Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Meets acceptable scientific standards with acceptable restrictions. 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:
Developmental toxicity risk assessment has typically relied on the estimation of reference doses or reference concentrations based on the use of NOAELs divided by uncertainty factors. The benchmark dose (BMD) approach has been proposed as an alternative basis for reference value calculations. In this analysis of the developmental toxicity observed in rats exposed to boric acid in their diet, BMD analyses have been conducted using two existing studies. By considering various endpoints (rib XIII effects, variations of the first lumbar rib) and fetal weight changes and various modelling approaches for those endpoints, the best approach for incorporating all of the information available from the studies was determined. In this case, the approach involved combining data from two studies which were similarly designed and were conducted in the same laboratory to calculate BMDs that were more accurate and more precise than from either study alone.
GLP compliance:
not specified
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

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
20 days
Frequency of treatment:
continuously in diet
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
(Heindel et al., 1992) - Study A
Dose / conc.:
78 mg/kg bw/day (nominal)
Remarks:
(Heindel et al., 1992) - Study A
Dose / conc.:
163 mg/kg bw/day (nominal)
Remarks:
(Heindel et al., 1992) - Study A
Dose / conc.:
330 mg/kg bw/day (nominal)
Remarks:
(Heindel et al., 1992) - Study A
Dose / conc.:
539 mg/kg bw/day (nominal)
Remarks:
(Heindel et al., 1992) - Study A
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
(Price et al., 1994, 1995) - Study B
Dose / conc.:
19 mg/kg bw/day (nominal)
Remarks:
(Price et al., 1994, 1995) - Study B
Dose / conc.:
36 mg/kg bw/day (nominal)
Remarks:
(Price et al., 1994, 1995) - Study B
Dose / conc.:
55 mg/kg bw/day (nominal)
Remarks:
(Price et al., 1994, 1995) - Study B
Dose / conc.:
76 mg/kg bw/day (nominal)
Remarks:
(Price et al., 1994, 1995) - Study B
Dose / conc.:
143 mg/kg bw/day (nominal)
Remarks:
(Price et al., 1994, 1995) - Study B
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)

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
BMD:
Effect level:
59 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: Decreased foetal body weight provided the best basis for BMD calculations. The benchmark dose is defined as the 95% lower bound on the dose corresponding to a 5% decrease in the mean fetal weight (BMDL05).
Remarks:
Results are based on the studies of Heindel et al. (1992), Price, Marr & Myers (1994) and Price et al. (1996) (cited in Allen et al., 1996).
Dose descriptor:
BMD:
Effect level:
10.3 mg/kg bw/day
Based on:
element
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: Results are based on the studies of Heindel et al. (1992), Price, Marr & Myers (1994) and Price et al. (1996) (cited in Allen et al., 1996).

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- incidence of total malformations, enlarged lateral ventricles in the brain, agenesis or shortening of rib XIII , and variations of the first lumbar rib, as well as decreased fetal weights.

Effect levels (fetuses)

open allclose all
Dose descriptor:
BMD:
Effect level:
59 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: Decreased foetal body weight provided the best basis for BMD calculations. The benchmark dose is defined as the 95% lower bound on the dose corresponding to a 5% decrease in the mean fetal weight (BMDL05).
Remarks:
Results are based on the studies of Heindel et al. (1992), Price, Marr & Myers (1994) and Price et al. (1996) (cited in Allen et al., 1996).
Dose descriptor:
BMD:
Effect level:
10.3 mg/kg bw/day
Based on:
element
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: Results are based on the studies of Heindel et al. (1992), Price, Marr & Myers (1994) and Price et al. (1996) (cited in Allen et al., 1996).

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Developmental toxicity risk assessment has typically relied on the estimation of reference doses or reference concentrations based on the ues of NOAELs divided by uncertainty factors. The benchmark dose approach has been proposed as an alternative basis for reference value calculations. In the analysis presented of the developmental toxicity of rats exposed to boric acid in their diet, BMD analyses have been conducted using two existing studies. By considering various endpounts (rib XIII effects, variations of the first lumbar rib) and fetal weight changes and various modelling approachesfor those endpoints the best approach for incorporating all the information was determined. Decreased foetal body weight provided the best basis for BMD calculations. The BMD was calculated as 59 mg/kg bw/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.