Barium di(acetate)

Toxicity to reproduction

Administrative data

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.

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

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

barium dichloride dihydrate

Cas Number:

10326-27-9

Molecular formula:

BaCl2*2H2O

IUPAC Name:

barium dichloride dihydrate

Test material form:

solid: crystalline

Details on test material:

Chemical Name: Barium Chloride Dihydrated
CAS number: 10326-27-9
Empirical formula: BaCl2 * 2 H2O
Physical appearance: white odourless crystals
Water solubility: 400 g/L at 20°C

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)

- no further significant details stated

Administration / exposure

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.
- 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

Details on study schedule:

- no further significant details stated

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 ppm

Remarks:

Doses / Concentrations:
1000 ppm BaCl2 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

Doses / concentrations 2

Dose / conc.:

2 000 ppm

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

Doses / concentrations 3

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.
- no further significant details stated

Positive control:

not required

Examinations

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
- no further significant details stated

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.
- no further significant details stated

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

- no further significant details stated

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.

- no further significant details stated

Postmortem examinations (offspring):

- no data

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).

Reproductive indices:

- no significant details stated

Offspring viability indices:

- no significant details stated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

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

- no further significant details stated

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

4 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: fertility impairment

2

Dose descriptor:

NOAEL

Effect level:

201.5 mg/kg bw/day (nominal)

Based on:

other: barium

Sex:

male

Basis for effect level:

other: fertility impairment

3

Dose descriptor:

NOAEL

Effect level:

179.5 mg/kg bw/day (nominal)

Based on:

other: barium

Sex:

female

Basis for effect level:

other: fertility impairment

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Details on results (F1)

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)

- no further significant details stated

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: development toxicity, but the NOAEL is of limited value to evaluate the potential for barium to induce developmental 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 impairmentwas 4,000ppm 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.