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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable well documented publication which meets basic scientific principles. Read-across is justified on the following basis: The family of zinc borates that include Zinc Borate 500, Zinc Borate 2335 and Zinc Borate 415 (also known as Zinc Borate 411). Zinc borate 500 is anhydrous Zinc Borate 2335 and Zinc Borate 415 has different zinc to boron ratio. Zinc borate 2335 (in common with other zinc borates such as Zinc borate 415 and 500) breaks down to Zinc Hydroxide (via Zinc oxide) and Boric Acid, therefore the family of zinc borates shares the same toxicological 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 2335 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 2335:zinc oxide = 37.45% (30.09% Zn) B2O3 = 48.05% (14.94% B) Water 14.5% Zinc borate 415: 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)

Data source

Reference
Reference Type:
publication
Title:
Benchmark dose analysis of developmental toxicity in rats exposed to boric acid.
Author:
Allen, B.C., Strong, P.L., Price, C.J., Hubbard, S.A. & Daston, G.P.
Year:
1996
Bibliographic source:
Fundamental and Applied Toxicology 32: 194 - 204.

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
BMD for boron was determined.
GLP compliance:
no
Remarks:
not applicable (it is a publication)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Boric acid
EC Number:
233-139-2
EC Name:
Boric acid
Cas Number:
10043-35-3
Molecular formula:
H3BO3
IUPAC Name:
Boric acid
Details on test material:
- Name of test material (as cited in study report): Boric acid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
No details given

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
No details given
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no details given
Duration of treatment / exposure:
20 days
Frequency of treatment:
ad libitum in feed
Doses / concentrationsopen allclose all
Remarks:
0, 0.025, 0.05, 0.075, 0.1 & 0.2% equivalent to 0, 19, 36, 55, 76 & 143 mg Boric acid/kg bw (Price et al., 1994, 1995) - Study B
Basis: nominal in diet
Remarks:
0, 0.1, 0.2, 0.4 & 0.8 % equivalent to 0, 78, 163, 330 & 539 mg Boric acid/kg bw (Heindel et al., 1992) - Study A
Basis: nominal in diet
No. of animals per sex per dose:
- 29 time-mated females/group (study A);
- 60 time-mated females/group (study B).
Control animals:
yes, plain diet
Details on study design:
The studies consist of two phases:
- Phase I: developmental toxicity termination on gd 20;
- Phase II: Postnatal recovery termination on pnd 21 (has not been considered in the analyses dicussed in the publication)
Positive control:
None.

Results and discussion

Effect levels

open allclose all
Dose descriptor:
BMD: developmental toxicity
Effect level:
59 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
BMD: developmental toxicity
Effect level:
10.3 mg/kg bw/day (nominal)
Based on:
element
Remarks:
boron
Sex:
female
Basis for effect level:
other: see "Remarks"

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The specific BMD is 59 mg/kg/day. This BMD is based on the combined results of the two studies that were similarly designed and were conducted in the same laboratory. The selected value much less than the lowest dose tested in Study A (78 mg/kg/day, which was considered to be a LOAEL) and is very close to the NOAEL determined in Study B, 55 mg/kg/day.
Executive summary:

A benchmark dose developed by Allen et al. (1996) was based on the studies of Heindel et al. (1992), Price, Marr & Myers (1994) and Price et al. (1996). The benchmark dose is defined as the 95 % lower bound on the dose corresponding to a 5 % decrease in the mean fetal weight (BMDL05). The BMDL05of 10.3 mg/kg body weight per day as boron is close to the Price et al. (1996) NOAEL of 9.6 mg/kg body weight per day.

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