Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data regarding effects on fertility are available for boron orthophosphate. Reliable data are available from boric acid (CAS 10043-35-3). The boron ion is considered to be the toxicologically relevant element and thus a read across to boric acid is reliable.

3 -generation study, rat, oral, feed (CAS 1004 3-35-3): NOAEL fertility = 17.5 mg boron/kg bw/day = 171.8 mg boron orthophosphate/kg bw/day*; LOAEL fertility = 58.8 mg boron/kg bw/day = 577.4 mg boron orthophosphate/kg bw/day*

2 -generation study, continuous breeding protocol (NTP), mice, oral, feed (CAS 10043 -35 -3): LOAEL = 26.6 mg boron/kg bw/day = 261.1 boron orthophosphate/kg bw/day*

* based on MW of boron (10.8 g/mol) and boron orthophosphate (106.0 g/mol)

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
fertility, rat
Effect level:
17.5 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other: 3-generation study (Weir 1972)
Key result
Dose descriptor:
LOAEL
Remarks:
fertility, mice
Effect level:
26.6 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Sex:
male
Basis for effect level:
reproductive function (sperm measures)
Remarks on result:
other: 2-generation study (Fail, 1991)
Key result
Dose descriptor:
NOAEL
Remarks:
fertility, mice
Effect level:
26.6 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
female
Basis for effect level:
body weight and weight gain
reproductive performance
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
26.6 mg/kg bw/day (actual dose received)
System:
male reproductive system
Organ:
testes
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
17.5 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other: 3-Gen study (Weir, 1972)
Key result
Dose descriptor:
LOAEL
Effect level:
26.6 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
other: significant decrease in reproductive parameters; increased uterine weight and kidney/adrenal weight, shortened estrus cycle and reduction in sperm concentration
Remarks on result:
other: 2-Gen study (Fail, 1991)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
26.6 mg/kg bw/day (actual dose received)
System:
other: male and female reproductive system
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Generation:
F1a
Effect level:
17.5 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
other: no adverse effects described
Remarks on result:
other: 3-Gen study (Weier 1972)
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Generation:
F1b
Effect level:
17.5 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
other: no adverse effects described
Remarks on result:
other: 3-Gen study (Weier 1972)
Dose descriptor:
NOAEL
Remarks:
mice
Generation:
F1
Remarks on result:
not measured/tested
Remarks:
2-Gen study (Fail, 1991)
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Generation:
F2a
Effect level:
17.5 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
other: no adverse effects described
Remarks on result:
other: 3-Gen study (Weir, 1972)
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Generation:
F2b
Effect level:
17.5 mg/kg bw/day
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
other: no adverse effects described
Remarks on result:
other: 3-Gen study (Weir, 1972)
Dose descriptor:
NOAEL
Remarks:
mice
Generation:
F2
Remarks on result:
not measured/tested
Remarks:
2-Gen study (Fail, 1991)
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
26.6 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
As a result of all data given the following conclusion can be made:
Boron orthophosphate is toxic to reproduction. Several studies with different species (mice and rats) are available from structural analogue boric acid. Boric acid showed reproductive toxicity. The lowest NOAEL for fertility (17.5 mg boron/kg bw/day) was found in rats. Furthermore, boric acid has a harmonised classification as Repr. Cat. 1B. As explained in the analogue justification, boron is considered to be the toxic element. Therefore, it is considered that the target and the source substances are unlikely to lead to differences in reproduction toxicity potential.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
171.8 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, from a reference substance with similar structure and intrinsic properties. Read-across is justified based on same element boron (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7.3, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data regarding effects on fertility are available for boron orthophosphate. Reliable data are available from boric acid (CAS 10043 -35 -3). The boron ion is considered to be the toxicologically relevant element and thus a read across to boric acid is reliable (for more details please refer to the analogue justification). Boric acid has a harmonized classification for reproductive toxicity (Cat. 1B, H360FD) therefore, only the key studies leading to the classification were included in this dossier.

In a three generation study in rats groups of 8 males and 16 females were treated with boric acid equivalent to 0, 5.9, 17.5 and 58.8 mg boron/kg bw/day. The high dose P1-generation failed to produce litter. Male rats in the high dose group were all sterile. Also when females of that group were mated with untreated males they had no offspring, indicating that the female reproduction was affected. A decreased ovulation in the majority of ovaries examined in that group was mentioned not to be sufficient to explain the observed infertility. Only ovaries of high dosed females were examined. Gross necropsy revealed atrophied testes in all P1 males at 58.8 mg boron/kg bw/day. No information on F1 and F2 generations for this endpoint is available (Weir and Fisher, 1972). The NOAEL was 17.5 mg boron/kg bw/day (equivalent to 171.8 mg boronorthophosphate/kg bw/day) , however, as also stated in WHO (1998) the small group size (n=8), low control fertility (60%), limited data reported, and inappropriate statistics all limit the applicability of these data for risk assessment. But, as comparable results were obtained with disodium tetraborate decahydrate and effects were seen at equivalent concentrations on the basis of boron equivalents, the results of the study can be utilized in order to complement the picture of the reprotoxic effects of boric acid.

In a continuous breeding study of boric acid in mice (Fail et al., 1991), three doses were administered 26.6 mg boron/kg bw/day), 111.3 mg boron/kg bw/day and 220.9 mg boron/kg bw/day. A dose-related effect on the testes (testicular atrophy and effects on sperm motility, morphology and concentration) was noted; fertility was partially reduced at 111 mg boron/kg bw/day, and absent at 221 mg boron/kg bw/day. For cross over mating only the mid dose group (111.3 mg boron/kg bw/day) could be mated with control animals, since the high dose produced no litter. Indices of fertility for mid dose males with control females, control males with mid dose females and control males with control females were 5%, 65% and 74%, respectively. The according indices of mating (incidence of copulatory plugs) were 30%, 70% and 79%. This indicates that the primary effect was seen in males, however, slight effects were also noted in females. Live pup weight (adjusted for litter size) was significantly reduced compared to control litters, the average dam weight was significantly lower on postnatal day 0 compared to control dams and the average gestational period of the mid dose females was 1 day longer than in control females. In task 4 of this continuous breeding study, control animals and low-dose F1 animals were mated because in the high dose groups no litters and in the mid dose group only 3 litters were produced. While mating, fertility and reproductive competence were unaltered compared to control, the adjusted pup-weight (F2) was slightly but significantly decreased. P1 females had significantly increased kidney/adrenal and uterus weights and the oestrus cycle was significantly shorter compared to control females. In P1 males a reduction in sperm concentration was observed, but no other sperm parameters were influenced. While in this study the NOAEL for females of the P0-generation is 26.6 mg boron/kg bw/day, this is a LOAEL for males of the P0-generation (motility of epididymal sperms was significantly reduced: 78% ± 3% in controls vs. 69% ± 5% at 26.6 mg boron/kg bw/day). For the P1-generation 26.6 mg boron/kg bw/day can be identified as a LOAEL, based on the 25% reduction of sperm concentration in males and increased uterine and kidney/adrenal weights and the shortened oestrus cycle in females at this dose. Further, though normal in number, the F2-pups had reduced adjusted bodyweights at 26.6 mg boron/kg bw/day, which is therefore also a LOAEL for F2-generation.

As described in the SVHC support document for boric acid by ECHA (2010) the following conclusion can be made: Results from animal experiments demonstrate that boric acid adversely effects fertility and development. Feeding studies in different animal species (rats, mice and dogs) have consistently demonstrated that the male reproductive system is the principle target in experimental animals, although effects on the female reproductive system have also been reported. Testicular damage ranging from mildly inhibited spermiation to complete atrophy has been demonstrated following oral administration of boric acid. Effects on fertility were observed at lower dose levels compared to dose levels, where signs of general toxicity appeared. 17.5 mg boron /kg bw/day (equivalent to 171.8 mg boronorthophoshpate/kg bw/day) was derived as a NOAEL for male and female fertility in the rat.

References:

ECHA 2010: SVHC Support Document, Member State Committee Draft Support Document for Identification of Boric Acid as a Substance of Very High Concern because of CMR Properites, June 2010; https://echa.europa.eu/documents/10162/d51fd473-40ec-4831-bc2d-6f53bdf9cbbe

WHO 1998: IPCS Environmental Health Criteria 204, Boron; http://apps.who.int/iris/bitstream/10665/42046/1/9241572043_eng.pdf

Effects on developmental toxicity

Description of key information

No data regarding effects on developmental toxicity is available for boron orthophosphate. Reliable data are available from boric acid (CAS 10043 -35 -3). The boron ion is considered to be the toxicologically relevant element and thus a read across to boric acid is reliable.

OECD 414, rat, oral feed (CAS 1004 3 -35 -3): NOAEL developmental = 9.6 mg boron/kg bw/day = 94.2 boron orthophosphate/kg bw/day*; NOAEL maternal toxicity = 25.2 mg boron/kg bw/day

OECD 414 rabbit, oral gavage (CAS 10043 -35 -3): NOAEL developmental = 21.9 mg boron/kg bw/day = 214.9 boron orthophosphate/kg bw/day*; NOAEL maternal toxicity = 21.9 mg boron/kg bw/day

* based on MW of boron (10.8 g/mol) and boron orthophosphate (106.0 g/mol)

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
25.2 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Basis for effect level:
other: no maternal toxicity observed
Remarks on result:
other: Price, 1996
Key result
Dose descriptor:
NOAEL
Remarks:
rabbit
Effect level:
21.9 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: Price, 1996
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
28.5 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: Heindel, 1992
Dose descriptor:
LOAEL
Remarks:
mice
Effect level:
43 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: Heindel, 1992
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
9.6 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Remarks on result:
other: Price, 1996
Key result
Dose descriptor:
NOAEL
Remarks:
rabbit
Effect level:
21.9 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
visceral malformations
Remarks on result:
other: Price, 1996
Dose descriptor:
LOAEL
Remarks:
rat
Effect level:
13.7 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Remarks on result:
other: Heindel, 1992
Dose descriptor:
NOAEL
Remarks:
mice
Effect level:
43 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
boron
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
skeletal malformations
Remarks on result:
other: Heindel, 1992
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: rib
Description (incidence and severity):
observed in rats and mice
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
visceral/soft tissue: cardiovascular
Description (incidence and severity):
in rabbits
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
13.3 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
As a result of all data given the following conclusion can be made:
Boron orthophosphate is toxic to prenatal development. Several studies with different species (mice, rats and rabbits) are available from structural analogue boric acid. Boric acid showed developmental toxicity. The lowest NOAEL for developmental toxicity (9.6 mg boron/kg bw/day) was found in rats. Furthermore, boric acid has a harmonised classification as Repr. Cat. 1B. As explained in the analogue justification, boron is considered to be the toxic element. Therefore, it is considered that the target and the source substances are unlikely to lead to differences in developmental toxicity potential.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
94.2 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, from a reference substance with similar structure and intrinsic properties. Read-across is justified based on same element boron (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7.3, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No data regarding effects on developmental toxicity are available for boron orthophosphate. Reliable data are available from boric acid (CAS 10043-35-3). The boron ion is considered to be the toxicologically relevant element and thus a read across to boric acid is reliable (for more details please refer to the analogue justification). Boric acid has a harmonized classification for reproductive toxicity (Cat. 1B, H360FD) therefore, only the key studies leading to the classification were included in this dossier.

In a GLP study consisting of a prenatal and postnatal development part the developmental toxicity potential of boric acid in rats was examined (Price, 1996). In this dietary study groups of Sprague-Dawley rats were dosed with boric acid corresponding to boron levels of either 0, 3.3, 6.3, 9.6, 13.3, or 25 mg boron/kg bw/day from gestational day 0 to 20 (phase 1) or 0, 3.3, 6.3, 9.8, 12.9, or 25.4 mg boron/kg bw/day from gestational day 0 to 20 (phase 2). In phase 1, which was conducted according to OECD guideline 414, dams killed on gestation day 20 and uterine contents were examined. For the low to high-dose groups, fetal body weights were 99, 98, 97, 94, and 88% of controls, the reduction was significant only in the 13.3 and 25 mg boron/kg bw/day groups. At non-maternally toxic doses, there was a reduction on foetal weight and skeletal malformations (increase in incidence of wavy ribs and short rib XIII, decreased incidence of rudimentary extra rib on lumbar 1). In phase 2, boric acid exposure stopped at birth and dams were allowed to deliver and rear their litters until postnatal day 21. On postnatal day (PND) 0 of phase 2, there were neither effects of boric acid on offspring body weights, nor were any differences seen through postnatal day 21. On postnatal day 21 the percentage of pups per litter with short rib XIII was elevated only in the 25.3 mg boron/kg bw/day group, but there was no treatment-related increase in wavy rib or extra rib on lumbar 1. Maternal liver weight (absolute and relative to body weight) and maternal right kidney weight (absolute) were not affected. Relative kidney weight was increased at 25 mg boron/kg bw/day in the diet on gestational day 20, with no treatment-related effects on PND 21. The NOAELs for developmental toxicity in rat for the prenatal (Phase 1) and postnatal phase (Phase 2) were 9.6 and 12.9 mg boron/kg bw/day, respectively. There was little evidence of maternal toxicity at any of the doses tested (NOAEL maternal toxicity = 25.2 mg boron/kg bw/day).

In a further GLP study performed similar to OECD 414 in rats (Sprague-Dawley), average doses were 0, 13.7, 28.5, 57.8 (on GD 0-20) and 94.3 (on GD 6-15) mg boron/kg bw/day (Heindel, 1992). This study shows that boric acid treatment in rats during gestation causes maternal and developmental toxicity. In general, however, indices of maternal toxicity induced by boric acid treatment during gestation were not striking since effects on food and water consumption were minimal and the decreased maternal weight gain appeared to be secondary to developmental toxicity (i.e., body weight gain corrected for gravid uterine weight was not significantly reduced). The major indicators of maternal toxicity were increased liver and kidney weights. The increased kidney weight was with no demonstrable histopathological lesions at 28.5 mg boron/kg bw/day, with both parameters being normal at 13.7 mg boron/kg bw/day treatment. Thus, 28.5 mg boron/kg bw/day was the maternal NOAEL. Average fetal body weight/litter was reduced at all doses. Prenatal mortality was increased only at 57.8 mg boron/kg bw/day. The incidence of foetal malformations was significantly increased at ≥ 28.5 mg boron/kg bw/day. The most frequently observed malformations were enlarged lateral ventricles of the brain, and agenesis or shortening of rib XIII. As an associated finding, the incidence of lumbar I rib(s), a common variation in this rat, was reduced following boric acid treatment. Embryo/foetal toxicity occurred in all treatment groups therefore, no NOAEL could be established. The LOAEL for maternal toxicity is therefore 13.7 mg boron/kg bw/day.

In a further GLP study performed similar to OECD 414 in mice, similar findings were observed. Swiss albino CD-1 mice received boric acid equivalent to doses of 0, 43, 79, and 175 mg boron/kg bw/day on gestation days 0-20 in feed (Heindel, 1992). Maternal toxicity was indicated by mild renal lesions - and at the highest dose – by increases in the relative kidney weight and food and water intake. A NOAEL for maternal toxicity was not reached in the mouse study due to these renal lesions found in the lowest dose group and therefore the LOAEL is 43 mg boron/kg bw/day. The key developmental effects in mice observed were similar to those seen in rats, which were investigated in the same study as well, i.e. a reduction in foetal body weight at the mid dose (79 mg boron/kg) and an increase in skeletal malformations (missing lumbar vertebrae, fused vertebral arches and short rib XIII) and resorptions at the highest dose, where slight maternal toxicity was recorded. The NOAEL for developmental effects in mice was 43 mg boron/kg bw/day, the LOAEL was 79 mg boron/kg bw/day.

In a further GLP study performed similar to OECD 414 New Zealand White rabbits were administered boric acid once daily by gavage at doses corresponding to 0, 10.9, 21.9 and 43.8 mg boron/kg bw/day during major organogenesis on GD 6-19 (Price, 1996). Rabbits exposed to 43.8 mg boron/kg bw/day on gestation day 6-19 revealed decreased food intake during treatment, relative but not absolute kidney weight increase and vaginal bleeding. At the highest dose, prenatal mortality was increased (90% resorption/litter versus 6% in controls). In this dose group 14 live fetuses (6 live litters) were available for evaluation, compared to 153 - 175 live fetuses (18 - 23 live litters) in the other groups. The resorption rate was consistent with other studies, but the incidence of resorptions was disproportionally high in boric acid-exposed rabbits relative to rabbits with even greater restriction of food intake (ECHA, 2010). Development of the cardiovascular system was particularly sensitive. The types of malformations (primarily cardiovascular) were dissimilar to those reported after diet restriction in other rabbit studies. Decreased maternal food intake may have been a contributing factor, but cannot be solely responsible for the range and severity of adverse developmental effects observed at the high dose of boric acid. Malformed fetuses/litters were present in 72% of the high-dose fetuses versus 3% in controls. The only skeletal effect observed was a decreased incidence of rudimentary extra rib on lumbar I which was not considered biologically significant. Mild maternal effects, but severe developmental toxicity was observed at 43.8 mg boron/kg bw/day (NOAEL maternal toxicity = 43.8 mg boron/kg bw/day). Based on these findings the NOAEL for developmental effects in rabbits was 21.9 mg boron/kg bw/day.

As described in the SVHC support document for boric acid by ECHA (2010) the following conclusion can be made: Developmental toxicity of boric was investigated in the rat, the rabbit and the mouse. In two independent rat studies, the reduction in fetal body weight at 0.1% or 0.2% boric acid in feed from GD 0 to 20 was comparable, maternal toxicity in mice and rats was not striking, since effects on food and water consumption were minimal. Observed weight gain changes seemed to be secondary to developmental toxicity, because body weight gain corrected for gravid uterine weight was not significantly reduced. Studies in rats failed to provide evidence for any treatment related renal pathology. Thus, in the rat, developmental toxicity (decreased foetal weight: at 13.7 mg boron/kg bw/day) occurred in the absence of marked maternal toxicity. For developmental toxicity, a NOAEL of 9.6 mg boron kg bw/day has been derived.

 

References:

ECHA 2010: SVHC Support Document, Member State Committee Draft Support Document for Identification of Boric Acid as a Substance of Very High Concern because of CMR Properites, June 2010; https://echa.europa.eu/documents/10162/d51fd473-40ec-4831-bc2d-6f53bdf9cbbe

Justification for classification or non-classification

The available data on toxicity to reproduction meet the criteria for classification according to Regulation (EC) 1272/2008, and boron orthophosphate is therefore classified as toxic to Reproduction Category 1B (H360FD - May damage fertility. May damage the unborn child). There is no specific concentration limit for Boron orthophosphate.

This classification is based on the classification according to the first ATP to Regulation (EC) No 1272/2008 for boric acid.