptionhuman.

DNEL for Boron = 10.3 mg B/kg bw/25 = 0.41 mg B/kg bw.

DNEL for Zinc borate heptahydrate (ZB 2335) = 10.3 mg/kg bw/0.1494 = 68.94 mg ZB 2335/kg bw/ 25 = 2.76 mg/kg bw.

DNEL for Zinc botae anhydrous = 10.3 mg/kg bw/0.171 = 60.23 mg ZB Anhydrous /kg bw/ 25 = 2.41 mg/kg bw.

Assessment factors are: 4 – interspecies (TK), 1 – remaining interspecies differences (TD), 2 – intraspecies TK,3.16 – intraspecies TD ,1 – study duration (developmental toxicity), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 25.

Selected General Population DNELs

DNEL for Zinc borate heptahydrate (ZB 2335), systemic inhalation = 9.5 mg/m³

DNEL for Zinc borate anhydrous, systemic inhalation = 8.3 mg/m³

 

DNEL for Zinc borate heptahydrate (ZB 2335), systemic dermal (long term) = 1379 mg/kg bw

DNEL for Zinc borate anhydrous systemic, dermal (long term) = 1205 mg/kg bw

 

DNEL for Zinc borate heptahydrate (ZB 2335), systemic oral (long-term) = 2.8 mg/kg bw

DNEL for Zinc borate anhydrous, systemic oral (long-term) = 2.4 mg/kg bw