Barium bis(dihydrogenorthophosphate)

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Subchronic Toxicity of Barium Chloride Dihydrate Administered to Rats and Mice in the Drinking Water

Author:

D.D. Dietz, M.R, Elwell, W.E. Davis, Jr., E.F. Meirhenry

Year:

1992

Bibliographic source:

Fundamental and Applied Toxicology 19, 527-537

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

adopted: 29 July 2016

Deviations:

yes

Remarks:

limited documentation

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Barium chloride dihydrate

IUPAC Name:

Barium chloride dihydrate

Test material form:

solid

Details on test material:

- State of aggregation: solid, white crystalline
- purity: 99 - 100%
- Lot/batch No.: 123120 and 423103 (obtained from J.T. Baker Chemical Company, Phillipsburg, NJ, USA)

Test animals

Species:

rat

Strain:

Fischer 344

Remarks:

Fischer 344/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories, Inc., Gilroy, CA, USA
- Age at study initiation: not specified
- Weight at study initiation: not specified
- Housing: 5 per cage (polycarbonate cages)
- Diet: ad libitum (NIH-07 open-formula pellets diet; Zeigler Brothers, Inc., Gardners, PA, USA)
- Water: ad libitum
- Acclimation period: 10 -11 days

DETAILS OF FOOD AND WATER QUALITY: diet contains less than 20 ppb barium

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24
- Humidity (%): 40 - 62
- Air changes (per hr): 13.5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: no details provided

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 1 week
- Proof of pregnancy: sperm in vaginal smear

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

males: 60 days prior to mating
females: 30 days prior to mating

Frequency of treatment:

continuously

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 ppm (nominal)

Remarks:

corresponding to 65 mg barium/kg bw/day for males and females

Doses / concentrations 2

Dose / conc.:

2 000 ppm (nominal)

Remarks:

corresponding to 110 or 115 mg barium/kg bw/day for males or females, respectively

Doses / concentrations 3

Dose / conc.:

4 000 ppm (nominal)

Remarks:

corresponding to 200 or 180 mg barium/kg bw/day for males or females, respectively

No. of animals per sex per dose:

20

Control animals:

yes, plain diet

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

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

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

Parameters examined in all P male parental generations:
testis weight, epididymis weight, sperm motility, sperm morphology, density, and motility

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain

GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities; possible cause of death was not determined for pups born or found dead.

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: not specified
- Maternal animals: All surviving animals on Days 96 and 97

GROSS NECROPSY
- Gross necropsy consisted of examination of vagina, cervix, oviducts, and ovaries. Implantation sites in the uteri were counted.

HISTOPATHOLOGY / ORGAN WEIGHTS
no data

Postmortem examinations (offspring):

SACRIFICE
- All offsprings were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) for external abnormalities.

GROSS NECROPSY
- Gross necropsy consisted of external examinations.

HISTOPATHOLOGY / ORGAN WEIGTHS
not examined

Statistics:

Each parameter for which individual values were available was subjected to a linear least squares regression over the dose levels 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 was employed for pairwise comparisons of these variables between dosed groups and controls. Fisher's exact test was used to make pairwise comparisons of discrete variables between dosed groups and controls and the Cochran-Armitage test was used to assess the significance of dose-related trends. Temporal and dose-related variations were evaluated using a repeated measures analysis of variance. When a collection of measurements were made on each animal, a multivariate analysis of variance was used to test for the simultaneous equality of measurements across dose levels.

Reproductive indices:

No indices calculated, but gestation lenght was estimated.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

one female animal was terminated in a moribund state 21 days after mating

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No effect of the test substance could be detected on vaginal cytology.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

No effect of the test substance could be detected on epididymal sperm counts, sperm motility, and sperm morphology.

Reproductive performance:

no effects observed

Description (incidence and severity):

Although the pregnancy rates (from 40% in controls to 65% in the 4000 ppm group) were below the generally accepted norms for reproduction studies, this problem was not corrected by remating due to restrictions in the study dosing schedule/design. All pregnant dams produced live litters except for one in the 4000 ppm group which was terminated in a moribund state 21 days after mating. The average gestation period of surviving dams was 22 to 22.5 days in the various groups. The average live litter size at birth and on Postpartum Day 5 was marginally reduced in the high-dose group (4000 ppm) rats compared with controls (Day 0, 9.0 ± 1.37 pups compared to 7.2 ± 0.52 pups; Day 5, 9.3 ± 1.16 pups compared to 7 .1 ± 0.56 pups; mean ± SEM) but not statistical significant (p < 0.05). The number of implants per pregnant dam was also marginally reduced from 9.6 ± 1.10 pups in controls to 7.7 ± 0.52 pups in the high-dose group and statistical significant (p < 0.05).

Details on results (P0)

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.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 4 000 ppm (nominal)

Based on:

test mat.

Remarks:

equivalent to 200 or 180 mg barium/kg bw/day for male and female rats, respectively

Sex:

male/female

Basis for effect level:

other: no effects observed up to highest dose tested

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Description (incidence and severity):

Pup survival to Day 5 was 99% or greater in all rat treatment groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the high-dose group, the live pup weight at birth (5.20 ± 0.06 g) was significantly less (p < 0.01) than the control values (5.70 ± 0.09 g). A comparison of pup weights on Day 5 (9.93 ± 0.20 g for high dose compared to 10.55 ± 0.26 g for controls) failed to show significant changes. Weight gain during this period, however, was comparable among all pup groups.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

No external abnormalities were observed in the rat offspring.

Histopathological findings:

not examined

Other effects:

not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

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 highest dose tested

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

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 200 and 170 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.