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

Toxicity to reproduction

Administrative data

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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: Comparable to guideline study with acceptable restrictions.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1966

Report date:

1966

Reference 2

Reference Type:

publication

Title:

Toxicologic studies on borax and boric acid.

Author:

Weir RJ & Fisher RS

Year:

1972

Bibliographic source:

Toxicology and Applied Pharmacology 23: 351 - 364.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: No guideline specified, but conforms to the standard 3 generation 2 litters per generation MGS normally used at that time.

Deviations:

not specified

GLP compliance:

no

Remarks:

Study pre-dates GLP

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1303-96-4

EC Number:

603-411-9

Cas Number:

1303-96-4

IUPAC Name:

1303-96-4

Details on test material:

- Name of test material: Sodium tetraborate decahydrate (borax)
- Physical state: Fine white powder without odour
- Analytical purity: > 99 %
- Stability under test conditions: Stable

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, USA.
- Weight at study initiation: (P) Males: 130 - 135 g; Females: 110 - 149 g
- Diet (e.g. ad libitum): Ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

This was a three generation multigeneration study with two matings (two litters) per generation. The F1a, F2a and F3a litters were sacrificed at weaning, and the F1b and F2b litters raised and used for breeding, and the F3b killed at weaning.

Details on mating procedure:

- M/F ratio per cage: 1 M and 2 F per cage
- Length of cohabitation: 21 days on each occassion

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

Groups of 8 males and 16 females were used for all generations. 14 weeks before mating.
From beginning of the study until sacrifice of parents P0, and from weaning till sacrifice for the parents of the F1 and F2-generations. The high dose group P animals were sterile so only controls, low and mid dose groups were taken to the F2 and F3 generations.

Frequency of treatment:

No data

Details on study schedule:

Offspring were culled to 8 per litter at 24 h after delivery.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1030, 3080 or 10300 ppm borax (0, 117, 350 and 1,170 ppm boron) in the diet, equivalent to 0, 50 (5.9), 155 (17.5) and 518 (58.5) mg borax (mg B)/kg bw/day respectively
Basis:
nominal in diet

No. of animals per sex per dose:

8 males, 16 females per group

Control animals:

yes, plain diet

Positive control:

No data

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


FOOD CONSUMPTION AND COMPOUND INTAKE: Yes, weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE : No

Oestrous cyclicity (parental animals):

No data

Sperm parameters (parental animals):

No data, except in the high dose group in which histology of the testes was performed.

Litter observations:

Number and sex of pups, still births, livebirths, presence of gross abnormalities, weight gain, physical or behavioural abnormalities.

Postmortem examinations (parental animals):

Organ weights: Uterus, ovaries, testes, brain, liver, kidneys, spleen, thyroid and adrenals
Histopathology: All parental animals were necropsied and a range of tissues preserved in formalin but not examined histologically except for testes, ovaries and uterus of the high dose group only.

Postmortem examinations (offspring):

Organ weights: Uterus, ovaries, testes, brain, liver, kidneys, spleen, thyroid and adrenals
Histopathology: 5 of each sex from all groups of the F3b litters were necropsied and a range of tissues fixed in formalin but not examined histologically.

Statistics:

No data

Reproductive indices:

No data

Offspring viability indices:

No data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

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:

not specified

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

effects observed, treatment-related

Reproductive performance:

effects observed, treatment-related

Details on results (P0)

Parent males:
Rats exposed to the high dose of 518 mg/kg borax (corresponding to a level of 58.5 mg B/kg bw) had reduced bodyweights though food intake was not affected and they were sterile. Microscopic examination of the atrophied testes of all males in this group showed no viable sperm. There were no adverse effects on reproduction reported at exposures of 5.9 and 17.5 mg B/kg bw. The authors reported no adverse effects on fertility, lactation, litter size, progeny weight or appearance in rats exposed to either 5.9 or 17.5 mg B/kg bw. Also, no gross abnormalities were observed in the organs from these dose groups.

Parent females:
The high dose groups of the P0 generation had reduced bodyweight without any effect on food intake. Evidence of decreased ovulation in about half of the ovaries examined from the females exposed to 58.5 mg B/kg bw and only two of 16 females produced a litter (one of which was cannibalised within 24 h) when mated with control male animals. There were no adverse effects on reproduction and no gross abnormalities were observed in the organs at exposures of 5.9 and 17.5 mg B/kg bw.

The high dose group (58.5 mg B/kg bw) males and females showed clinical signs of toxicity with rough fur, scaly tails, respiratory distress and inflamed eyelids.

Effect levels (P0)

1

Dose descriptor:

LOAEL

Effect level:

518 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Equivalent to 1170 boron in the diet based on sterility in males and females.

2

Dose descriptor:

NOAEL

Effect level:

155 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Equivalent to 350 ppm boron in the diet.

3

Dose descriptor:

LOAEL

Effect level:

58.5 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

other: Based on sterility in males.

4

Dose descriptor:

NOAEL

Effect level:

17.5 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

other: There were no adverse effects on reproduction reported at exposures of 5.9 and 17.5 mg B/kg bw.

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Details on results (F1)

F1 and F2 males and females: There were no adverse effects on reproduction and no gross abnormalities were observed in the organs at exposures of 5.9 and 17.5 mg B/kg bw.

Effect levels (F1)

1

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

155 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Equivalent to 350 ppm boron in the diet.

2

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

17.5 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

other: There were no adverse effects on reproduction reported at exposures of 5.9 and 17.5 mg B/kg bw.

Results: F2 generation

Effect levels (F2)

1

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

155 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Equivalent to 350 ppm boron in the diet.

2

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.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Parameter			Control		Low dose		Medium dose			High dose
		Generation	m	f	m	f	m	f		m	f
Mortality	Incidence	P	0	0	0	0	0	0		1	0
		F1	0	0	0	0	1	0		0	0
		F2	0	0	0	0	0	0		0	0
Food consumption	% of control	Not affected
Body weight gain	% of control		-	-	-	-	-	-	¯		¯
Clinical Observations	Incidence		-	-	-	-	-	-	+		+
Organ weights	% of control	Only effect noted was increase in absolute and relative thyroid wt. in low and mid dose groups (not thought to biologically significant)
Pathology
Histopathologic examination	Incidence	Evidence of testis atrophy in high dose males of P0 generation. Evidence in ovary of reduced ovulation in high dose females.
Reproductive Performance		P0 to F1a				F1b to F2b			F2b to F3b
		cont	low	mid	high	cont	low	mid	cont		low	mid
Mating index: (No. pregnant/No. mated)	%	63	69	75	0	80	75	94	69		88	100
Fertility index: No. litters born/No. Pregnant	%	100	100	100	-	100	100	100	91		100	100
Birth index
Live birth index: No.pups alive/No. born	%	98	98	100		99	92	99	100		100	100
Litter size	Mean	12	12	13		12	15	12	12		12	12
Pup weight at 24h (g)	Mean	7.0	6.8	7.1		6.4	6.2	7.0	6.0		7.0	8.0
Sex ratio	Male/female	6/6	6/6	6/7		6/6	8/7	5/7	6/6		7/5	6/6
Lactation index: Pup wt. at weaning		55	55	51		56	58	53	48		52	52

Applicant's summary and conclusion

Conclusions:

Rats exposed to the high dose of 518 mg/kg bw of borax (corresponding to a level of 58.5 mg B/kg bw) were sterile. Microscopic examination of the atrophied testes of all males in this group showed no viable sperm. The authors also reported evidence of decreased ovulation in the majority of ovaries examined from the females exposed to 58.5 mg B/kg bw and no litters were obtained from these high dose females when mated with control male animals. There were no adverse effects on reproduction reported at exposures of 50 and 155 mg/kg bw borax ( 5.9 and 17.5 mg B/kg bw). The authors reported no adverse effects on fertility, lactation, litter size, progeny weight or appearance in rats exposed to either 5.9 or 17.5 mg B/kg bw. Also, no gross abnormalities were observed in the organs examined from either parents or weanlings from these dose groups. Based on these study data, the authors concluded that exposure of rats at levels up to 17.5 mg B/kg bw in the diet in a 3 generation reproduction study was without adverse effect. Data presented with boric acid data to support the data obtained with boric acid.