Reaction products of boric acid and calcium dihydroxide and lithium hydroxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a combined 28 -day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) of dilithium tetraborate by oral gavage in rats, no treatment-related changes were noted the reproductive parameters examined in this study (i.e. mating and fertility indices, precoital time, number of implantation sites, estrous cycle, spermatogenic profiling, and histopathological examination of reproductive organs) up to the highest dose level tested ( 150 mg/kg). The NOAEL (reproductive effects) based on the outcome of this study is therefore 150 mg/kg (bw).
At physiological pH, all category members dissociate and release boric acid and lithium/calcium ions as a result of relevant transformation pathways. It will the boric acid component of the substances which will drive the mammalian toxicity endpoints.
The target UVCB substance has a higher precursor molar ratio for lithium hydroxide than for calcium hydroxide, and therefore the precautionary principle should be applied and read across from dilithium tetraborate where relevant to consider the worst case.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

boric acid and calcium dihydroxide and lithium hydroxide in the category approach.
The UVCB - Reaction products of boric acid and calcium dihydroxide and lithium hydroxide (EC # 701-453-3) has structural similarities to two already established categories: lithium salts of the oxyacids of boron (B); and calcium salts of the oxyacids of boron (B). Dilithium tetraborate (EC# 234-514-3) (source substance #1) and calcium metaborate (EC# 237-224-5) (source substance #2) will be used to predict the properties for the target substance.
At physiological pH, all category members dissociate and release boric acid and lithium/calcium ions as a result of relevant transformation pathways. It will the boric acid component of the substances which will drive the mammalian toxicity endpoints.
The target UVCB substance has a higher precursor molar ratio for lithium hydroxide than for calcium hydroxide, and therefore the precautionary principle should be applied and read across from dilithium tetraborate where relevant to consider the worst case.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

>= 150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Dose descriptor:

NOAEL

Effect level:

ca. 50 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: based on reduced gestation index, marked

Key result

Reproductive effects observed:

no

Conclusions:

In a combined 28 -day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) of dilithium tetraborate by oral gavage in rats, no treatment-related changes were noted the reproductive parameters examined in this study up to the highest dose level tested. The reproduction NOAEL is therefore at least 150 mg/kg.

The NOAEL (Developmental toxicity) was determined to be 50 mg/kg (bw) - this is based on reduced gestation index, marked reductions in post-implantation survival, live litter size, live birth, viability and lactation indices, a high number of total litter losses, and reduced pup birth weight and postnatal growth at 150 mg/kg
The parental NOAEL was determined to be 50 mg/kg (bw) - this is based on reduced body weight gain at gestation and lactation.

Dilithium tetraborate rapidly dissociates in aqueous media yielding the same compound, boric acid/borates at physiological pH.
The target UVCB substance has a higher precursor molar ratio for lithium hydroxide than for calcium hydroxide, and therefore the precautionary principle should be applied and read across from dilithium tetraborate where relevant to consider the worst case.

It is therefore expected that Reaction products of boric acid and calcium dihydroxide and lithium hydroxide will exhibit the same prenatal developmental toxicity.

Executive summary:

In a combined 28 -day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) of dilithium tetraborate by oral gavage in rats using doses, no treatment-related changes were noted the reproductive parameters examined in this study (i.e. mating and fertility indices, precoital time, number of implantation sites, estrous cycle, spermatogenic profiling, and histopathological examination of reproductive organs) up to the highest dose level tested ( 150 mg/kg)
Developmental toxicity was observed at 150 mg/kg. There were no explanatory morphological findings in parental reproductive organs. The developmental toxicity at 150 mg/kg was characterized by a reduction in the gestation index, marked reductions in post-implantation survival index, live litter size, live birth index, viability index and lactation index, and reduced birth weight and postnatal growth of pups.
The parental NOAEL based on the outcome of this study is 50 mg/kg (bw). This is based on reduced body weight gain at gestation and lactation.
At physiological pH, all category members dissociate and release boric acid and lithium/calcium ions as a result of relevant transformation pathways. It will the boric acid component of the substances which will drive the mammalian toxicity endpoints.
The target UVCB substance has a higher precursor molar ratio for lithium hydroxide than for calcium hydroxide, and therefore the precautionary principle should be applied and read across from dilithium tetraborate where relevant to consider the worst case.
A reproductive classification of Category 2 is therefore proposed for all borate substances.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 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

Effects on developmental toxicity

Description of key information

In a combined 28 -day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) of dilithium tetraborate by oral gavage in rats, developmental toxicity was observed at 150 mg/kg. This was characterized by a reduction in the gestation index, marked reductions in post-implantation survival index, live litter size, live birth index, viability index and lactation index, and reduced birth weight and postnatal growth of pups.
The developmental NOAEL based on the outcome of this study is therefore 50 mg/kg (bw).
At physiological pH, all category members dissociate and release boric acid and lithium/calcium ions as a result of relevant transformation pathways. It will the boric acid component of the substances which will drive the mammalian toxicity endpoints.
The target UVCB substance has a higher precursor molar ratio for lithium hydroxide than for calcium hydroxide, and therefore the precautionary principle should be applied and read across from dilithium tetraborate where relevant to consider the worst case.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

On the basis of the developmental effects observed in the oral gavage OECD TG 422 study with dilithium tetraborate, a classification of Category 2 - H361d: Suspected of damaging the unborn child. The same classification is proposed for Reaction products of boric acid and calcium dihydroxide and lithium hydroxide in the category approach.