2-tetradecyloxirane, reaction products with boric acid

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2016-02-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Valid and conclusive statement

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The reproductive and developmental toxicity, and endocrine disruption, potential of the test material were assessed based on the physical chemical properties and toxicity data on the substance and with reference to the residual levels of boric acid (approx. 3 wt%).

Test material

Test material information

Constituent 1

Reference substance name:

2-tetradecyloxirane, reaction products with boric acid

EC Number:

701-392-2

IUPAC Name:

2-tetradecyloxirane, reaction products with boric acid

Details on test material:

- Physical state: Off-white, waxy solid
- Storage condition of test material: Room temperature, protected from light
- Stability under test conditions: Considered stable under these conditions

Administration / exposure

Details on exposure:

Exposure Routes
The potential for exposure to this substance is limited by its use and physico-chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a negligible vapour pressure (OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa). Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public. In the professional work environment dermal exposure will be limited because precautions have been taken because this chemical possesses skin-sensitising properties.

Results and discussion

Effect levels

Dose descriptor:

other: Expert statement

Basis for effect level:

other: No evidence that boric acid has a mechanism of action relating to endocrine disruption

Remarks on result:

not measured/tested

Remarks:

Effect level not specified (migrated information)

Any other information on results incl. tables

Summary of Effects on fertility and developmental toxicity

In an OECD 422: combined 28-day repeated dose oral (gavage) toxicity study with reproduction/developmental toxicity screening test in rats, with recovery groups, the test item, in the vehicle (peanut oil) was administered orally by gavage once daily to 3 groups of Crl: CD(SD) rats. The low- and mid-dose groups each consisted of 12 rats/sex and the high-dose group consisted of 17 rats/sex. Dosage levels were 250, 500, and 1000 mg/kg bw/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 17 rats/sex received the vehicle on a comparable regimen. Males and females were approximately 10 or 11 weeks of age at the beginning of test item administration.

 

F0 male and female mating and fertility, male copulation, and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test item administration at all dosage levels. No test item related effects were observed on F0 spermatogenesis endpoints (mean testicular and epididymal sperm numbers and sperm production rate, motility, and morphology) in males at any dosage level. Mean numbers of implantation sites, corpora lutea, unaccounted-for sites, mean number of F1 pups born, live litter size, the percentage of F1 males at birth, and F1 postnatal survival in the 250, 500, and 1000 mg/kg bw/day groups were similar to the control group values. Mean F1 birth weights (PND 1) for the 1000 mg/kg bw/day group were 9.9% (males) and 7.6% (females) lower than the control group. During PND 1-4, mean pup body weight gains were lower than the control group and resulted in mean pup body weightsinthe 1000 mg/kg bw/day group that were 17.8% (males) and 18.6% (females) lower than the control group on PND 4. Mean pup body weights and body weight changes in the 250 and 500 mg/kg bw/day groups were not remarkably different than the control group. There were no test item-related internal findings or effects on organ weights observed at any dosage level at the scheduled necropsy.

 

Under the test conditions, the NOAEL of test item was 1000 mg/kg bw/day for reproductive toxicity in rats and the NOAEL of test item was 500 mg/kg bw/day for neonatal toxicity, based on the lower mean F1 birth weights, pup body weight gains during PND 1-4 and pup body weights on PND 4 at 1000 mg/kg bw/day in male and female rats.

 

A single oral boric acid dose of 3000 mg/kg body weight given to female mice on the day of insemination inhibited embryonal development almost completely. In a study of the influence of boric acid on the development of rat embryos, female Sprague-Dawley (CD) rats were given 0.1 %, 0.2% or 0.4% boric acid in the diet from day 0 to day 20 of gestation or 0.8 % from day 6 to day 15.

Applicant's summary and conclusion

Conclusions:

There is no evidence that boric acid has a mechanism of action relating to endocrine disruption and whilst the exact mechanism has not been fully elucidated there are some proposed mechanisms but these do not involve endocrine disruption.

Executive summary:

Introduction

 

The reproductive and developmental toxicity, and endocrine disruption, potential of the test material were assessed based on the physical chemical properties and toxicity data on the substance and with reference to the residual levels of boric acid (approx. 3 wt%). 

 

Metabolism

 

Borate esters are present as components of the UVCB substance. However, the UVCB test item as a whole is hydrophobic and insoluble (water solubility < 0.17 mg/L at 20 °C and pH 4.4). As a result, borate esters will not be present in solution and hydrolysis and enzymatic metabolism of these components is not expected. This prediction is supported by the absence of reproductive effects characteristic of boric acid exposure in studies with the test material.

 

The absorbable components of this UVCB substance are expected to be metabolised via a number of metabolic pathways although the OECD Toolbox v2.3.0 QSAR system predicts that the metabolism/bioaccumulation will be slow or very slow for the dimer and trimers and moderate for the monomer. Cytochrome P450 (CYP450) enzymes are a superfamily of oxidative catalysts important in the biosynthesis and metabolism of a wide range of endogenous molecules as well as the metabolism of xenobiotics. The four main components of this UVCB substance were subjected to metabolite profiling using the OECD Toolbox v2.3.0 QSAR system and the predicted metabolites were partitioned into chemical categories based on USEPA rules (ECOSAR). The Toolbox predicted a total of 52 potential metabolites from the representative structures; boric acid is not one of the predicted metabolites.

 

Exposure Routes

 

The potential for exposure to this substance is limited by its use and physico-chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a negligible vapour pressure (OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa). Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public. In the professional work environment dermal exposure will be limited because precautions have been taken because this chemical possesses skin-sensitising properties.

 

Summary of Effects on fertility and developmental toxicity

 

In an OECD 422: combined 28-day repeated dose oral (gavage) toxicity study with reproduction/developmental toxicity screening test in rats, with recovery groups, the test item, in the vehicle (peanut oil) was administered orally by gavage once daily to 3 groups of Crl: CD(SD) rats. The low- and mid-dose groups each consisted of 12 rats/sex and the high-dose group consisted of 17 rats/sex. Dosage levels were 250, 500, and 1000 mg/kg bw/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 17 rats/sex received the vehicle on a comparable regimen. Males and females were approximately 10 or 11 weeks of age at the beginning of test item administration.

 

F0 male and female mating and fertility, male copulation, and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test item administration at all dosage levels. No test item related effects were observed on F0 spermatogenesis endpoints (mean testicular and epididymal sperm numbers and sperm production rate, motility, and morphology) in males at any dosage level. Mean numbers of implantation sites, corpora lutea, unaccounted-for sites, mean number of F1 pups born, live litter size, the percentage of F1 males at birth, and F1 postnatal survival in the 250, 500, and 1000 mg/kg bw/day groups were similar to the control group values. Mean F1 birth weights (PND 1) for the 1000 mg/kg bw/day group were 9.9% (males) and 7.6% (females) lower than the control group. During PND 1-4, mean pup body weight gains were lower than the control group and resulted in mean pup body weights in the 1000 mg/kg bw/day group that were 17.8% (males) and 18.6% (females) lower than the control group on PND 4. Mean pup body weights and body weight changes in the 250 and 500 mg/kg bw/day groups were not remarkably different than the control group. There were no test item-related internal findings or effects on organ weights observed at any dosage level at the scheduled necropsy.

 

Under the test conditions, the NOAEL of test item was 1000 mg/kg bw/day for reproductive toxicity in rats and the NOAEL of test item was 500 mg/kg bw/day for neonatal toxicity, based on the lower mean F1 birth weights, pup body weight gains during PND 1-4 and pup body weights on PND 4 at 1000 mg/kg bw/day in male and female rats.

 

Endocrine disruption potential of boric acid

 

The ECHA Endocrine Disruptor Expert Group focuses on substances with endocrine disrupting properties. The most widely accepted definition for endocrine disruptors is the one by the International Programme for Chemical Safety (IPCS, 2002): "Endocrine disruptors have been defined as exogenous substances that alter function(s) of the endocrine system and consequently cause adverse health effects in an intact organism or its progeny, or (sub)populations".

 

The mechanism of action by which boric acid causes testicular toxicity has been investigated and it has been proposed that decreased testosterone production arises via a CNS mediated mechanism. It is not likely that hormone changes can explain the testicular atrophy observed at high dose levels since it has been shown that spermatogenesis can be maintained in the presence of significantly decreased intra-testicular testosterone levels. The fact that testicular damage was reversible and less extensive in younger sexually immature males than in mature animals also argues against an endocrine disruptor mechanism because younger animals still in development may be expected to be more sensitive to anti-androgenic effects than adults.

 

Inhibition of spermiation has been investigated and the involvement of Sertoli cells is suggested, as effects on these cells can lead to testicular atrophy. The changes in serum hormone levels may reflect an indirect effect on the CNS mediated by paracrine and/or autocrine influences.

 

There is no evidence that boric acid has a mechanism of action relating to endocrine disruption and whilst the exact mechanism has not been fully elucidated there are some proposed mechanisms but these do not involve endocrine disruption.