Reaction product of mixed inorganic base and acid resulting in dipotassium hydroxytetrafluoro triborontrioxide, potassium trihydroxy fluoroborate, dipotassium tetrahydroxy tetraboronpentaoxide dehydrate in powder form.

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Comparable to a guideline study. This study is conducted on an analogue substance. Read-across is justified on the following basis: In aqueous solutions at physiological and acidic pH, low concentrations of simple inorganic borates such as boric acid, disodium tetraborate decahydrate, disodium tetraborate pentahydrate, boric oxide and disodium octaborate tetrahydrate will predominantly exist as undissociated boric acid. At about pH 10 the metaborate anion (B(OH)4-) becomes the main species in solution (WHO, 1998). This leads to the conclusion that the main species in the plasma of mammals and in the environment is un-dissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as un-dissociated boric acid under the same conditions. For comparative purposes, exposures to borates are often expressed in terms of boron (B) equivalents based on the fraction of boron in the source substance on a molecular weight basis. Some studies express dose in terms of B, whereas other studies express the dose in units of boric acid. Since the systemic effects and some of the local effects can be traced back to boric acid, results from one substance can be transferred to also evaluate the another substance on the basis of boron equivalents. Therefore data obtained from studies with these borates can be read across in the human health assessment for each individual substance. Conversion factors are given in the table below. Conversion factor for equivalent dose of B Boric acid H3BO3 0.175 Boric Oxide B2O3 0.311 Disodium tetraborate anhydrous Na2B4O7 0.215 Disodium tetraborate pentahydrate Na2B4O7•5H2O 0.148 Disodium tetraborate decahydrate Na2B4O7•10H2O 0.113 Disodium octaborate tetrahydrate Na2B8O13•4H2O 0.210 Sodium metaborate (anhydrous) NaBO2 0.1643 Sodium metaborate (dihydrate) NaBO2•2H2O 0.1062 Sodium metaborate (tetrahydrate) NaBO2•4H2O 0.0784 Sodium pentaborate (anhydrous) NaB5O8 0.2636 Sodium pentaborate (pentahydrate) NaB5O8∙5H2O 0.1832 References: WHO. Guidelines for drinking-water quality, Addendum to Volume 1, 1998.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

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: Boric acid
- Analytical purity: > 99.7 %
- stability: Stable
- Lot/batch No.: 872703

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Products Inc., Denver, PA, USA
- Age at study initiation: 5 months of age
- Weight at study initiation: 2690-4380 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

VEHICLE
- Concentration in vehicle: 55 mg/mL boric acid
- Amount of vehicle: 5 mg/mL boric acid

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Details on mating procedure:

- Impregnation procedure: Artificial insemination; designated Day 0

Duration of treatment / exposure:

Groups of 30 rabbits were used treated on Day 6 - 19 post-mating

Frequency of treatment:

No data

Duration of test:

Terminated on Day 30 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 62.5, 125 or 250 mg/kg bw boric acid equivalent to 0, 10.9, 21.8 and 43.5 mg B/kg bw
Basis:
no data

No. of animals per sex per dose:

30 females/group

Control animals:

yes

Details on study design:

No data

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 30
- Organs examined: Uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
- Other:
Uteri were stained with ammonium sulphide as no implantations were visible.
Litter size, number of dead foetuses and foetal weight were assessed.

Fetal examinations:

- External examinations: Yes, including assessment for cleft palate
- Soft tissue examinations: Yes by dissection (Staples) and sex determined
- Skeletal examinations: Yes, all foetuses were skinned and cleaned and stained with alcian blue/alizarin red S
- Head examinations: Yes

Statistics:

No data

Indices:

No data

Historical control data:

No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Pregnant does exhibited no overt symptoms attributable to boric acid toxicity except in the high dose group. A decreased food intake (30 % reduction vs. controls during exposure period) and decreased maternal bodyweight were observed. Vaginal bleeding was noted at 43.5 mg B/kg bw between gestational days 19 - 30. All high-dose animals with vaginal bleeding had no live foetuses at sacrifice. At mid dose, increased body weight gain not clearly adverse. The authors considered 43.5 mg B/kg bw as the LOAEL for pregnant does and 21.8 mg B/kg bw as the NOAEL for maternal toxicity.

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

LOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

4

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

5

Dose descriptor:

LOAEL

Effect level:

43.5 mg/kg bw/day

Based on:

element

Basis for effect level:

other: maternal toxicity

6

Dose descriptor:

NOAEL

Effect level:

21.8 mg/kg bw/day

Based on:

element

Basis for effect level:

other: maternal toxicity

7

Dose descriptor:

LOAEL

Effect level:

43.5 mg/kg bw/day

Based on:

element

Basis for effect level:

other: developmental toxicity

8

Dose descriptor:

NOAEL

Effect level:

21.8 mg/kg bw/day

Based on:

element

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At the highest dose in this study of 250 mg/kg bw boric acid (43.5 mg B/kg bw/day), 90 % of implants/litter were resorbed compared to 6 % for controls, and 73 % had complete litter loss (0 % in controls). In the mid and low dose groups, no difference in percentage resorptions per litter was seen, compared to controls.
Average foetal bodyweight per litter was 92 % of the controls at the high dose (43.5-mg B/kg bw) but even at this exposure, it did not reach statistical significance possibly due to the low number of pups surviving (14 fetuses from 6 litters).
An increased incidence of malformed live foetuses/litter was observed at 43.5 mg B/kg bw, primarily due to cardiovascular defects (72 % for major defects of heart and/or great vessel in the high-dose group vs. 3 % in controls). In the mid and low dose groups, there was no increase in malformations per litter or total malformations. There were no variations between any groups concerning the incidence of skeletal malformations.
The only skeletal variations of interest was a dose related reduction in the incidence of extra ribs on Lumbar I which the authors did not consider to be toxicologically important.
Since no definitive developmental effects were observed in animals exposed to either 62.5 or 125 mg/kg bw boric acid (10.9 or 21.8 mg B/kg bw/day), the authors concluded that 125 mg/kg boric acid per day (21.8 mg B/kg bw/day) was the NOAEL for developmental toxicity.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

>= 21.8 mg/kg bw/day (nominal)

Based on:

element

Sex:

male/female

Basis for effect level:

other: Since no definitive developmental effects were observed in animals exposed to 62.5 or 125 mg/kg bw boric acid (10.9 or 21.8 mg B/kg bw/day), it is concluded that 125 mg/kg boric acid per day (21.8 mg B/kg bw/day) was the NOAEL for developmental toxicity.

2

Dose descriptor:

NOAEL

Effect level:

>= 125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Since no definitive developmental effects were observed in animals exposed to 62.5 or 125 mg/kg bw boric acid (10.9 or 21.8 mg B/kg bw/day), it is concluded that 125 mg/kg boric acid per day (21.8 mg B/kg bw/day) was the NOAEL for developmental toxicity.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Maternal effects

Parameter	Study control data	Low dose	Medium dose	High dose
Number of dams examined	30	30	30	30
Clinical findings during application of test substance				reduced food and bodyweight
Mortality of dams (%)	0	1	1	0
Abortions	0	0	0	3
Body weight gain               day 6-19                                              day 0-30	93 357	132 493	97 543	-137* 226
Food consumption g/kg/day  day 0-6                                                  day 6-19                                                  day 19-25	48.1 38.8 36.9	48.0 40.0 37.0	48.9 38.7 40.0	46.4 26.6* 44.9
Pregnancies  % pregnant at sacrifice	75	89	87	96
Necropsy findings in dams dead before end of test		gavage error lungs	stomach damage

* P < 0.05.

 

Litter response (Caesarean section data)

Parameter	Control data	Low dose	Medium dose	High dose
Corpora lutea                        number                                                  ±SEM mean No. per dam	12.2 0.7	10.7 0.5	11.5 0.4	10.0* 0.7
Implantations sites per litter     number                                                      ±SEM total/number of dams	9.5 0.8	8.4 0.6	8.3 0.5	8.6 0.7
Resorptions % per litter               % total/number of dams          ±SEM	6.3 2.4	5.9 1.9	7.7 2.1	89.9 5.0
total number of foetuses	159	175	153	14
total number of litters	18	23	20	6
live foetuses / litter                 number state ratio                               ±SEM	8.8 0.8	7.6 0.6	7.7 0.5	2.3* 0.8
dead foetuses / litter        % state ratio	0	2.8	0.4	0
foetus weight (mean)                   weight (g)                                                         ±SEM	44.8 1.5	46.5 1.4	45.7 1.2	41.1 2.7
Foetal sex ratio    % male per litter                                    ±SEM	50 5	51 4	55 4	69 10

* P<0.05

 

Examination of the foetuses

Parameter	Control data	Low dose	Medium dose	High dose
External malformations^* % foetuses per litter  ±SEM	0.8 0.8	1.4 1.0	1.0 1.0	11.1* 8.2
External malformations    No. of foetuses	1	2	1	2
Skeletal malformations^* % foetuses per litter ±SEM	19.9 5.4	19.9 4.0	24.3 6.4	38.9 20.0
Skeletal malformations     No. of foetuses	30	39	44	4
Visceral malformations^* % foetuses per litter  ±SEM	7.3 1.9	5.9 2.0	7.4 2.0	80.6* 16.3
Visceral malformations      No. of foetuses	13	11	12	11
% foetuses with cardiovascular       % malformations                               ±SEM	2.7 1.6	3.1 1.5	4.2 1.3	72.2* 16.5

* P<0.05

Applicant's summary and conclusion

Conclusions:

The highest dose was very toxic to dams and 90 % of implants were resorbed at the highest dose level, and 72 % of surviving foetuses had cardiac or great vessel malformations or increase in resorptions were reported in the mid and low dose groups.
Read-across is justified on the basis detailed in the rationale for reliability above. This study is therefore considered to be of sufficient adequacy and reliability to be used as a supporting study and no further testing is justified.