Borate(1-), tris(acetato-.kappa.O)hydro-, sodium, (T-4)-

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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: Acceptable, well documented publication with the decomposition product boric acid which meets basic scientific principles

Qualifier:

equivalent or similar to guideline

Guideline:

other: No guideline specified, but equivalent to the standard 3 generation study/multi-generation studies normally used at that time.

Principles of method if other than guideline:

No guideline specified, but equivalent to the standard 3 generation study/multi-generation studies normally used at that time.

GLP compliance:

no

Remarks:

prior to GLP

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Cesarean-derived from Charles River
- Weight at study initiation: 110 - 150 g
- Housing: Individidually housed
- Diet (e.g. ad libitum): Purina Laboratory Chow; ad libitum

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

- M/F ratio per cage: 1:2
- Length of cohabitation: 21
- Breeding schedule:
24 h after birth, the F1 litters were reduced to a maximum of eight pups and discarded when they reached 21 days of age.
The parents in the control and two lower test groups were mated again. At the time of resulting weaning animals (F1B) 16 females and 8 males from the control and two test groups were chosen randomly and designated as the second parental generation (P2) for continuation of the reproduction study. These animals were bread to produce the F2A and F2B litters as before with the F2B litter becoming the P3 generation which was bread to produce the F3A and F3B litters.
Additional breeding of the high dose P1 with control males was performed to investigate whether the female reproductive system was affected.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

From premating for 14 days until scheduled necropsy of F3 generation

Frequency of treatment:

Daliy, ad libitum

Details on study schedule:

- Schedule:
F1a, F2a and F3a litters were sacrificed at weaning, while F1b and F2b litters raised and used for breeding.

Remarks:

Doses / Concentrations:
34, 100, 336 mg/kg bw/d
Basis:
nominal in diet
Boric acid

Remarks:

Doses / Concentrations:
670, 2000, 6700 ppm
Basis:
nominal in diet
Boric acid

Remarks:

Doses / Concentrations:
5.9, 17.5, 58.8 mg/kg bw/d
Basis:
nominal in diet
Element Boron

No. of animals per sex per dose:

P1: 8 males and 16 females
P2: 8 males and 16 females
P3: 8 males and 16 females

Control animals:

yes, plain diet

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): weekly

Sperm parameters (parental animals):

Parameters examined in all male parental generations: analysis of sperm viability

Litter observations:

STANDARDISATION OF LITTERS
- Yes, maximum of 8 pups/litter; excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in all offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Reproductive indices:

Fertility index = number of pregnancies/number of matings x 100
Lactation index = number weaned/numbe left to nurse x 100

Offspring viability indices:

Live birth index= number of pups born alive/number of pups born x 100

Clinical signs:

not specified

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

effects observed, treatment-related

Reproductive performance:

effects observed, treatment-related

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
The high dose group (58.5 mgB/kg bw) males and females showed clinical signs of toxicity with rough fur, scaly tails, respiratory distress and inflamed eyelids.

REPRODUCTIVE FUNCTION:
When females of that group were mated with untreated males they had no offspring, indicating that the female reproduction was affected. A decreased ovulation in the majority of ovaries examined in that group was mentioned not to be sufficient to explain the observed infertility.
The high dose group P animals showed lack of viable sperm.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no adverse effect on the reproduction in low and mid dose animals.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No abnormalities were observed in the examined organs, except atrophied tested in the high dose males.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Atrophied tested in the high dose males were seen.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

Boric acid in diet

Sex:

male/female

Basis for effect level:

other: Arophied testes in all P1 males

Dose descriptor:

NOAEL

Effect level:

17.5 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Boron in diet

Sex:

male/female

Basis for effect level:

other: atrophied testes in all P1 males

Dose descriptor:

LOAEL

Effect level:

336 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

Boric acid in diet

Sex:

male/female

Basis for effect level:

other: histopathology;

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

Boric acid in diet

Sex:

male/female

Basis for effect level:

other: Atrophied testes in all P1 males

Remarks on result:

other: Generation: F1, F2 (migrated information)

Dose descriptor:

NOAEL

Effect level:

17.5 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Boron in diet

Sex:

male/female

Basis for effect level:

other: Atrophied testes in all P1 males

Remarks on result:

other: Generation: F1, F2 (migrated information)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

not examined

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

VIABILITY (OFFSPRING)
No change in litter size and livebirth index was noted in F1, F2 and F3 litters in low and high dose groups compared with control values.

BODY WEIGHT (OFFSPRING)
No change in body of pups in low and high dose groups weights was noted in F1, F2 and F3 litters in compared with control values.

GROSS PATHOLOGY (OFFSPRING)
No abnormalities were observed in the examined organs.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Equivalent to 350 ppm of Boron in the diet.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

17.5 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

other: None

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Equivalent to 350 ppm of Boron in the diet.

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

17.5 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

other: No adverse effects in mid and low dose groups in any generation.

Reproductive effects observed:

not specified

Reproduction data:

	Control	Dietary level of Boric acid		Control	Dietary level of Boric acid
Index		34 mg/kg bw/d	100 mg/kg bw/d		34 mg/kg bw/d	100 mg/kg bw/d
	P1 - F1A			P1 - F1B
Fertility index	62.5	87.5	81.3	60	87.5	75
lactation index	56.3*	96.2	70.3*	58.8	85.6*	80.0*
Live birth index	98.4	96	97.2	99.1	99.4	100
	P2 - F2A			P2 - F2B
Fertility index		81.3	93.8	80	93.8	93.8
lactation index		48.3	79.2*	92.1	81	98
Live birth index		97.8	100	98.6	99.4	97.9
	P3 - F3A			P3 - F3B
Fertility index	68.8	100	87.5	68.8	93.8	93.8
lactation index	91.5	82.5	86.5	89.7	86.7	87.9
Live birth index	100	99.5	97.9	100	99	98.8

* significantly higher than control

Conclusions:

Based on the sterility in the highest dose group, the NOAEL for reproduction was found to be 100 mg/kg bw/d Boric acid in diet corresponding to 17.5 mg/kg bw Boron.

Executive summary:

In a three generation study in rats groups of 8 males and 16 females were treated with boric acid equivalent to 0, 5.9, 17.5 and 58.8 mg boron/kg bw/day. The high dose P1-generation failed to produce litter. Also when females of that group were mated with untreated males they had no offspring, indicating that the female reproduction was affected. A decreased ovulation in the majority of ovaries examined in that group was mentioned not to be sufficient to explain the observed infertility since only ovaries of high dosed females were examined. However, gross necropsy revealed atrophied testes in all P1 males at 58.8 mg boron/kg bw/day. Based on the sterility in the highest dose group, the NOAEL for reproduction was found to be 100 mg/kg bw/d Boric acid in diet corresponding to 17.5 mg/kg bw Boron.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

343 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a three generation study in rats groups of 8 males and 16 females were treated with boric acid equivalent to 0, 5.9, 17.5 and 58.8 mg boron/kg bw/day. The high dose P1-generation failed to produce litter. Also when females of that group were mated with untreated males they had no offspring, indicating that the female reproduction was affected. A decreased ovulation in the majority of ovaries examined in that group was mentioned not to be sufficient to explain the observed infertility since only ovaries of high dosed females were examined. However, gross necropsy revealed atrophied testes in all P1 males at 58.8 mg boron/kg bw/day. Based on the sterility in the highest dose group, the NOAEL for reproduction was found to be 100 mg/kg bw/d Boric acid in diet corresponding to 17.5 mg/kg bw Boron and 343 mg/kg bw/d for Sodium triacetoxyborohydride respectively.

Short description of key information:
Reproduction: NOAEL = 343 mg/kg bw/d (= 100 mg/kg bw Boric acid or 17.5 mg/kg bw/d for element Boron; 3-Generation study in rats)

Justification for selection of Effect on fertility via oral route:
Reliable published study, peer reviewed and already internationally used for risk assessment

Effects on developmental toxicity

Description of key information

Developmental toxicity: NOAEL = 428 mg/kg bw/d (= 125 mg/kg bw Boric acid or 21.8 mg/kg bw/d for element Boron (comp. OECD 414)

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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: Acceptable, well documented publication of a study performed equivalent to OECD guideline with the decomposition product boric acid

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

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: approx. 5 months
- Weight at study initiation: 2690 - 4380 g
- Housing: individually in stainless steel cages with mesh flooring
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow (No. 5322), Ralston Purina Co., St. Louis, MO, USA; ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 - 26.1
- Humidity (%): 47 - 89
- Photoperiod (hrs dark / hrs light): 12 / 12 (females), 10 / 14 (males)

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled/deionized

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
dose volume was adjusted daily.


VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Assays (UVNIS spectroaxtry) conducted prior to dosing indicated that all formulations were within a range of 94-106% of the theoretinl concentrationa Formulations were used within the period of demcostrued stability.

Details on mating procedure:

- Impregnation procedure: artificial insemination
- Any other deviations from standard protocol: The study was performed in two replicates with two consecutive breeding days within each replicate
and 34 days between replicates.

Duration of treatment / exposure:

Treatment: on gestational days 6 - 19
Termination: at day 30 of gestation

Frequency of treatment:

Once daily on the mornings, 7 d/weeks

Duration of test:

30 days (gestation days 0 - 30)

Remarks:

Doses / Concentrations:
62.5, 125 or 250 mg/kg bw
Basis:
actual ingested
Boric acid

Remarks:

Doses / Concentrations:
10.9, 21.8 and 43.5 mg/kg bw
Basis:
actual ingested
Element Boron

No. of animals per sex per dose:

30

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on reults of preliminary toxicity study where nonpregnant female rabbits (2/group) were dosed with BA (0 or 275 mg/kg bw/day, po) using a dose volume of 5 mL/kg in distilled/deionized water.

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6-19, 25 and 30

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, at 2-3 days intervals
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 30
- Organs examined: liver, kidneys,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 resorptions: Yes

Fetal examinations:

- External examinations: Yes: All per litter, including cleft palate
- Soft tissue examinations: Yes: All per litter, including sex determination
- Skeletal examinations: Yes: All per litter
- Head examinations: Yes: Half per litter

Litter size, number of dead foetuses and foetal weight were assessed.

Statistics:

The doe or litter was considered the experimental unit for all statistical analyses . General Linear Models (GLM) procedures were applied for the analyses of variance (ANOVA) of maternal and fetal parameters . Prior to GLM analysis, an arcsinesquare root transformation was performed on all litter-derived percentage data and Bartlett's test for homogeneity of variance was performed on all data to be analysed by ANOVA . GLM analysis determined the significance of dose-response relationships and the significance of dose effects, replicate effects, and dose X replicate interactions . When ANOVA revealed a significant (p < 0 .05) dose effect, Dunnett's multiple comparison test compared exposed groups to control groups. One-tailed tests were used for all pairwise comparisons except maternal body and organ weights and fetal body weight. Nominal scale measures were analyzed by x² test for independence and by a test for linear trend on proportions. When a x² test showed significant groupwise differences, a one-tailed Fisher's exact probability test was used for pairwise comparisons of control and BA groups.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
No treatment-related clinical signs of toxicity were observed during the study, except for vaginal bleeding noted in 2-11 does/day on gd 19-30 at the high dose; these does had no live fetuses on day 30. Vaginal bleeding was also observed in one female in the low-dose group and in one in the mid-dose group. Two maternal deaths occurred (one each at the low- and mid-dose), but were not treatment-related. Food intake was decreased relative to that of controls on treatment days 6-15 at the high dose, and was increased after treatment ceased on days 25-30 at the mid and high doses. Body weight on gd 9-30, weight gain on gd 6-19, gravid uterine weight, and number of corpora lutea per dam were each decreased in the high-dose group. After correction for gravid uterine weights, however, maternal body-weight gain was increased at both the mid-and high- doses. Treatment with boric acid did not affect absolute or relative liver weight. Relative, but not absolute kidney weight increased at the high dose; kidney histopathology was unremarkable.

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

Boric acid

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

21.9 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Boron

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

Boric acid

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Effect level:

21.9 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Boron

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Developmental effects were noted in the high dose group which consisted of a high rate of prenatal mortality (90% of implants/litter were reabsorbed compared with 6% in controls). Also, the percentage of pregnant females with no live fetuses was greatly increased (73% compared with 0% in controls), whereas the number of live fetuses per litter on day 30 was significantly reduced (2.3/litter compared with 8.8/litter in controls). Malformed live fetuses per litter increased significantly at the high dose, primarily due to the incidence of fetuses with cardiovascular defects, the most prevalent of which was interventricular septal defect (8/14 at high dose compared with 1/159 in controls). The incidence of skeletal malformations was comparable among groups. Relative to controls, the percentage of fetuses with variations (all types combined) was not significantly increased in any treated group, but the percentage with cardiovascular variations was significantly increased from 11% in controls to 64% in the high-dose group. Fetal body weights per litter at the high dose were depressed relative to control, but the difference was not statistically significant; however, this could have been due to the small sample size in the high-dose group. No developmental effects were found in the low- and mid-dose groups.

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on increased resorptions and CVS malformations in surviving fetuses at 250 mg/kg bw/day

Abnormalities:

not specified

Developmental effects observed:

not specified

Maternal toxicity:

		Boric acid (mg/kg bw/d)
		0	62.5	125	250
No. pregnant at euthanization		18	23	20	22
No. of live litters		18	23	20	6
No. of live fetuses		159	175	153	14
Maternal weight change (g)	Treatment period (GD 6 to 19)	93 ± 30*	132 ± 40	97 ± 51	-137 ± 42**
	Gestation period (GD 0 to 30)	357 ± 69*	493 ± 51	543 ± 63**	226 ± 35
	Corrected gestation wt. gain	-205 ± 78*	-52 ± 63	40 ± 57**	165 ± 40**
	Gravid uterine wa (g)a	562 ± 40*	504 ± 26	502 ± 28	62 ± 18**
Maternal liver weight (% bw)		2.56 ± 0.13	2.8 ± 0.09	2.78 ± 0.08	2.87 ± 0.09
Maternal kidney weight (% bw)		0.46 ± 0.02	0.46 ± 0.01	0.47 ± 0.01	0.51 ± 0.01**
Renal pathology		0/18	2/23	0/20	1/22
Relative food consumption (g/kg/day)	Pretreatment period  (GD 0 to 6)	48.1 ± 1.7	48.0 ± 1.8	48.9 ± 2.4	46.4 ± 1.5
	Treatment period (GD 6 to 19)	38.8 ± 1.7*	40.0 ± 2.0	38.7 ± 2.3	26.6 ± 2.2**
	Posttreament (GD 19-25)	36.9 ± 2.5*	37.0 ± 2.6	40.0 ± 3.1	44.9 ± 2.2
	Posttreament (GD 25-30)	24.5 ± 3.0	30.9 ± 2.1	33.9 ± 1.9**	41.9 ± 1.6**

* p < 0.05, linear trend. .

** p < 0.05, Dunnett's teat.

Developmental effects:

		Boric acid (mg/kg bw/d)
		0	62.5	125	250
No. implantation sites per litter (a)		9.5 ± 0.8	26.1 ± 3.8	8.3 ± 0.5	8.6 ± 0.7
% Resorptions per litter (a)		6.3 ± 2.4*	5.9 ± 1.9	7.7 ± 2.1	89.9 ± 5.0**
% Litters with one or more resorptions		39	39	45	95***
% Litters with 100% resorptions		0	0	0	73***
No. live fetuses per litter (b)		8.8 ± 0.8*	7.6 ± 0.6	7.7 ± 0.5	2.3 ± 0.8**
Average fetal body wt (g) per litter (b)		44.8 ± 1.5	46.5 ± 1.4	45.7 ± 1.2	41.1 ± 2.7
All malformations	% Fetuses per litter (b)	25.5 ± 5.8*	26.1 ± 3.8	30.4 ± 6.3	80.6 ± 16.3**
	%Litters	72	78	75	83
External malformations	% Fetuses per litter (b)	0.8 ± 0.8*	1.4 ± 1.0	1.0 ± 1.0	11.1 v 8.2**
	%Litters	6	9	5	33
Skeletal malformations	% Fetuses per litter (b)	19.9 ± 5.4	19.9 ± 4.0	24.3 ± 6.4	38.9 ± 20.0
	%Litters	61	65	55	50
Visceral malformations	% Fetuses per litter (b)	7.3 ± 1.9*	5.9 ± 2.0	7.4 ± 2.0	80.6 ± 16.3**
	%Litters	50	35	45	83
Cardiovascular malformations	% Fetuses per litter (b)	2.7 ± 1.6*	3.1 ± 1.5	4.2 ± 1.3	72.2 ± 16.5**
	%Litters	17*	22	35	83***
All variations	% Fetuses per litter (b)	67.7 ± 7.2	54.8 ± 5.1	40.4 ± 5.2	86.1 ± 9.0
	%Litters	94	100	90	100
Cardiovascular variations	% Fetuses per litter (b)	10.6 ± 5.5*	5.7 ± 1.8	7.2 ± 2.5	63.9 ± 17.4**
	%Litters	44	35	35	83

a) Includes all dams pregnant at euthanization; litter size is number of implantation sites per dam; mean ± SEM.

b) Includes only dams with live fetuses; litter size is number of live fetuses per dam; mean ± SEM.

* p < 0.05, linear trend. .

** p < 0.05, Dunnett's teat.

*** p< 0.05, Fisher’s exact test.

Conclusions:

Due to observed maternal and developmental effects at 125 mg/kg bw/d Boric acid, this dose corresponding to 21.8 mg/kg bw/d Boron was determined to be the NOAEL.

Executive summary:

Developmental toxicity of Boric acid was evaluated in a GLP study performed equivalent to OECD guideline 414, where groups of 30 New Zealand White) rabbits were administered boric acid once daily by gavage at doses corresponding to 0, 10.9, 21.9 and 43.8 mg boron/kg bw/day during major organogenesis on GD 6-19. The rabbits exposed to 43.8 mg boron/kg bw/day on gestation day 6-19 revealed decreased food intake during treatment, relative but not absolute kidney weight increase and vaginal bleeding. At the highest dose, prenatal mortality was increased (90% resorption/litter versus 6% in controls). In this dose group the number of live fetuses available for evaluation where dramaticall decreased compared to live fetuses in the other groups. Additionally, the resorption rate was disproportionally high (95%) and an increased incidente of malformed live foetuses/litter was observed primarily due to cardiovascular effects. Based on these results, the NOAEL for maternal and developmental toxicity was 125 mg/kg bw/d boric acid corresponding to 21.8 mg/kg bw/d Boron, respectively.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

428 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity of Boric acid was evaluated in a GLP study performed equivalent to OECD guideline 414, where groups of 30 New Zealand White) rabbits were administered boric acid once daily by gavage at doses corresponding to 0, 10.9, 21.9 and 43.8 mg boron/kg bw/day during major organogenesis on GD 6-19. The rabbits exposed to 43.8 mg boron/kg bw/day on gestation day 6-19 revealed decreased food intake during treatment, relative but not absolute kidney weight increase and vaginal bleeding. At the highest dose, prenatal mortality was increased (90% resorption/litter versus 6% in controls). In this dose group the number of live fetuses available for evaluation where dramaticall decreased compared to live fetuses in the other groups. Additionally, the resorption rate was disproportionally high (95%) and an increased incidents of malformed live foetuses/litter was observed primarily due to cardiovascular effects. Based on these results, the NOAEL for maternal and developmental toxicity was 125 mg/kg bw/d boric acid corresponding to 21.8 mg/kg bw/d Boron and 428 mg/kg bw/d for Sodium triacetoxyborohydridee, respectively.

Justification for selection of Effect on developmental toxicity: via oral route:
Reliable published GLP study comparable to OECD 414, peer reviewed and already internationally used for risk assessment

Justification for classification or non-classification

The available data on toxicity to reproduction of the test substance do not meet the criteria for classification Repr. 1B (according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

No information is available on effects via lactation.