Reaction product of mixed inorganic base and acid resulting in complex boron, potassium and fluoride constituents in powder form.

Carcinogenicity

Description of key information

A 2 year carcinogenicity study of boric acid (NTP, 1987) equivalent to OECD Guideline 451 was carried out in mice. The study showed that boric acid was non-oncogenic by the oral route. The NOAEL is equivalent to 201 mg B/kg bw/day.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

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: see 'Remark'

Remarks:

Comparable to guideline study with acceptable restrictions. This study is conducted on an analogue substance. Read-across is justified on the following basis: In aqueous solutions at physiological and acidic pH, low concentrations of simple inorganic borates such as boric acid, disodium tetraborate decahydrate, disodium tetraborate pentahydrate, boric oxide and disodium octaborate tetrahydrate will predominantly exist as undissociated boric acid. At about pH 10 the metaborate anion (B(OH)4-) becomes the main species in solution (WHO, 1998). This leads to the conclusion that the main species in the plasma of mammals and in the environment is un-dissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as un-dissociated boric acid under the same conditions. For comparative purposes, exposures to borates are often expressed in terms of boron (B) equivalents based on the fraction of boron in the source substance on a molecular weight basis. Some studies express dose in terms of B, whereas other studies express the dose in units of boric acid. Since the systemic effects and some of the local effects can be traced back to boric acid, results from one substance can be transferred to also evaluate the another substance on the basis of boron equivalents. Therefore data obtained from studies with these borates can be read across in the human health assessment for each individual substance. Conversion factors are given in the table below. Conversion factor for equivalent dose of B Boric acid H3BO3 0.175 Boric Oxide B2O3 0.311 Disodium tetraborate anhydrous Na2B4O7 0.215 Disodium tetraborate pentahydrate Na2B4O7•5H2O 0.148 Disodium tetraborate decahydrate Na2B4O7•10H2O 0.113 Disodium octaborate tetrahydrate Na2B8O13•4H2O 0.210 Sodium metaborate (anhydrous) NaBO2 0.1643 Sodium metaborate (dihydrate) NaBO2•2H2O 0.1062 Sodium metaborate (tetrahydrate) NaBO2•4H2O 0.0784 Sodium pentaborate (anhydrous) NaB5O8 0.2636 Sodium pentaborate (pentahydrate) NaB5O8∙5H2O 0.1832 References: WHO. Guidelines for drinking-water quality, Addendum to Volume 1, 1998.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

The full report is not published by the NTP. Sufficient detail is available to make an assessment of chronic toxicity and carcinogenesis although limited details are available and all individual animal data are not available.

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Frederick Cancer Research Center, Frederick MD, USA
- Age at study initiation: 7 weeks
- Weight at study initiation: Males 21.6-21.8 g; females 17.1-17.7 g

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

In food at 0, 2500, 5000 ppm boric acid equivalent to 0, 446 and 1150 mg/kg bw/d food consumption per day ad libitum

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

Daily; food available ad libitum

Post exposure period:

No data

Remarks:

Doses / Concentrations:
0, 446, or 1150 mg/kg bw/d In a bioassay fifty B6C3F, mice per group and sex were administered 0, 2,500 and 5,000 ppm boric acid in the diet for 103 weeks (NTP, 1987). The average amount of boric acid consumed daily was approximately 400-500 mg/kg low
Basis:
actual ingested

No. of animals per sex per dose:

50/sex/group

Control animals:

yes, plain diet

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- 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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
Reduced survival in all dose groups including control. In the males the final survival was 82 % , 64 % and 44 % with increasing dosage which may have reduced the sensitivity of the study. Final survival in females was 66 %, 66 % and 74 % for 0, 446, and 1150 mg/kg bw/d respectively, which was adequate for assessment of the study. Bodyweight gain reduced during the first year, mean final bodyweights were 75 and 13 % below control values for exposed males and 7 % and 20 % below control values for females. No chemically related clinical signs were reported.

An increase of testicular atrophy was seen at the high dose (3/49 control, 6/50 low dose and 27/47 high dose) and interstitial cell hyperplasia (0/49, 0/50, 7/47) in male mice. There was variable loss of spermatogenia, and and various stages of spermatogenesis from the seminiferous tubles. There were no treatment related increase in tumours.

Survival in high dose males was significantly lower than controls after week 63, and in the low dose males after week 84 except for week 101. No significant differences in females. There was a dose related reduction in bodyweight gain after week 30 in both males and females.


BODY WEIGHT AND WEIGHT GAIN
Bodyweight gain reduced during first year; mean final bodyweights were 7 % and 13 % below control values for exposed males and 7 % and 20 % below control values for females.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The average daily consumption in low and high dose males was 118 % and 160 % of controls, and in low and high dose females was 118 % and 136 % of controls. These were thought to be probably related to spillage caused by reduced palatability.


HISTOPATHOLOGY:
An increase of testicular atrophy was seen at the high dose (3/49 control, 6/50 low dose and 27/47 high dose) and interstitial cell hyperplasia (0/49, 0/50, 7/47) in male mice. There was variable loss of spermatogenia, and various stages of spermatogenesis from the seminiferous tubules. No evidence of carcinogenicity was found.

Relevance of carcinogenic effects / potential:

Reduced survival in all dose groups including control. In the males the final survival was 82 %, 64 % and 44 % with increasing dosage which may have reduced the sensitivity of the study. Final survival in females was 66 %, 66 % and 74 % for 0, 446, and 1150 mg/kg w/d respectively, which was adequate for assessment of the study. Bodyweight gain reduced during the first year, mean final bodyweights were 75 and 13 % below control values for exposed males and 7 % and 20 % below control values for females. No chemically related clinical signs were reported. An increase of testicular atrophy was seen at the high dose (3/49 control, 6/50 low dose and 27/47 high dose) and interstitial cell hyperplasia (0/49, 0/50, 7/47) in male mice. There was variable loss of spermatogenia, and various stages of spermatogenesis from the seminiferous tubles. There were no treatment related increase in tumours.

Dose descriptor:

NOEL

Effect level:

> 5 000 ppm (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: No evidence of carcinogenicity (NTP classification meaning no chemically related increase in benign or malignant neoplasms).

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

 

Parameter	Control data				Low dose		Medium  dose		High dose		Dose- response + /
	Historical		Study
	m	f	m	f	m	f	m	f	m	f	m	f
Number of animals examined			50	50	50	50	-	-	50	50
Mortality			9	18	20	17			28	13	Y	N
clinical signs			0	0	0	0			0	0
body weight gain			20.3g	27.2g	17.5g	24.1g			14.7g	18.8g	Y	Y
food consumption			na	na	na	na			na	na
clinical chemistry			Not done
haematology			not done
urinalysis			not done
Overall tumour incidence:			31	25	37	27			23	26	N	N
No. of animals with neoplasms			31	25	37	27			23	26	N	N
No. of animals with benign neoplasms			23	8	22	11			16	14	N	N
No. of animals with malignant neoplasms			13	20	23	15			11	17	N	N
No. of animals with > 1 neoplasm

 

Conclusions:

An OECD 451 study in B6C3F1 mice consisting of 50 per sex per group treated in diet for 103 weeks with 0, 2500 or 5000 ppm boric acid showed no evidence of carcinogenicity (NTP classification meaning no chemically related increase in benign or malignant neoplasms).
Read-across is justified on the basis detailed in the rationale for reliability above. This study is therefore considered to be of sufficient adequacy and reliability to be used as a supporting study and no further testing is justified.

Endpoint conclusion

Dose descriptor:

NOAEL

1 086.5 mg/kg bw/day

Justification for classification or non-classification

No classification is required for dipotassium tetraborate regarding carcinogenicity as all results for boric acid were negative.

Additional information

In long term feeding studies on boric acid and disodium tetraborate decahydrate in both rats and mice, no carcinogenic effects were observed (Weir, 1966a, b; Weir and Fisher, 1972).

An OECD 451 equivalent study in B6C3F1 mice consisting of 50 per sex per group treated in diet for 103 weeks with 0, 2500 or 5000 ppm boric acid showed no evidence of carcinogenicity (NTP classification meaning no chemically related increase in benign or malignant neoplasms).

Based on the mouse NTP-study (1987) boric acid is not regarded carcinogenic. Although not carried out according to modern standards, nor to GLP, the 2-year studies in rats and dogs support this finding. While in the 2-year rat studies, only 10 animals/sex of the control and high-dose group were macroscopically and histologically examined, only 1-2 animals/sex/dose/time were examined in the 2-year studies in dogs, which limits the conclusions that can be derived from these studies. However, they were well performed and reported and are adequate to evaluate the carcinogenicity of boric acid and sodium borates. It can be concluded that boric acid and sodium borates are not carcinogenic and there is no concern for carcinogenic effects in humans.

Since all the borates will exist as undissociated boric acid under physiological and environmental conditions, the toxicology of all these simple borates is similar on an equivalent boric acid basis or boron basis. Therefore the data for boric acid and disodium tetraborate decahydrate can be read across to the other borates for toxicological effects. 

The following oral data were obtained (NOAEL):

Dipotassium tetraborate (anhydrous): 1086.5 mg/kg bw/day

Dipotassium tetraborate (tetrahydrate): 1420.5 mg/kg bw/day

Assessment entity approach

"Brazing fluxes" are mixtures of boron-containing constituents (potassium(fluoro)borates), which undergo chemical exchanges (anion exchange) and condensation reactions (e.g. formation of oligoborates, polyborates) upon mixing and further manufacturing. This results in a complex mixture of potassium borates, which cannot be fully chemically characterised for substance identity. Thus, according to the definition under REACH, such brazing fluxes must be described as a UVCB substance.

 

Data specifically on the UVCB substance to be registered are not available. An assessment entity approach is followed based on the transformation products of this UVCB uppon dissolution in aqueous media. The substance is highly soluble and forms complex boron, potassium and fluoride constituents. The quantitatively predominant transformation product of this UVCB is represented by boric acid, which is assumed to be the determinant of human health effects because of its classification and its toxicity. For this reason, the assessment is based on information for “borates” (including potassium borate, boric acid and other borate substances).

 

Based on the information provided below, it may safely be assumed that under physiological conditions the chemical speciation of most of the unknown potassium boron compounds corresponds to boric acid. Thus, from a chemical point of view, there is no reason to assume that brazing fluxes would behave differently than boric acid and/or borates under physiological conditions.

 

The basis of this assessment entity approach is further justified by the following reasoning:

In aqueous solutions at physiological and acidic pH, low concentrations of simple inorganic borates such as boric acid B(OH)₃, potassium pentaborate (K₂B₁₀O₁₆*8H₂O), potassium tetraborate (K₂B₄O₇*4H₂O), disodium tetraborate decahydrate (Na₂B₄O₇.10H₂O; borax), disodium tetraborate pentahydrate (Na₂B₄O₇*5H₂O; borax pentahydrate), boric oxide (B₂O₃) and disodium octaborate tetrahydrate (Na₂B₈O₁₃*4H₂O) will predominantly exist as undissociated boric acid. Above pH 9 the metaborate anion (B(OH)₄^-) becomes the main species in solution (WHO, 1998). This leads to the conclusion that the main species in the plasma of mammals and in the environment is undissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as undissociated boric acid under the same conditions.

For comparative purposes, exposures to borates are often expressed in terms of boron (B) equivalents based on the fraction of boron in the source substance on a molecular weight basis. Some studies express dose in terms of B, whereas other studies express the dose in units of boric acid. Since the systemic effects and some of the local effects can be traced back to boric acid, results from one substance can be transferred to also evaluate the another substance on the basis of boron equivalents. Therefore data obtained from studies with these borates can be read across in the human health assessment for each individual substance. Conversion factors are given in the table under CSR section 5.1.3, which corresponds to IUCLID section 7.1 (toxicokinetics, metabolism and distribution endpoint summary).

References:

WHO. Guidelines for drinking-water quality, Addendum to Volume 1, 1998