Barium titanium trioxide

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

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

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.

Justification for type of information:

Research document on water-soluble form of barium salt. Both rats and mice examined
Considered suitable as source data for barium salts

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Subchronic toxicity of barium chloride dihydrate administered to rats and mice in the drinking water.

Author:

Dietz, D.D.; et al.

Year:

1992

Bibliographic source:

Fund. Appl. Tox. 19, 527-537

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

10326-27-9

Cas Number:

10326-27-9

IUPAC Name:

10326-27-9

Constituent 2

Reference substance name:

barium chloride dihydrate

IUPAC Name:

barium chloride dihydrate

Details on test material:

- Name of test material (as cited in study report): Barium chloride dihydrate
- EC number: 233-788-1
- Molecular formula (if other than submission substance): BaCl2 x 2H2O
- Molecular weight (if other than submission substance): 226.3 g (calculated from molecular formula)
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: technical product
- Physical state: white, crystalline solid
- Analytical purity: 99.5 % (by EDTA titration)
- Lot/batch No.: 123120 (from Baker Chemical Co., Phillipsburg, NJ)

Test animals

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)

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

- 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.
- no further significant details stated

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

2 000 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

4 000 ppm (nominal)

No. of animals per sex per dose:

20 each sex

Control animals:

yes, concurrent vehicle

Details on study design:

No remating was performed due to restriction in the study dosing schedule/design

Examinations

Parental animals: Observations and examinations:

Yes, twice daily, including clinical, body weight, water and food consumption

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

Litter observations:

F1 offspring:
- 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
- examination of dead pups

Postmortem examinations (offspring):

All surviving animals were terminated on days 96 and 97.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

4 000 ppm (nominal)

Based on:

element

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Dose descriptor:

NOAEL

Effect level:

179.5 mg/kg bw/day (nominal)

Based on:

element

Sex:

female

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

3

Dose descriptor:

NOAEL

Effect level:

201.5 mg/kg bw/day (nominal)

Based on:

element

Sex:

male

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

4 000 ppm (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.