Registration Dossier

Administrative data

Endpoint:
fertility, other
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.
Cross-reference
Reason / purpose:
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
Deviations:
not applicable
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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
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
Doses / concentrationsopen allclose all
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

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
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).

Results and discussion

Results: P0 (first parental animals)

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
Gross pathological findings:
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

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
4 000 ppm (nominal)
Sex:
male/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)

Effect levels (F1)

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

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.