Barium bis(dihydrogenorthophosphate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data regarding reproductive toxicity is available for barium bis(dihydrogen orthophosphate). Reliable data is available for structural similar substance barium chloride dihydrate (CAS 10326-27-9).

NOAEL (fertility), rat, oral = 200 (male) and 180 (female) mg barium/kg bw/day

NOAEL (fertility), mice, oral = 205 (male) and 200 (female) mg barium/kg bw/day

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to the analogue justification attached to chapter 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Study in rats: Drinking water containing 1000, 2000, or 4000 ppm barium chloride dihydrate was estimated to deliver daily doses of 65, 110, or 200 mg barium/kg bw to male and 65, 115, or 180 mg barium/kg bw to female rats.

Study in mice: Drinking water containing 500, 1000, or 2000 ppm barium chloride dihydrate was estimated to deliver daily doses of 55, 100, or 205 mg barium/kg bw to male and 60, 110, or 200 mg barium/kg bw to female mice.

Key result

Dose descriptor:

NOAEL

Remarks:

rat

Effect level:

>= 4 000 ppm (nominal)

Based on:

test mat.

Remarks:

equivalent to 200 or 180 mg barium/kg bw/day for males or females, respectivley

Sex:

male/female

Basis for effect level:

other: no effects observed up to the highest dose tested

Key result

Dose descriptor:

NOAEL

Remarks:

mice

Effect level:

>= 2 000 ppm (nominal)

Based on:

test mat.

Remarks:

equivalent to 205 or 200 mg barium/kg bw/day for males or females, respectivley

Sex:

male/female

Basis for effect level:

other: no adverse effects observed up to the highest dose tested

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Remarks:

rat

Generation:

F1

Effect level:

>= 4 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed up to the highest dose tested

Key result

Dose descriptor:

NOAEL

Remarks:

mice

Generation:

F1

Effect level:

>= 2 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed up to the highest dose tested

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

Taken together all data of these studies, there are no indications of a substantial impairment of fertility in rats up to the highest dose tested. Thus, the NOAEL was 4000 ppm (to average doses of 200 and 180 mg barium/kg bw/d to male and and female rats, respectively). NOAELs on developmental toxicity for rats of 4000 ppm were derived from this study. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation.
Regarding mice, there are also no indications of a substantial impairment of fertility in mice up to the highest dose tested. Thus, the NOAEL was 2000 ppm (to average doses of 205 and 200 mg barium/kg bw/d to male and and female mice, respectively). NOAELs on developmental toxicity for mice of 2000 ppm were derived from this study. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation.
Thus, as explained in the analogue justification barium bis(hydrogen orthophosphate) is also considered to have no potential for developmental toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

180 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 similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details).
The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, 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 reproductive toxicity is available for barium bis(dihydrogen orthophosphate). Reliable data is available for barium chloride dihydrate (CAS 10326-27-9). Since the main toxicity of barium bis(dihydrogen orthophosphate) can be attributed to barium, barium chloride dihydrate can be used as read across. For more detail on the read across justification please refer to the analogue justification provided in section 13.

The data base consists of single-generation reproductive toxicity studies in rats and mice (Dietz et al., 1992) which is similar to OECD guideline 421. In this study, groups of male and female F-344/N rats and B6C3F1 mice (20/sex/species/group) were exposed to barium chloride dihydrate in the drinking water for 60 days (males) or 30 days (females). The barium chloride dihydrate concentrations were 0, 1000, 2000, or 4000 ppm for the rats and 0, 500, 1000, or 2000 ppm for the mice. Estimated doses were not reported for this study. The dosages from a subchronic study conducted by the same authors (NTP, 1994; Dietz et al., 1992) were therefore used to represent approximate dosages for this study. For the rats, estimated barium doses were 0, 65, 110, and 200 mg/kg-day for males and 0, 65, 115, and 180 mg/kg-day for females. For mice the estimates were 0, 55, 100, and 205 mg/kg-day for males and 0, 60, 110, and 200 mg/kg-day for females. After the exposure period, males and females from the same exposure groups were housed together until there was evidence of mating or until the end of the mating period (8 days). The following endpoints were used to assess potential reproductive toxicity: length of pregnancy, number of implantation sites, number of live and dead offspring, pup weights at birth and on the fifth day after parturition, external abnormalities of pups, gross examination of the vagina, cervix, oviduct, and uterus of the F0 dams, and evaluation of sperm density, morphology, and motility, and reproductive organ weights of the F0 males.

Pregnancy rates in the rat study were below historically normal values for the laboratory, ranging from 40% in the controls to 65% in the high dose group, but barium treatment did not appear to be the reason. The problem of low fecundity was not investigated by remating because of schedule restrictions. No significant alterations in gestation length, pup survival, or occurrence of external abnormalities were observed. A marginal but statistically not significant reduction in live litter sizes was observed in the 4000 ppm treatment group compared to controls at birth and day 5 (day 0, 9.0 ± 1.37 pups in controls compared to 7.2 ± 0.52 pups in the 4000 ppm treatment group; day 5, 9.3 ± 1.16 pups in controls compared to 7.1 ± 0.56 in 4000 ppm treatment group; mean ± SEM). The number of implants per pregnant dam were also marginally reduced from 9.6 ± 1.10 in controls to 7.7 ± 5.2 in pups in the 4000 ppm treatment group, but the effect was not statistically significant. A statistically significant (p < 0.01) decrease in live pup weight at birth was observed in the 4000 ppm group (5.2 g vs. 5.7 g in controls); however, no significant alterations in pup body weight were observed at 5 days of age.

Pregnancy rates in mice ranged from 55% in controls to 55% - 70% in the barium-exposed groups. No alterations in maternal weight gain, average length of gestation, pup survival, or pup weights were observed in mice. A statistically significant (p < 0.05) decrease in average litter size occurred on days 0 and 5 in the 1000 ppm treatment group but not in the 2000 ppm treatment group (day 0, 10.7 ± 0.40 pups in controls compared to 7.9 ± 1.02 pups for 1000 ppm treatment group; day 5, 10.8 ± 0.38 pups compared to 7.7 ± 0.97 pups in the 1000 ppm treatment group). No external abnormalities were observed in the mouse offsprings.

No alterations in epididymal sperm counts, sperm motility, sperm morphology, testicular or epididymal weights, or vaginal cytology were observed in rats or mice.

Based on the limited amount of data available, it is not possible to make a definitive conclusion about the potential for barium to impair reproductive functions but it does not indicate that barium impairs fertility so no further study regarding reproductive toxicity is justified for that tonnage band.

Effects on developmental toxicity

Description of key information

No data regarding developmental toxicity is available for barium bis(dihydrogen orthophosphate). Reliable data is available for the strucatural similar substance barium chloride dihydrate (CAS 10326-27-9).

OECD 414 (oral, rat):

NOAEL (materanl toxicity) = 30 mg /kg bw/day corresponding to 17 mg Ba/kg bw/day

NOAEL (developmental toxicity) >= 100 mg/kg bw/day corresponding to 56 mg Ba/kg bw/day

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:

Please refer to the analogue justification attached to chapter 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

mortality

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects up to the highest dose tested

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

Daily administration of the source substance barium chloride dihydrate at dose levels of 0, 10, 30 or 100 mg/kg bw/day to pregnant rats from gestation day 1 up to and including gestation day 20, resulted in maternal toxicity as evidenced by the spontaneous deaths of two animals on gestation day 21 and the conditional decline of another animal on gestation day 21 in the high dose group. No developmental toxicity was observed. The NOAEL for maternal toxicity was therefore 30 mg/kg bw/day. In absence of developmental effects the NOAEL for prenatal developmental toxicity in the rat was ≥ 100 mg/kg bw/day. As explained in the analogue justification the target and the source substances are considered to be similar in their toxicological behvior. Therefore, it is considered that the target and the source substance is unlikely to lead to differences in developemtnal toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

56 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 1) and consistent study, from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details).
The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, 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 reproductive toxicity is available for barium bis(dihydrogen orthophosphate). Reliable data is available for barium chloride dihydrate (CAS 10326-27-9). Since the main toxicity of barium bis(dihydrogen orthophosphate) can be attributed to barium, barium chloride dihydrate can be used as read across. For more detail on the read across justification please refer to the analogue justification provided in section 13.

 

Developmental toxicity of barium chloride dihydrate was evaluated in a recent prenatal developmental toxicity study according to OECD 414 by daily administration of the test item at dose levels of 0, 10, 30 or 100 mg barium chloride dihydrate/kg bw/day to pregnant rats from gestation day 1 up to and including gestation day 20 (TNO, 2014). No effects on body weights, food consumption and clinical signs were observed. Maternal toxicity was evidenced by the spontaneous deaths of two animals on gestation day 21 only and the conditional decline of another animal on gestation day 21 in the high dose group (100 mg/kg bw/day).

 

No developmental toxicity or treatment-related observations, whatsoever in external, visceral and skeletal foetal examinations were observed in any dose level.

 

The NOAEL for maternal toxicity was therefore 30 mg barium chloride dihydrate/kg bw/day (equivalent to 17 mg barium/kg bw/day). In absence of developmental effects, the NOAEL for prenatal developmental toxicity in the rat was ≥ 100 mg barium chloride dihydrate/kg bw/day (equivalent to ≥ 56 mg barium/kg bw/day).

Justification for classification or non-classification

The available data on reproductive toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.