Pentaboron sodium octaoxide

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 (corresponding to a NOAEL of 762.5 mg/kg bw/day for sodium pentaborate (anhydrous) and 1097.2 mg/kg bw/day for sodium pentaborate pentahydrate).

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: Comparable to guideline study with acceptable restrictions

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:

 

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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

762.5 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Comparable to guideline study with acceptable restrictions.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No classification according to Regulation (EC) No 1272/2008 is required for sodium pentaborate 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, data for boric acid and disodium tetraborate decahydrate can be read across to the other borates for toxicological effects. 

Please also refer to the read-across statement attached to section 13.