barium(2+); oxygen(2-); titanium(4+); zirconium(4+) ;calcium (2+)

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Link to relevant study records

Reference

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

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:

Study well documented, meets generally accepted scientific principles, acceptable for assessment. Data and Rating according to the SIDS 2005 on barium cabonate. Deviances when comparing to OECD421: dosing only prior to mating, no individual animal data/tables provided, histopathologic examination, data on food consumption only provided for core study animals, no humidity, sex of pups, and data on stability of test substance in vehicle given. Only the average results of the controls and the high dose groups of each species were available.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

In parallel with a subchronic toxicity core study, a premating study was performed with separate groups of rats and mice. Premating exposure period with Barium chloride dihydrate was 60 days for males and 30 days for females.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: Fischer 334/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonson Laboratories, Gilroy, CA
- Age at study initiation: (P) 32 days
- Housing: five per cage in drawer-type polycarbonate cages (shelves covered with filter sheets, bedding, cages and water bottles were changed twice a week, feeders once a week, racks and filters every other week); after 60 days of exposure, the males were placed in individual cages and one female receiving the same dose level (but exposed for 30 days) was cohabited with the male. After mating the females were separated.
- Diet: NIH-o7 pellets (Ziegler Brothers, Gardners, PA)
- Water: ad libitum (dosed or undosed) for 92 consecutive days
- Acclimation period: 10 to 11 days (quarantined)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24 °C
- Air changes (per hr): 13.5 room vol.
- Photoperiod (hrs dark / hrs light): 12/12 (fluorescent lighting)

Route of administration:

oral: drinking water

Type of inhalation exposure (if applicable):

other: not applicable

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Solutions were made weekly in 19-liter quantities by dissolving weighed portions of the test substance in glass-distilled water.
- Concentration in vehicle: 0, 1000 and 4000 ppm
- no further significant details stated

Details on mating procedure:

- M/F ratio per cage: 1 male / 1 female rat
- Length of cohabitation: up to one week
- Proof of pregnancy:Examination of microscopic evidence of sperm in vaginal swab every morning
- When evidence of mating was found, the females was separated from the male.
- After mating determinations were made on the eighth day of cohabition and all remaining pairs were separated.
- No remating was performed although pregnancy rate was low.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses were performed on all levels before and after use, and at the beginning and midway through the test period. The concentrations were within 1 to 6 % of the theoretical concentration. Method of analysis was not stated.

Duration of treatment / exposure:

Premating exposure period: 60 days for males and 30 days for females

Frequency of treatment:

continuous

Details on study schedule:

- no further significant details stated

Remarks:

Doses / Concentrations:
1000 ppmBaCl2 x 2H2O
Basis:
nominal in water
calculated average dose: 63.5 mg Ba/kg bw/d to males and 64.5 mg Ba/kg bw/d to females

Remarks:

Doses / Concentrations:
2000 ppm BaCl2 x 2H2O
Basis:
nominal in water
calculated average dose: 112 mg Ba/kg bw/d to males and 114 mg Ba/kg bw/d to females

Remarks:

Doses / Concentrations:
4000 ppm BaCl2 x 2H2O
Basis:
nominal in water
calculated average dose: 201.5 mg Ba/kg bw/d to males and 179.5 mg Ba/kg bw/d to females

No. of animals per sex per dose:

20 male and 20 female rats

Control animals:

yes, concurrent vehicle

Details on study design:

- Other: No remating was performed due to restriction in the study dosing schedule/design.

Positive control:

not required

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly and females were weighed when evidence of mating was found an on the day of parturition.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: twice weekly


OTHER:
- determination of pregnancy rates in dosed and control animals
- determination of average gestation period

Oestrous cyclicity (parental animals):

- Evaluation of vaginal cytology was performed among treated and control groups.

Sperm parameters (parental animals):

Parameters examined in P male parental generations:
- An evaluation of sperm morphology, density, and motility and sperm count was performed among treated and control groups.

Litter observations:

PARAMETERS EXAMINED
The following examinations were performed in F1 offspring:
- pups were examined at birth and day 5
- number of live litter, average litter size at day 0 and 5, pup survival to day 5, pup weight at birth and day 5, external abnormalities

GROSS EXAMINATION OF DEAD PUPS:
- yes, dead pups were examined for external abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: not stated
- Maternal animals: All surviving animals were terminated on days 96 and 97.

GROSS NECROPSY
- The vagina, cervix, oviducts, and ovaries were grossly examined and the implantation sites in the uteri were counted.
- The male reproductive organ weights (testis, epidimymal) was determined among treated and control groups.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Complete histologic exams were performed in the parallel animal groups which were not used for reproductive and fertility assessment.

Statistics:

Each parameter for which individual values were available was subjected to a linear least squares regression over the doselevels and the direction of the slope and the p value indicating the significance of the deviation of the slope from 0 was determined. Group means and standard deviations or standard errors were calculated for continuous variables. The multiple comparison procedure of Dunnett (1955) was used for comparison between dosed and control groups. Further, Fisher's extract test, the Cochran-Armitage test (Armitage, 1971; Gart et al., 1979) was used as well as repeated measures analysis of variance (WInter, 1971) and a multivariate analysis of variance (Morrison, 1976).

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- one pregnant dam in the 4000 ppm group was terminated in a moribund state 21 days after mating

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
- only determined for core study animals

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- There were no treatment-related effects of barium chloride dihydrate on vaginal cytology up to 4000 ppm.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
- There were no treatment-related effects of barium chloride dihydrate on epididymal sperm count, sperm motility, sperm morphology, up to 4000 ppm.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- The pregnancy rates were below generally accepted norms: from 40 % in the controls and 65 % in the 4000 ppm group.
- All pregnant dams produced litters except for one in the 4000 ppm group, which was terminated
- The average gestation period of surviving dams was 22 to 22.5 days (in various groups).
- The number of implants per pregnant dam was marginally reduced in the 4000 ppm group compared with the controls (but without statistical significance at p<0.05)

ORGAN WEIGHTS (PARENTAL ANIMALS)
- no effect could be detected on testis or epididymal weight

GROSS PATHOLOGY (PARENTAL ANIMALS)
- necropsy of the terminated dam revealed 7 fetuses and one resorption site

Dose descriptor:

NOAEL

Effect level:

4 000 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: fertility impairment

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

VIABILITY (OFFSPRING)
- Pup survival to day 5 was 99 % or greater in all treatment groups.

CLINICAL SIGNS (OFFSPRING)
- No external abnormalities were observed in the rat offspring.

BODY WEIGHT (OFFSPRING)
- Rats receiving 4000 ppm exhibited significant although marginal reductions in pup weights at birth (5.20 +/- 0.06 g compared to 5.70 +/- 0.09 g); a comparision of pups weight on day 5 showed no significant differences. Weight gain was comparable among all pup groups.

OTHER
- The average litter size at birth and on postpartum day 5 was marginally reduced in the 4000 ppm group compared with the controls (but without statistical significance at p<0.05)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

4 000 ppm (nominal)

Sex:

not specified

Basis for effect level:

other: development toxicity, but the NOAEL is of limited value to evaluate the potential for barium to induce developmental effects

Reproductive effects observed:

not specified

Only the average results of the controls and the high dose groups of each species were available.

No-observed-adverse-effect level (NOAEL) for fertility impairment was 4,000 ppm in rats. These NOAEL values correspond to average doses of 201.5 and 179.5 mg Ba/kg bw/d to male and and female rats, respectively.

A NOAEL on developmental toxicity of 4,000 ppm is also reported. However, the NOAEL is of limited value to evaluate the potential for barium to induce developmental effects. The reason for this limitation is based on the fact that the premating study design did not include exposure of female animals during the gestational period to barium chloride. Therefore, the premating study has to be considered as an inadequate study of developmental toxicity and cannot be used to determine the occurrence of developmental toxicity.

Conclusions:

Taken together all data of this study, 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 201.5 and 179.5 mg Ba/kg bw/d to male and and female rats, respectively). No-observed-adverse-effect levels (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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

307 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

There is a reliable in vivo study available to assess the potential of toxicity to reproduction of the analogous test substance barium dichloride dihydrate after oral administration.

For read-across barium chloride is adopted as it is also an inorganic barium salt whose relevant eco-/toxicological nature depends on the common cation barium whereas the toxicological nature of the anion is negligible. The substances differ in solubility. Barium chloride is soluble while barium titanium trioxide is slightly soluble. But this difference is considered as negligible as it is supported by the absence of any adverse findings in acute toxicity for the analogue substance. In conclusion, read-across for the endpoint toxicity to reproduction is justified.

Toxicity to reproduction – oral

In a non guideline conform study the potential of the analogous test substance barium dichloride dihydrate (purity: >99.5 weight-%) to assess the toxicity to reproduction after oral ingestion was carried out using Fischer 344 rats (Dietz et al., 1992). The test substance was given to male rats 60 days and to female rats 30 days before mating period in the concentrations: 1000, 2000 and 4000 ppm.

One pregnant dam in the 4000 ppm dose group was terminated in a moribund state 21 days after mating.

No treatment-related effects of barium chloride dihydrate could be found on vaginal cytology, on epididymal sperm count, sperm motility and sperm morphology up to 4000 ppm.

The pregnancy rates were below generally accepted norms: from 40 % in the controls and 65 % in the 4000 ppm dose group. All pregnant dams produced litters except for one in the 4000 ppm dose group, which was terminated. Necropsy of the terminated dam revealed 7 foetuses and one resorption site.

The average gestation period of surviving dams was in the normal range.

The number of implants per pregnant dam was marginally reduced in the 4000 ppm dose group compared with the controls (but without statistical significance at p < 0.05)

No effect could be detected on testis or epididymal weight.

Pup survival to day 5 was 99 % or greater in all treatment groups. No external abnormalities were observed in the rat offspring. Rats receiving 4000 ppm exhibited significant although marginal reductions in pup weights at birth (5.20 +/- 0.06 g compared to 5.70 +/- 0.09 g); a comparison of pups weight on day 5 showed no significant differences. Weight gain was comparable among all pup groups.

The average litter size at birth and on postpartum day 5 was marginally reduced in the 4000 ppm dose group compared with the controls (but without statistical significance at p < 0.05).

Taken together all data of this study, 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 201.5 and 179.5 mg Ba/kg bw/d to male and female rats, respectively).

Based on this screening study the NOAEL of Ba 2+ ions is 179.5 mg /kg bw/day for female rats resultant a NOAEL of barium calcium zirconium titanate for fertility impairment of ≥ 307 mg/kg bw/day (calculated from its molecular weight).

Under the conditions of this screening test, barium calcium zirconium titanate is considered not to be toxic to reproduction in rats.

Short description of key information:
Toxicity to reproduction - oral:
read-across, key study, oral, Fischer 344 rats; NOAEL ≥ 307 mg/kg bw/d (no guideline followed, Dietz et al., 1992)

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008:

Based on the results, the classification of the test substance for toxicity to reproduction under Regulation 1272/2008 is not warranted.