Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed

Toxicity to reproduction: other studies

Description of key information

Weight of Evidence Considerations for Developmental Toxicity Classification of Boric Acid

 

 

 

Although reproductive and developmental effects have been demonstrated in laboratory animals exposed to high doses of boric acid in their feed, similar effects have not been observed in highly exposed human populations or workers. 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, which may explain in part the absence of fertility and developmental effects in humans.

There is limited evidence that zinc interacts with boron in the body reducing the toxicity of boron.  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 compared to disodium tetraborate pentahydrate (similar % boron composition as zinc borate) with a LD50 value of 3300 mg/kg-body weight. 

This indicates that zinc interacts with boron in the body reducing the toxicity of boron. 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. 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 human

 

 Introduction

 

Observations of human populations and workers exposed to high doses of boric acid

have not shown any of the reproductive and developmental effects which

have been demonstrated in laboratory animals

 

 

Methods

A weight of evidence approach was used in evaluating numerous independent studies

on the determination of the hazard of boric acid to humans. Separate lines of evidence

included data from occupational exposures, epidemiological studies, reproductive health

assessments, mechanistic studies, in vitro tests, as well as the animal data.

 

 

Results and Discussion

 

Fertility Effects

 

Extensive evaluations of sperm parameters in highly exposed workers in Turkey and

China have demonstrated no effects on male

fertility (Duydu et a..2011; Robbins et al. 2010, Scialli et al. 2010).

 

The studies included semen analysis, the most sensitive test for testicular toxicity in humans. . Workers in boron mining and processing industries represent the maximum possible human exposure.

 

However, tissue concentrations of these workers (Table 1) showed internal B concentrations to be less than measured in rats fed only untreated control

diets (Ball, 2012).

 

Developmental Effects

 

No evidence of developmental effects in humans attributable to boron (B) has been observed in studies of populations with high exposures to boron.

Although each study has methodological limitations or deficiencies, collectively these studies consistently show an absence of effects in highly exposed populations

.

Tuccar et al. (1998) investigated reproductive and developmental effects of boron in

three generations of families living in boron rich regions of Turkey.

Daily exposures of 6.77 mg/day for males living in the boron-rich region. 226 families over three

-generations were evaluated in the high-boron area.

Cöl et al. (2000) investigated infertility rates, gender ratio, stillbirths and spontaneous abortions, premature births or low birth weights, and infant mortality rates among the families of 799 workers (642 production workers, 157 office workers) at three production facilities in Turkey.

The boron level in drinking water ranged from 1.7 - 9.4 ppm Region I, 2.79 - 5.94 Region II and 0.36 -0.62 Region III.

 

Chang et al. (2006) evaluated reproductive health in a cohort of boron mining and processing male workers (N=936) and a comparison group of males (N=251) in northeast China. Well water in the boron group ranged from 37 to 600 times the comparison group, and the mean boron concentrations in legumes and potatoes from the boron group was approximately double those found in the comparison group. No statistically significant differences were observed between the boron workers and the comparison group in delay in pregnancy, multiple births, spontaneous miscarriage, induced abortion, stillbirth, tubal or ectopic pregnancy, and boy/girl ratio

.

HDACi and Hox Genes

 

Recent studies provide evidence that boric acid and sodium salycilate may act by similar

mechanisms in causing developmental effects in mice. Sodium salycilate is the natural deacetylatedform of aspirin and a rodent teratogen. Although aspirin is known to cause

developmental effects in laboratory animals, controlled human studies have not demonstrated

developmental effects in humans. Mechanisms likely include effects on Hoxgene expression

and inhibition of embryonic histone deacetylases

 

 

The reported developmental effects in rodents, axial abnormalities, for both boric acid and

sodium salycilate have been attributed to a shift in Hox gene expressions (Wery

et al., 2005, Di Renzo 2008).

 

Inhibition of histone deacetylases(HDACi) by sodium salicylate and boric acid has been shown as a mechanism of teratogenesis (axial skeletal malformations) in laboratory

animals (Di Renzo et al. 2008).

 

Recent studies provide evidence that alteration of Hoxgene expression might also be associated with male fertility effects in laboratory animals, a mechanism also linked to developmental effects (

Wery et al. 2005).

 

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.

 

Zinc

 

Normal levels of zinc in humans may interact with boron to reduce hazard of toxic effects

.

 

Zinc levels in soft tissue in humans are over 2 times greater than in comparative tissues

in laboratory animals, see figure below (King et al. 2000; Ranjanet al. 2011; Yamaguchi

et al. 1996).

 

Zinc has been shown to protect against testicular toxicity of cobalt and

cadmium (Anderson et al. 1993), and developmental toxicity of cadmium (Fernandez et

al. 2003). A similar interaction with boron could explain in part the absence of fertility

and developmental effects in humans

.

The interaction of Zn and boric acid was demonstrated by the low acute toxicity of zinc

borate (ZB) with a LD50 value greater than 10 g/kg-bwin rats (Daniels 1969) compared

to disodium tetraborate pentahydrate with a LD50 value of 3.3 g/kg-

bw (ZB and disodium tetraborate pentahydrate have equivalent boron concentrations.) Furthermore, no toxic effects were observed in the testes of males administered 1000 mg ZB/kg/day in a 28-day repeated dose oral gavage toxicity study, equivalent dose of 50 mg B/kg

bw (Wragget al. 1996). The LOAEL for testicular effects is 26 mg B/kg body weight. This

indicates that Zn interacts with boric acid in the body reducing the toxicity of boric acid

 

 

 

Conclusion

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.

Introduction

Observations

of human populations and workers exposed to high doses of boric acid

have not shown any of the reproductive and developmental effects which have




References

Anderson et al. (1993) Reprod Toxicol 7:49-54.

Ball (2012) Toxicology Letters 211S:188 

Chang et al. (2006) AAOHN 54(10) 435 – 443

Cöl et al. (2000) T Klin Med Res 18: 10 - 16.

Daniels (1969) Hill Top Research Inc. Report No T-258.

Di Renzo et al. (2008) Tox Sciences 104(2), 397–404

Duydu et   al..(2011) Arch Toxicol 85:589–600

Fernandez et al. (2003) Tox Sciences 76:162-170

King et al. (2000) J.   Nutr. 130: 1360S—1366S

Ranjan et al. (2011) Research Report -Fluoride 44(2):83-88

Robbins et al. (2010) Reproductive Toxicology 29: 184 - 190

Scialli et al. 2010) Reproductive Toxicology 29 (2010) 10–24

Tuccar et al. (1998) Biological Trace Element Research 66: 401- 407.

Wery et al. (2005) Reproductive Toxicology 20 (2005) 39–45

Wragg et al (1996) Safe Pharm Laboratories Ltd. Report no.: 801/003.

Yamaguchi et al. (1996) The Journal of Toxicological Sciences, Vol. 21, 17-187, 1996

Mode of Action Analysis / Human Relevance Framework

Weight of Evidence Considerations for Developmental Toxicity Classification of Boric Acid

 

 

 

Although reproductive and developmental effects have been demonstrated in laboratory animals exposed to high doses of boric acid in their feed, similar effects have not been observed in highly exposed human populations or workers. 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 actionof 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, which may explain in part the absence of fertility and developmental effects in humans.

There is limited evidence that zinc interacts with boron in the body reducing the toxicity of boron.  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 compared to disodium tetraborate pentahydrate (similar % boron composition as zinc borate) with a LD50 value of 3300

mg/kg-body weight. 

This indicates that zinc interacts with boron in the body reducing the toxicity of boron. 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. 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 human

 

 

 

 

 

Introduction

 

Observations of human populations and workers exposed to high doses of boric acid

have not shown any of the reproductive and developmental effects which

have been demonstrated in laboratory animals

 

 

Methods

A weight of evidence approach was used in evaluating numerous independent studies

on the determination of the hazard of boric acid to humans. Separate lines of evidence

included data from occupational exposures, epidemiological studies, reproductive health

assessments, mechanistic studies, in vitro tests, as well as the animal data.

 

 

Results and Discussion

 

Fertility Effects

 

Extensive evaluations of sperm parameters in highly exposed workers in Turkey and

China have demonstrated no effects on male

fertility (Duydu et a..2011; Robbins et al. 2010, Scialli et al. 2010).

 

The studies included semen analysis, the most sensitive test for testicular toxicity in humans. . Workers in boron mining and processing industries represent the maximum possible human exposure.

 

However, tissue concentrations of these workers (Table 1) showed internal B concentrations to be less than measured in rats fed only untreated control

diets (Ball, 2012).

 

 

 

Developmental Effects

 

No evidence of developmental effects in humans attributable to boron (B) has been observed in studies of populations with high exposures to boron.

Although each study has methodological limitations or deficiencies, collectively these studies consistently show an absence of effects in highly exposed populations

.

Tuccar et al. (1998) investigated reproductive and developmental effects of boron in

three generations of families living in boron rich regions of Turkey.

Daily exposures of 6.77 mg/day for males living in the boron-rich region. 226 families over three

-generations were evaluated in the high-boron area.

Cöl et al. (2000) investigated infertility rates, gender ratio, stillbirths and spontaneous abortions, premature births or low birth weights, and infant mortality rates among the families of 799 workers (642 production workers, 157 office workers) at three production facilities in Turkey.

The boron level in drinking water ranged from 1.7 - 9.4 ppm Region I, 2.79 - 5.94 Region II and 0.36 -0.62 Region III.

 

Chang et al. (2006) evaluated reproductive health in a cohort of boron mining and processing male workers (N=936) and a comparison group of males (N=251) in northeast China. Well water in the boron group ranged from 37 to 600 times the comparison group, and the mean boron concentrations in legumes and potatoes from the boron group was approximately double those found in the comparison group. No statistically significant differences were observed between the boron workers and the comparison group in delay in pregnancy, multiple births, spontaneous miscarriage, induced abortion, stillbirth, tubal or ectopic pregnancy, and boy/girl ratio

.

HDACi and Hox Genes

 

Recent studies provide evidence that boric acid and sodium salycilate may act by similar

mechanisms in causing developmental effects in mice. Sodium salycilate is the natural deacetylatedform of aspirin and a rodent teratogen. Although aspirin is known to cause

developmental effects in laboratory animals, controlled human studies have not demonstrated

developmental effects in humans. Mechanisms likely include effects on Hoxgene expression

and inhibition of embryonic histone deacetylases

 

 

The reported developmental effects in rodents, axial abnormalities, for both boric acid and

sodium salycilate have been attributed to a shift in Hox gene expressions (Wery

et al., 2005, Di Renzo 2008).

 

Inhibition of histone deacetylases(HDACi) by sodium salicylate and boric acid has been shown as a mechanism of teratogenesis (axial skeletal malformations) in laboratory

animals (Di Renzo et al. 2008).

 

Recent studies provide evidence that alteration of Hoxgene expression might also be associated with male fertility effects in laboratory animals, a mechanism also linked to developmental effects (

Wery et al. 2005).

 

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.

 

Zinc

 

Normal levels of zinc in humans may interact with boron to reduce hazard of toxic effects

.

 

Zinc levels in soft tissue in humans are over 2 times greater than in comparative tissues

in laboratory animals, see figure below (King et al. 2000; Ranjanet al. 2011; Yamaguchi

et al. 1996).

 

Zinc has been shown to protect against testicular toxicity of cobalt and

cadmium (Anderson et al. 1993), and developmental toxicity of cadmium (Fernandez et

al. 2003). A similar interaction with boron could explain in part the absence of fertility

and developmental effects in humans

.

The interaction of Zn and boric acid was demonstrated by the low acute toxicity of zinc

borate (ZB) with a LD50 value greater than 10 g/kg-bwin rats (Daniels 1969) compared

to disodium tetraborate pentahydrate with a LD50 value of 3.3 g/kg-

bw (ZB and disodium tetraborate pentahydrate have equivalent boron concentrations.) Furthermore, no toxic effects were observed in the testes of males administered 1000 mg ZB/kg/day in a 28-day repeated dose oral gavage toxicity study, equivalent dose of 50 mg B/kg

bw (Wragget al. 1996). The LOAEL for testicular effects is 26 mg B/kg body weight. This

indicates that Zn interacts with boric acid in the body reducing the toxicity of boric acid

 

 

 

Conclusion

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.

Introduction

Observations

of human populations and workers exposed to high doses of boric acid

have not shown any of the reproductive and developmental effects which have




References

Anderson et al. (1993) Reprod Toxicol 7:49-54.

Ball (2012) Toxicology Letters 211S:188 

Chang et al. (2006) AAOHN 54(10) 435 – 443

Cöl et al. (2000) T Klin Med Res 18: 10 - 16.

Daniels (1969) Hill Top Research Inc. Report No T-258.

Di Renzo et al. (2008) Tox Sciences 104(2), 397–404

Duydu et   al..(2011) Arch Toxicol 85:589–600

Fernandez et al. (2003) Tox Sciences 76:162-170

King et al. (2000) J.   Nutr. 130: 1360S—1366S

Ranjan et al. (2011) Research Report -Fluoride 44(2):83-88

Robbins et al. (2010) Reproductive Toxicology 29: 184 - 190

Scialli et al. 2010) Reproductive Toxicology 29 (2010) 10–24

Tuccar et al. (1998) Biological Trace Element Research 66: 401- 407.

Wery et al. (2005) Reproductive Toxicology 20 (2005) 39–45

Wragg et al (1996) Safe Pharm Laboratories Ltd. Report no.: 801/003.

Yamaguchi et al. (1996) The Journal of Toxicological Sciences, Vol. 21, 17-187, 1996

Justification for classification or non-classification