Registration Dossier

Administrative data

Description of key information

No information on repeated dose toxicity of the UVCB test item brazing fluxes is available. A number of sub-chronic and chronic studies on boric acid and disodium tetraborate decahydrate were carried out in rats, mice and dogs. In some cases these studies are research studies (Dixon et al, 1976; Seal and Weeth, 1980; Lee et al., 1978; Treinen and Chapin, 1991; Ku et al., 1993), but most support that boron can cause adverse haematological effects and that the main target organ of boron toxicity is the testis. The NOAEL is equivalent to 17.5 mg B/kg bw/day.
Based on the proposed assessment entity approach described under `discussion`, this result ia also applicable to the brazing fluxes.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: 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:
Meets generally accepted scientific standards 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:
according to
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
2 year dietary feeding study in Sprague Dawley rats, 35 per sex per treated group and 70 controls per sex with interim kills of 5/sex/group at 6 and 12 months at 0; 670 (117); 2000 (350); 6690 (1170) ppm boric acid (ppm as boron equivalents) equivalent to 0, 33 (5.9), 100 (17.5), 334 (58.5) mg boric acid (B)/kg bw per day.
GLP compliance:
no
Remarks:
Study pre-dates GLP
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: Males 93 - 129 g; females 86 - 128 g
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily; ad libitum.
Remarks:
Doses / Concentrations:
0; 670 (117); 2000 (350); 6690 (1170) ppm boric acid (ppm as boron equivalents) equivalent to 0, 33 (5.9), 100 (17.5), 334 (58.5) mg boric acid (B)/kg bw per day
Basis:
nominal in diet
No. of animals per sex per dose:
35/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: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: recorded weekly for the first 52 weeks, then 4 weekly


BODY WEIGHT: Yes
- Time schedule for examinations: recorded weekly for the first 52 weeks, then 4 weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): recorded weekly for the first 52 weeks, then 4 weekly
- 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


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood:at 1, 2, 3, 6 ,12, 18 and end of study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: on 5/sex/group
- Parameters examined: Haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at interim sacrifice at 6, 18 and 24 months for blood pH, sodium, potassium, chloride and carbon dioxide combining power; and at 6, 12 and 24 months for SGOT and SGPT
- Animals fasted: No data
- How many animals: 2/sex/group except SGOT and SGPT which were in 5/sex/group in the hihg and control dose groups
- Parameters: blood pH, sodium, potassium, chloride, carbon dioxide combining power, SGOT and SGPT


URINALYSIS: Yes
- Time schedule for collection of urine: at 6 months
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: appearance, volume, osmolality, specific gravity, pH, protein, glucose, blood, acetone, bilirubin and microscopy
Sacrifice and pathology:
GROSS PATHOLOGY: Yes at 6 and 12 months 5 rats per sex per group, all interim deaths and at termination in 10 per sex per group in controls and high dose surviving animals.
Organs: Brain, pituitary, thyroid, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, lungs, gonads, urinary bladder, sternum, rib junction and all unusual lesions.

HISTOPATHOLOGY: Yes 10 rats per sex per group from the mid and low dose groups had gonads examined histologically
Other examinations:
Samples of blood, brain, liver and kidney were taken at 6, 12 and 24 months and frozen for boron analysis.
Statistics:
As appropriate.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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
No signs in the low and mid dose groups. Coarse hair coats, hunched position, swollen pads and inflamed bleeding eyes were observed in animals receiving the highest dose of boric acid.
Survival at 6, 12 and 24 months was comparable in all groups including controls.


BODY WEIGHT AND WEIGHT GAIN
No difference from controls in the low and mid dose group. Retarded body weight gain in animals receiving the highest dose of boric acid.


FOOD CONSUMPTION AND COMPOUND INTAKE
No difference from controls in the low and mid dose group. Reduced food intake in the highest dose group during weeks 1-13 in males, and in weeks 1-13 and 42-52 in females.


HAEMATOLOGY
No difference from controls in the low and mid dose groups. Significantly decreased red cell volume and haemoglobin were observed in the high dose group males at 3, 6, 12, 18 and 24 months. Hemoglobin values for the males in the high level test group were consistently below the normal range for adult male rats. Cell volume values for this group were, at most periods of determination, also below normal or within low normal range. The total leukocyte counts for the high level males were lower than those for the male controls at each determination but generally within normal limits. The hematological values determined during the first year for the low and intermediate level males and the females at all three test levels were generally within normal limits and comparable with the control values.


CLINICAL CHEMISTRY
No significant differences between groups.

URINALYSIS
No significant differences between groups.


ORGAN WEIGHTS
The testes weights and the testes/bodyweight ratios were significantly lower in the high dose group than those of control animals. The brain- and thyroid-to-bodyweight ratios in the high dose females were significantly higher than those of controls. This was thought to relate to the reduced bodyweight of the animals.

GROSS PATHOLOGYAND HISTOPATHOLOGY
Atrophic testes were found in all males exposed to the high dose 334 (58.5) mg boric acid (B)/kg bw) of boric acid at 6, 12 and 24 months. Microscopic examination of the tissue revealed atrophied seminiferous epithelium and decreased tubular size in the testes. Cysts in the eyelids, probably in the Meiobomian glands were observed in 4 high dose females, probably related to treatment. There was no treatment related increase in tissue masses.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on testicular atrophy in males and reduced body weight in females
Dose descriptor:
LOAEL
Effect level:
334 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on testicular atrophy in males and reduced body weight in females
Dose descriptor:
NOAEL
Effect level:
17.5 mg/kg bw/day (nominal)
Based on:
element
Sex:
male/female
Basis for effect level:
other: Based on testicular atrophy in males and reduced body weight in females
Dose descriptor:
LOAEL
Effect level:
58.5 mg/kg bw/day (nominal)
Based on:
element
Sex:
male/female
Basis for effect level:
other: Based on testicular atrophy in males and reduced body weight in females.
Critical effects observed:
not specified

 

Parameter

Control

Low

dose

Medium

dose

High

dose

Dose-

response

+/-

ma

fa

ma

fa

ma

fa

ma

fa

m

f

number of animals examined

70

70

35

35

35

35

35

35

 

 

Mortality at 104 weeks

25/60

20/60

6/25

8/25

9/25

10/24

7/25

5/25

N

N

clinical signs*

 

 

 

 

 

 

 

 

 

 

body weight gain

0-104 weeks (g)

557

405

546

318

499

359

449

238

Y

Y

food consumption

at week 52 (g/kg/day)

33.3

43.7

35.4

42.9

35.3

44.6

39.7

52.7

 

 

clinical chemistry*

no

differences

 

 

 

 

 

 

 

 

 

haematology*

see

separate

 table

 

 

 

 

 

 

 

 

 

urinalysis*

No

differences

 

 

 

 

 

 

 

 

 

testes weight*(g)

at 26 weeks

3.76+0.29

 

3.67+0.29

 

3.81+0.14

 

0.95+0.06

sig low

 

 

 

testes weight (g)

at 104 weeks

3.65+0.84

 

3.65+0.63

 

3.30+0.60

 

0.99+0.24

sig low

 

 

 

microscopic pathology*

Testes atrophy at 24 months

3/10

 

1/10

 

4/10

 

10/10

 

 

 

 

 


Summary of haematological data from 2 year rat study boric acid:

Months

Cell Volume (%)

Male

Control

0.067%

0.2%

0.67%

0

5.9

mg B/kg

17.5

mg B/kg

58.5

mg B/kg

1

42.6

45.3

42.7

39.0

2

44.1

44.9

45.5

40.8*

3

45.9

46.7

45.7

39.7*

6

45.4

45.9

46.5

44.6

12

47.3

45.5

44.8

41.4*

18

47.8

43.2*

42.8*

39.2*

24

46.4

36.4*

43.8

41.68

 

Female

1

42.1

44.5

42.4

43.3

2

41.7

43.7

43.0

40.8

3

44.2

47.2

45.1

42.0

6

43.3

44.7

Data missing

 

12

42.8

43.9

41.8

40.6

18

43.0

43.0

42.8

39.3*

24

46.2

45.6

44.4

41.6

 

 

Months

Hb Value (g/100 mL)

Male

Control

0.067%

0.2%

0.67%

0

5.9

mg B/kg

17.5

mg B/kg

58.5

mg B/kg

1

14.5

14.2

14.2

12.6*

2

14.7

14.1

14.4

13.2

3

15.7

15.2

14.9

13.3*

6

15.4

15.0

14.2

13.7*

12

14.1

13.2

13.4

12.6*

18

15.6

14.9

13.8*

12.7*

24

14.7

11.9

13.6*

12.8*

 

Female

1

14.6

15.3

14.3

14.0

2

14.9

15.2

14.4

14.7

3

14.9

15.7

14.0

14.2

6

14.5

14.8

Data missing

 

12

12.9

13.2

13.2

12.6

18

14.8

13.9

14.6

13.6

24

14.4

13.2*

13.0*

12.5*

 


 

Months

WBC Count (x103/cm2)

Male

Control

0.067%

0.2%

0.67%

0

5.9

mg B/kg

17.5

mg B/kg

58.5

mg B/kg

1

18.1

13.6

15.3

8.0*

2

19.3

18.4

16.8

14.7

3

20.9

23.4

19.4

16.7

6

19.4

15.6

14.3

15.3

12

10.9

10.9

10.9

10.5

18

23.4

22.9

19.5

18.4

24

19.8

18.1

14.3

13.2*

 

Female

1

19.8

20.9

17.3

14.7

2

16.6

28.9

17.1

17.4

3

26.6

19.0

18.6

21.1

6

14.6

14.1

Data missing

 

12

9.5

13.5

7.3

11.4

18

10.9

11.5

16.4

11.6

24

17.6

12.8

11.3

10.5

 

 

Months

RBC Count (x103/cm2)

Male

Control

0.067%

0.2%

0.67%

0

5.9

mg B/kg

17.5

mg B/kg

58.5

mg B/kg

1

 

 

 

 

2

8.2

7.68

7.98

7.00*

3

7.14

6.72

7.47

6.47

6

 

 

 

 

12

 

 

 

 

18

5.16

5.46

5.55

4.92

24

7.09

5.72

7.35

7.90

 

Female

1

 

 

 

 

2

7.36

7.44

7.46

7.57

3

5.64

7.03

6.47

6.52

6

 

 

 

 

12

 

 

 

 

18

6.58

6.11

5.69

5.73

24

6.22

6.24

6.22

5.92

* Significantly different from controls

Missing data not thought to be significant according to the summary of the study

 

Conclusions:
Endpoint Effect level
NOAEL 17.5 mg Boron/kg bw/day (nominal)
LOAEL 58.5 mg Boron/kg bw/day (nominal)

Testicular atrophy and seminiferous tubule degeneration was observed at 6, 12 and 24 months at the highest dose level only. No treatment related effects were observed in the mid and low dose groups.
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
127.8 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

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 below.

 

Substance

Formula

Conversion factor for equivalent dose of B (multiply by)

Boric acid

H3BO3

0.1748

Boric Oxide

B2O3

0.311

Disodium tetraborate anhydrous

Na2B4O7

0.2149

Disodium tetraborate pentahydrate

Na2B4O7•5H2O

0.1484

Disodium tetraborate decahydrate

Na2B4O7•10H2O

0.1134

Disodium octaborate tetrahydrate

Na2B8O13·4H2

0.2096

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

 Dipotassium tetraborate (anhydrous)

 

 K2B4O7

 

 0.185

 

 Dipotassium tetraborate (tetrahydrate)

 

 K2B4O7.4H2O

 

 0.1415

 

 Potassium pentaborate (anhydrous)

 

 B5KO8

 

 0.244

 

 Potassium pentaborate (tetrahydrate)

 

 B5KO8.4H2O

 

 0.1843

 

 

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

 

 

Read-across data (for borates):

Information on repeated dose toxicity of brazing fluxes is not available. For this reason, read-across is performed to a number of studies on boric acid or disodium tetraborate decahydrate in diet or via drinking water for periods of 30 days to two years in rats, mice and dogs are available.

Whereas the majority of these studies do not comply with current test guidelines and they lack essential information regarding e. g. histological descriptions and statistical evaluations of the results, the following conclusions can nevertheless be drawn in a weight-of-evidence approach:
most studies support that boron can cause adverse haematological effects and that the main target organ of boron toxicity is the testis. Other effects observed at high doses include rapid respiration, hunched position, bloody nasal discharge; urine stains on the abdomen, inflamed bleeding eyes, desquamation and swollen paws and tail, reduced food consumption and body weight gain. Treatment with boric acid and disodium tetraborate decahydrate disrupted spermiation, induced degeneration of testicular tubules and caused testicular atrophy. For effects on the blood system extramedullary haematopoiesis, reduced red cell volume and haemoglobin values and deposition of haemosiderin in spleen, liver and proximal tubules of the kidney were described. Several cases of anaemia have been observed in human poisoning cases. However, although doses in these poisoning cases are difficult to define, the effects occurred generally at relatively high concentrations.

Boric acid, the main species present under physiological conditions, acts as a Lewis acid and as such owns the ability to complex with hydroxyl, amino and thiol groups from diverse biomolecules, like e. g. carbohydrates and proteins (BfR, 2006). Such a mechanism could be involved in effects of boron on different enzyme activities (Huel et al., 2004).

A NOAEL for effects on testes and the blood system of 17.5 mg B/kg bw/day can be derived (with a LOAEL of 58.5 mg B/kg bwday) from two 2-year studies in rats on boric acid and disodium tetraborate decahydrate (Weir, 1966a, b).

The following oral data were obtained (NOAEL):

Dipotassium tetraborate (anhydrous): 94.6 mg/kg bw/day

Dipotassium tetraborate (tetrahydrate): 123.7 mg/kg bw/day

Brazing fluxes: 127.8 mg/kg bw/day


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: testes

Justification for classification or non-classification

Boric acid and disodium tetraborate are classified under the 1stATP to CLP as Repr. 1B; H360FD.

However, text of the 30th ATP as published in the EU Official Journal, 15 September 2008 stated that “The classification and labelling of the substances listed in this Directive should be reviewed if new scientific knowledge becomes available. In this respect, considering recent preliminary, partial and not peer-reviewed information submitted by industry, special attention should be paid to further results of epidemiological studies on the Borates concerned by this Directive including the ongoing study conducted in…”

While boron has been shown to adversely affect male reproduction in laboratory animals, there was no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers (Whorton et al. 1994; Sayli 1998, 2001; Robbins et al. 2010; Scialli et al. 2010). Not only are these the most exposed workers, but the Chinese worker study is themost sensitive study that has been carried out as semen analysis was performed, a very sensitive detection system for testicular damage. There is no evidence of developmental effects in humans attributable to boron in studies of populations with high exposures to boron (Tuccar et al 1998; Col et al. 2000; Chang et al. 2006).

A weight of evidence approach was used in evaluating numerous independent studies on the determination of the hazard of boric acid to humans. Information that was considered together included results of in vitro tests, animal data, occupational exposure data, epidemiological studies and mechanistic data.

Extensive evaluations of sperm parameters in highly exposed workers in Turkey and China have demonstrated no effects on male fertility. No evidence of developmental effects in humans attributable to boron (B) has been observed in studies of populations with high exposures to boron. Although the epidemiological studies have methodological deficiencies, collectively these studies consistently show an absence of effects in highly exposed populations.

Workers in boron mining and processing industries represent the maximum possible human exposure. However a comparison of blood, semen and target organ boron levels in studies of laboratory animals and human studies shows that boron industry worker exposures are lower than untreated control rats.

Mechanistic data provide possible explanations for the absence of developmental and reproductive effects in humans exposed to high levels of boron. Recent studies provide evidence that boric acid may act by similar mechanisms in causing developmental effects in mice as sodium salycilate (the natural deacetylated form of aspirin and a rodent teratogen) including effects on Hox gene expression and inhibition of embryonic histone deacetylases. Although aspirin is known to cause developmental effects in laboratory animals, controlled human studies have not demonstrated developmental effects in humans. Similar mechanisms of action of boric acid and aspirin, and the absence of developmental effects in humans ingesting aspirin suggest that boric acid related developmental effects in humans are unlikely. 

Additionally, zinc levels in soft tissue in humans is over 2 times greater than in comparative tissues in rats (King et al. 2000; Yamaguchi et al. 1996), which explain in part the absence of fertility and developmental effects in humans. Zinc has been shown to protect against testicular toxicity of cobalt and cadmium (Anderson et al. 1993), and the developmental effects of cadmium (Fernandez et al. 2003). There is evidence that zinc interacts with boric acid in the body reducing the toxicity of boric acid. The interaction of zinc and boric acid is evident by the low acute toxicity of zinc borate (absorbed as boric acid and zinc) with a LD50 value greater than 10,000 mg/kg-body weight in rats (Daniels 1969) compared to disodium tetraborate pentahydrat\e (similar % boron composition as zinc borate) with a LD50 value of 3300 mg/kg-body weight. Furthermore, no toxic effects were observed in the testes of males (a target organ of boric acid) administered 1000 mg zinc borate/kg/day in a 28-day repeated dose oral gavage toxicity study, equivalent dose of boron of 50 mg B/kg bodyweight (Wragg et al. 1996). The LOAEL for testicular effects is 26 mg B/kg body weight. 

Based on the total weight of evidence, the data show that it is improbable that boric acid will cause reproductive or developmental effects in humans.

Therefore, based on a total weight of evidence, Category 2 H361d: suspected human reproductive toxicant, suspected of damaging the unborn child is considered the appropriate classification. Extensive evaluations of sperm parameters in highly exposed workers have demonstrated no effects on male fertility. While no developmental effects have been seen in highly exposed populations, epidemiological studies of developmental effects are not as robust as the fertility studies, warranting the Category 2 H361d.

Because borates are considered the transformation product driving the human health effects for brazing fluxes, this weight of evidence approach is also applicable to brazing fluxes.