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Toxicological information

Carcinogenicity

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Description of key information

In accordance with REACH annex XI testing is not justified as trimethyl borate reacts nearly spontaneously when exposed to water forming boric acid.  Thus available data for boric acid should be acceptable instead of conducting new studies. 
Boric acid was tested by NTP in a lifetime bioassay in mice, with the result of no evidence for carcinogenicity at the highest dose tested, 1150 mg boric acid / kg bw/day. This carcinogenicity-related NOAEL corresponds to 1934 mg C3H9BO3/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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
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:
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 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).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 934 mg/kg bw/day
Study duration:
chronic
Species:
mouse

Additional information

In accordance with REACH annex XI testing is not justified as trimethyl borate reacts nearly spontaneously when exposed to water forming boric acid. Thus available data for boric acid should be acceptable instead of conducting new studies.

The below is based on the hydrolysis product boric acid.

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.


Justification for selection of carcinogenicity via oral route endpoint:
Only study

Justification for classification or non-classification

No evidence for carcinogenicity based on several chronic studies and one NTP lifetime assay on the hydrolysis product boric acid.