Hexaboron dizinc undecaoxide

Endpoint summary

Description of key information

- Muzzio and Johnson, 2010: data on oral absorption of zinc borate;
- Placke et al., 1990: subchronic inhalation study in rats: information on effects in lungs and tissue levels of zinc;
- Dourson et al., 1998: justification of data-specific assessment factors for toxicokinetics and toxicodynamic of boron.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

0.2

Absorption rate - inhalation (%):

100

Additional information

A summary of study results relevant for toxicokinetic and ADME parameters of zinc borate are summarizes below.

Following a single oral dose (1000 mg/kg) of zinc borate 2335, zinc and boron appeared in rat plasma and tissue samples, indicating the hydrolysis of zinc borate 2335 in the gastrointestinal tract and subsequent systemic absorption of zinc and boron (Muzzio and Johnson, 2010). In plasma, Tmax occurred between 5 and 6 h after administration, and Cmax ranges of 9.63 to 11.7 μg/mL for zinc and 26.7 to 27.9 μg/mL for boron were reached before concentrations decreased to background levels by 72 h post-dose; T1/2 ranged form 5.0 to 7.7 h (zinc and boron, respectively).

The gastrointestinal route was the primary elimination route for zinc, while urinary excretion via the kidneys was the primary elimination route for boron. Overall, approximately 70 % of intake zinc and 63 % of intake boron was recovered from excreta. Pancreas tissue had the highest level of zinc, followed by liver and femur tissue. Kidney had the highest level of boron, followed by femur tissue.

In a subchronic inhalation study in rats, Placke et al. investigated the potential toxicity of inhaled zinc oxide (Placke, 1990). The animals were exposed 5 days per week for 13 consecutive weeks. Additionally the concentration response was defined, the effects on target organs were identified and characterized, the tissue distribution of zinc as a function of concentration and continued exposure was determined, the reversibility of exposure-related toxic effects was determined, the specific toxic potential on the immune, haematopoietic, and reproductive systems was evaluated and the concentrations for a possible subsequent chronic toxicity and carcinogenicity study were selected.

With regard to the effects relevant for absorption and distribution of zinc oxide there were significant increases in group mean lung weights in all animals exposed to 10, 50 and 200 mg/m³ of ZnO. A patchy discoloration of the lung was considered to be related to ZnO exposure. The lesion of the greatest significance was an inflammation of the lungs with several lymph nodes in the chest cavity showing reactive hyperplasia.

Exposure to 200 mg/m³ of ZnO resulted in a significantly increased total body burden of zinc. Tissue levels of zinc increased in most tissues during exposure and returned to near control levels during the recovery period (with the exception of lung and bone which showed zinc retention). Tissues with the greatest increases were lung, liver, pancreas and femur (the findings in the additional groups are not presented here).

Based on the results of this study, all toxic effects appeared to be reversible. The no-effect concentration level was 3 mg/m³. However, the two higher concentrations of 50 and 200 mg/m³ caused many significant lesions considered health hazardous when respired.

In addition, a critical analysis of the existing data on boron toxicokinetics was conducted to clarify the appropriateness of replacing default uncertainty factors (10-fold for interspecies differences and 10-fold for intraspecies differences) with data-derived values (Dourson et al., 1998). The default uncertainty factor for variability in response from animals to humans of 10-fold (default values of 4-fold for kinetics and 2.5-fold for dynamics) was recommended, since clearance of boron is 3- to 4-fold higher in rats than in humans and data on dynamic differences — in order to modify the default value — are unavailable. A data-derived adjustment of 6-fold (1.8 for kinetics and 3.1 for dynamics) rather than the default uncertainty factor of 10-fold was considered appropriate for intrahuman variability, based on variability in glomerular filtration rate during pregnancy in humans and the lack of available data on dynamic differences. Moreover, information on absorption and elimination of boron from the human body was given. In detail, absorption of boron varied between 81 and 98 % in humans and excretion and elimination, respectively was found to be from 81 to 99 % (based on the studies: Hunt et al., 1997, Nielsen, 1996, Schou et al., 1984, Job, 1973, Kent and McCance, 1941 and Vanderpool et al., 1994, cited in Dourson et al., 1996).

Read-across is justified on the following basis:

The family of zinc borates includes Zinc Borate anhydrous, Zinc Borate heptahydrate and Zinc Borate hydrate. Zinc borate anhydrous is the anhydrous form of Zinc Borate heptahydrate and Zinc Borate hydrate has different zinc to boron ratio. Zinc borate heptahydrate (in common with other zinc borates such as Zinc borate hydrate and anhydrous) breaks down to Zinc Hydroxide (via Zinc oxide) and Boric Acid, therefore the family of zinc borates shares the same toxicolgical properties.

 

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, cited in Appendix D).

Based on this information following conclusions have been made:

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, see justification on No STOT-RE classification). 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.