Potassium metaborate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

reproductive toxicity, other

Remarks:

various methods are presented in this report

Type of information:

experimental study

Remarks:

publication / peer-reviewed report

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

peer-reviewed

Qualifier:

no guideline required

Principles of method if other than guideline:

Review of literature data

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: various

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Route of administration:

oral: unspecified

Conclusions:

The present information was based on a literature review (peer-reviewed) of sodium borate and boric acid studies. Most, but not all reviewed studies indicated that boron had adverse effects on reproduction, more specific on the gonads of the males. Nevertheless, due to the limited information, obvious threshold and some deviating results, data does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.

Executive summary:

A literature review of sodium borate and boric acid showed that these borates interfere with reproduction, mainly by effects on the gonads of the males. Data does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.

Reference 2

Endpoint:

reproductive toxicity, other

Remarks:

various methods are presented in this report

Type of information:

experimental study

Remarks:

publication / peer-reviewed report

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

no guideline required

Principles of method if other than guideline:

Review of literature data

GLP compliance:

no

Limit test:

no

Species:

other: rodents, including rats, mice, deer mice, and gerbils

Strain:

other: various

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Route of administration:

other: orally, via feed or unspecified

Vehicle:

not specified

Details on exposure:

see below

Details on mating procedure:

see below

Details on study schedule:

see below

Conclusions:

The present information was based on a literature review of borax and boric acid studies. Most, but not all reviewed studies indicated that boron had adverse effects on reproduction, more specific on the gonads of the males. Nevertheless, due to the limited information, obvious threshold and some deviating results, data does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.

Executive summary:

A literature review of borax and boric acid showed that these borates interfere with reproduction, mainly by effects on the gonads of the males. Data does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.

Reference 3

Endpoint:

three-generation reproductive toxicity

Type of information:

experimental study

Remarks:

reported in a publication

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Documentation slightly limited, but given data indicates that testing was performed scientifically reasonable.

Qualifier:

no guideline available

Principles of method if other than guideline:

- Principle of test: Rats were fed boron via diet, in total 3 generations were produced and observed
- Parameters analysed / observed: Fertility index, Lactation index, Live birth index, Litter size, weights of progeny and appearance, microscopic examination of the testes

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

Both borax (Na2B407. 10H2O) and boric acid (H3BO3) of ACS grade were supplied by the U.S. Borax Research Corporation, Anaheim, California. The boron equivalent is generally referred to throughout the text. Values for deriving these equivalents are as follows.
Weight boric acid (H3BO3) x 0.1750 = equivalent weight boron
Weight borax x 0.1134 = equivalent weight boron

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Pathogen Free and Cesarean-derived rats were used.
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: 110-150 g
- Fasting period before study: no
- Housing: Prior to initiation of the first breeding phase, the animals were maintained in individual cages and fed their respective diets for 14 wk.
- Diet (e.g. ad libitum): yes

Route of administration:

oral: feed

Vehicle:

not specified

Details on mating procedure:

Cesarean-derived rats (weighing 110-1 50 g) were randomized in groups of 8 males and 16 females. The animals received borax or boric acid at 117, 350 and 1170 ppm as boron equivalent in the diet.
Prior to initiation of the first breeding phase, the animals were maintained in individual cages and fed their respective diets for 14 wk. Body weight and food consumption were recorded weekly. After the 14 wk feeding period, 1 male and 2 females were placed in each breeding cage. At 24 hr after birth, the litters were reduced to a maximum of 8 progeny to be raised. The first filial generation (F1A) was carried through weaning and discarded. The parental generation (P1) was rebred to produce their second litter (F1B). At the time of weaning, 16 females and 8 males each from the control and test groups were selected at random and designated the second parental generation (P2) for continuation of the reproduction study. These animals were bred to produce the FZA and FZB litters as before. The F2B litter became the P3 generation and were bred to produce the F3A and F3B litters. With the exception of the P1, P2 and P3 control and test groups, necropsies were performed on all rats.

Analytical verification of doses or concentrations:

not specified

Details on study schedule:

see above

Dose / conc.:

0 ppm

Remarks:

control

Dose / conc.:

117 ppm

Dose / conc.:

350 ppm

Dose / conc.:

1 170 ppm

No. of animals per sex per dose:

8 males, 16 females

Control animals:

yes, plain diet

Details on study design:

- Rationale for animal assignment (if not random): random

Positive control:

not required

Parental animals: Observations and examinations:

no further data provided

Oestrous cyclicity (parental animals):

ovaries were examined

Sperm parameters (parental animals):

microscopic examination of the testes

Litter observations:

litter size, weights, appearance

Postmortem examinations (parental animals):

necropsy

Reproductive indices:

fertility index

Offspring viability indices:

lactation, live birth index

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic examination revealed the lack of viable sperm in the atrophied testes of all males at the 1170 ppm boron equivalent level of both borax and boric acid. Evidence was also found of decreased ovulation in the majority of the ovaries examined from the same level females sacrificed following the reproduction study.

Reproductive function: oestrous cycle:

effects observed, treatment-related

Description (incidence and severity):

Evidence was also found of decreased ovulation in the majority of the ovaries examined from the 1170 ppm females

Reproductive function: sperm measures:

effects observed, treatment-related

Description (incidence and severity):

Microscopic examination revealed the lack of viable sperm in the atrophied testes of all males at the 1170 ppm boron equivalent level of both borax and boric acid.

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

The high level test groups fed both borax and boric acid at 1170 ppm as boron equivalent were found to be sterile.

Key result

Dose descriptor:

NOAEL

Effect level:

350 ppm

Based on:

element

Remarks:

boron

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Remarks on result:

other: corresponding to 2651.7 mg/kg BHO2.K

Key result

Dose descriptor:

LOAEL

Effect level:

1 170 ppm

Based on:

element

Remarks:

boron

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Remarks on result:

other: corresponding to 8864.3 mg/kg BHO2.K

Critical effects observed:

not specified

Clinical signs:

not specified

Mortality:

no mortality observed

Description (incidence):

There were no adverse effects on the reproduction of rats receiving a diet containing either borax or boric acid at 117 and 350 ppm as boron equivalent. Litter size, weights of progeny and appearance were normal compared with those of the controls. The overall fertility indices for the two test compounds at levels of 177 and 350 ppm boron were significantly higher than those of the controls. Higher lactation indices also occurred in rats fed at the same levels of boric acid and in rats fed 350 ppm boron in borax. Live birth indices were within normal limits in the test groups. No gross abnormalities were observed in the organs examined from either parents or weanlings. The high level test groups fed both borax and boric acid at 1170 ppm as boron equivalent were found to be sterile.

Body weight and weight changes:

not specified

Reproductive effects observed:

yes

Lowest effective dose / conc.:

1 170 other: ppm boron equivalents

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

The study was performed as a three generation reproductive toxicity study with some deficiencies in documentation and performed on suitable read-across substances. The given data can hence be considered sufficiently reliable, however rather limited. Doses of 1170 ppm borax or boric acid as boron equivalent in feed were found to interfere with reproduction, while doses of 350 ppm boron in borax and boric acid had no adverse effect on fertility, lactation, litter size, weight or appearance. Nevertheless, due to the limited information and high threshold, data does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.

Executive summary:

A study was performed as a three generation reproductive toxicity study in rats. 0, 117, 350 or 1170 ppm borax or boric acid as boron equivalent in feed were applied. There were no adverse effects on the reproduction of rats receiving a diet containing either borax or boric acid at 117 and 350 ppm as boron equivalent. Litter size, weights of progeny and appearance were normal compared with those of the controls. The overall fertility indices for the two test compounds at levels of 177 and 350 ppm boron were significantly higher than those of the controls. The high level test groups fed both borax and boric acid at 1170 ppm as boron equivalent were found to be sterile. Given data however does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Justification for classification or non-classification

Regulation 1272/2008 and amendments foresee classifications for reproductive toxicity in the categories 1A, 1B, and 2.

According to the regulation, Category 1 is a known or presumed human reproductive toxicant. Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

 

Category 1A: Known human reproductive toxicant. The classification of a substance in Category 1A is largely based on evidence from humans.

There is no direct evidence for reproductive toxicity in humans.No definitive studies have been reported for humans. Two studies reported that sperm counts and sexual performance in Russian men were compromised due to boron content in drinking water; however, only sparse data were provided in these reports, and independent evaluation was not possible.

A questionnaire-based study of 542 men working in the production of borax (mining and processing sodium borates), exposed to as much as 23.2 mg borax/m³inhaled as soluble borates (0.48 mg BE/kg bw/d for as long as 5 years), revealed no obvious reproductive toxicity. Men were fertile at or above United States rates. [Fail PA et al., Reproductive Toxicology 12 (1) 1 – 18]

There is no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers (Whorton d,Environ. Health Perspect. 102 (Suppl. 7) 129 - 131; Sayli BS Biological Trace Element Research 66: 409 - 422; Robbins WA,Reproductive Toxicology 29: 184 - 190; Scialli AR, Reproductive Toxicology 29: 10 - 24.; Duydu Y, Arch Toxicol. 2011 Jun;85(6):589-600). There is also no evidence of developmental effects in humans attributable to boron in studies of populations with high exposures to boron (Tüccar E, Biological Trace Element Research 66: 401- 407; Col M, T Klin Med Res 18: 10 - 16; Chang Bl, AAOHN 54(10) 435 - 443). No boron accumulation occurs in soft tissues (testes) over plasma levels as seen during biological monitoring in humans. Workers in boron mining and processing industries represent the maximum possible human exposure. Extensive evaluations of sperm parameters in highly exposed workers have demonstrated no effects on male fertility. So classification asCategory 1A is definitively not required.

 

Category 1B: Presumed human reproductive toxicant. The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

Besides the fact that there is mechanistic information that raises doubt about the relevance of the effect for humans, the definition of category 2 is rather met, as will be outlined below, because the quality of evidence is considered less convincing to justify classification as Cat. 1B.

 

Category 2: Suspected human reproductive toxicant. Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

First of all, there are no studies on reproductive toxicity on the registered substance itself available. All information was gained from studies on mainly boric acid, but also borax and sodium borate. Hence, all information is in general accompanied with a certain level of uncertainty, so all information was per se rated as Klimisch 2, making the given information in general not sufficiently convincing to place the substance in Category 1. Further, no GLP guideline studies are available, all information is taken from publications. These studies of course allow in general the conclusion they were acceptable and performed in a scientifically reasonable manner, but do not provide information adequate to GLP guideline studies. This is however not relevant under REACH, as the substance of interest, potassium metaborate, is registered in a tonnage band of < 10 tpa. According to Annex VII, no data on reproductive toxicity is required in this case, and all information was only provided to support the assessment of the substance.

 

There is athree generation reproductive toxicity study available [Weir RJ, Toxicology and applied Pharmacology 23, 351-364 (1972)], with some deficiencies in documentation and performed on suitable read-across substances. Doses of 1170 ppm borax or boric acid as boron equivalent in feed were found to interfere with reproduction, while doses of 350 ppm boron in borax and boric acid had no adverse effect on fertility, lactation, litter size, weight or appearance.The overall fertility indices for the two test compounds at levels of 177 and 350 ppm boron were significantly higher than those of the controls. Higher lactation indices also occurred in rats fed at the same levels of boric acid and in rats fed 350 ppm boron in borax. Live birth indices were within normal limits in the test groups. No gross abnormalities were observed in the organs examined from either parents or weanlings. The high level test groups fed both borax and boric acid at 1170 ppm as boron equivalent were found to be sterile. The authors assessing other reproductive toxicity studies came to the following conclusions: In rat reproduction studies, doses of 1170 ppm borax or boric acid as boron equivalent were found to interfere with reproduction, while doses of 350 ppm boron in borax and boric acid had no adverse effect on fertility, lactation, litter size, weight or appearance. Ploquin (1967), reporting the work of Nguyen Phy Lich, indicated that boric acid at 350 ppm as boron equivalent produced stillbirth or death 3 or 4 days postpartum. Ploquin relates this to the earlier work of Caujolle et al. (1962) and the teratogenic effect observed by Ridgeway and Karnofsky (1952) and Landauer (1953) using the chick embryo technique. The controversy over the validity of the latter technique for evaluation of teratogenicity may make such a correlation undesirable even when the evidence by two techniques points in the same direction.

The results obtained from these studies indicate that there is a reasonable margin of safety between the toxic dose in animals and the levels of boron which may occur as incidental residues from the use of borax and boric acid in agriculture and industry. The toxicologic effects and levels which can be tolerated in the case of borax and boric acid are markedly similar when doses are compared on a boron equivalent basis. In these studies, 350 ppm boron equivalent in the chronic exposure of rats and dogs as well as in the reproduction study is without adverse effect and can be described as the no effect level.

 

Aliterature review (peer-reviewed) of sodium borate and boric acid studies indicated via most, but not all studies that boron had adverse effects on reproduction, more specific on the gonads of the males [CIR, Journal of the American College of Toxicology, Volume 2, Number 7, 1983].

In subchronic studies,0.37-7.44 mg/kg/day Sodium Borate did induce no effects on male fertility, incl. testes, prostate, or seminal vesicles

In a study where boric acidwas administered orally to male rats in doses of 0.015-0.3 mg/kg/day of boron (ca. 0.09 to 1.71 mg/kg/day Boric Acid) for six months, Boric Acid, at doses greater than 0.015 mg/kg of boron for six months, has an adverse effect on the gonads of male rats.

The remaining studies in this report indicated adverse effects on the gonads of rats, however at way higher dose levels. So from this data it is evident that there is a certain interspecies variation in the effects of boron, as well as a high doses required to induce any adverse effects, which are magnitudes above human exposure.

 

In a further literature review[Fail PA, Reproductive Toxicology 12 (1) 1 - 18.], similar information is given to allow reasonable doubt on the necessity for classification as Repr. 1, making Repr. 2 more appropriate. Similarly, at human relevant exposure levels, no effects on reproductive performance were noted in humans.

In Swiss mice housed continually as breeding pairs for11 weeks, boric acid at high doses (9000 ppm in feed; 220 mg BE/kg bw/d) caused infertility within 7 d and 4500 ppm (111 mg BE/kg bw/d) caused infertility at 45 to 60 d,with no effects on fertility at 1000 ppm [2.7 mg BE/kg bw/d]. Fertility was reduced in breeding pairs in the 4500 ppm group, and no litters were born to breeding pairs given 9000 ppm dietary boric acid. Thus, the severity of the effect on fertility was dose dependent.

It appears that within 7 d of daily exposure to high doses of boric acid, changes occur in the testes that include the disruption of spermatogenesis and degeneration of the seminiferous epithelium. Delayed spermiation (inhibited release of mature sperm) occurred within 7 d after continual treatment with 9000 ppm dietary boric acid in F344 rats (61 mg BE/kg bw/d). After Day 14, testicular spermatids and their residual bodies were retained in Stages IX to XIII. In Sprague-Dawley rats treated with 1000 or 2000 mg/kg bw (single oral dose; 175 or 350 mg BE/kg bw), exfoliation of the germinal epithelium began as early as Day 14,after 2000 mg/kg bw, an extremely high single dose of boric acid. Loss or immature germ cells from the testes was evident on Day 28 by their presence in the caput epididymis. After daily doses (9000 ppm dietary; 61 mg BE/kg bw/d), inhibited spermiation occurred by Day 7, accompanied by cell loss. By Day 28, exfoliation was well advanced and cell death frequent.

Mice respond differently than rats; in more recent studies with Swiss mice, boric acid, dosed by gavage at a single dose of 2000 mg/kg or lower daily dose, did not cause delayed spermiation after 14 d of treatment. Instead, sloughage of spermatids and vacuolation was observed (P. A. Fail, personal observation, 1996) as it was in rats. But, the testicular changes after boric acid exposure in mice did not include delayed spermiation, whereas in rats, delayed spermiation was a hallmark event.

Hence, also here interspecies differences in boron toxicity are evident.

 

As stated above, with regard to mechanistic toxicity, there are evident interspecies differences. E.g. in F344 rats, delayed spermiation (inhibited release of mature sperm) occurred within 7 d after continual treatment with 9000 ppm dietary boric acid (61 mg BE/kg bw/d). In studies with Swiss mice, boric acid, dosed by gavage at a single dose of 2000 mg/kg or lower daily dose, did not cause delayed spermiation after 14 d of treatment. In consequence, with these doubts arising, in can be furthermore assumed that the mode of action could be different in humans, compared with these standard models, too.

According to the RAC Opinion proposing harmonised classification and labelling at EU level of Disodium Octaborate Anhydrate [RAC, CLH-O-0000003654-72-03/F, Adopted 14 March 2014], several studies on zinc borate were announced and/or submitted. It was stated that zinc interacts with boric acid in the body, reducing the toxicity of boric acid. A reason for this assumption is that zinc borate is less toxic than other borates in experimental studies. It is further proposed that higher zinc stores in humans than in the experimental animals will provide some protection in humans against the toxic effects of boron, and that this species difference raises doubt about the human relevance of the reproductive toxicity seen in animals. It is possible that zinc quantitatively affects the toxicity of borates at some conditions, as well as boron might impair the physiological functions of zinc, an essential trace element involved in fertility and development in both animals and humans.

 

Inconsequence, due to the limited data availability, high toxicological threshold, inter-species differences including the higher zinc availability in humans, and some deviating results, data does not suffice for classification as Repr. 1B; Repr. 2 is rather indicated.