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Carcinogenicity

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Description of key information

There was no evidence of carcinogenic activity (showing no chemical related increase of malignant or benign neoplasms) of barium chloride dehydrate in both sexes of rats that received 500, 1250 and 2500 ppm. Thus, the concentration of 2500 ppm represents a NOAEL (corresponding to Ba doses of 60 and 75 mg/kg bw/d to male and female rats, respectively) (U.S. National Toxicology program, 1994). The recalculated NOAEL for barium nitrate is 114.2 mg/kg bw/day (for male animals).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented read-across study from barium chloride dihydrate.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Version / remarks:
Adopted in 12 May 1981
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frederic Cancer Research Facility (Frederick, MD)
- Age at study initiation: 7 weeks
- Weight at study initiation: not indicated
- Fasting period before study: not indicated
- Housing: rats were housed five per sex per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days males and 14 days females

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23°C
- Humidity (%): 45%-54%
- Air changes (per hr): 10/hour
- Photoperiod (hrs dark / hrs light): fluorescent light 12 hours/day

IN-LIFE DATES: not indicated
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dose formulations were prepared by mixing barium chloride dihydrate and water in a volumetric flask and stirring mechanically for 1 minute. Dose formulation were prepared weekly .

DOSING SOLUTIONS PREPARATION: formulations were prepared by mixing barium chloride dihydrate and distilled water in a volumetric flask and stirring mechanically for 1 minute.

STABILITY of DOSING SOLUTIONS: Stability studies of the 500 ppm dosed water solutions were performed using ultraviolet spectroscopy. Stability of dose formulations was confirmed for at least 3 weeks when stored in the dark at 25°C and for at least 3 days when stored exposed to air and light.

DIET PREPARATION
- Rate of preparation of diet (frequency): not indicated
- Mixing appropriate amounts with (Type of food): not indicated
- Storage temperature of food: Not indicated

VEHICLE
- Justification for use and choice of vehicle (if other than water): vehicle was water. Drinking water was selected as the route of administration because of the high water solubility of barium chloride dihydrate and because human exposure to this chemical is primarily by ingestion.
- Concentration in vehicle: 500, 1,250 and 2,500 ppm barium chloride dihydrate in drinking water corresponding to average daily doses of 15, 30 and 60 mg barium/kg body weight for males and 15, 45 and 75 mg barium/kg body weight for females.
- Amount of vehicle (if gavage): administered as drinking water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analysis of the dose formulations of barium chloride dihydrate were conducted using complexometric titration. The dose formulations were analysed at least once every 8 weeks. All the dose formulations were within 10% of the target concentrations.
Duration of treatment / exposure:
female rats: 105 weeks
male rats: 104 weeks
Frequency of treatment:
Animals received barium chloride dihydrate in drinking water. Animals had access to the drinking water ad libitum during the study.
Post exposure period:
No post exposure period
Dose / conc.:
0 ppm
Remarks:
nominal in water
Dose / conc.:
500 ppm
Remarks:
nominal in water
Dose / conc.:
1 250 ppm
Remarks:
nominal in water
Dose / conc.:
2 500 ppm
Remarks:
nominal in water
No. of animals per sex per dose:
60 male and 60 female per dose. 10 male and 10 females per dose were randomly selected for interim evaluation after 15 month of chemical administration.
Control animals:
yes
Details on study design:
- Dose selection rationale: The high dose of 2,500 ppm was selected based on decreased final mean body weights, mortality, decreased water consumption and chemical-related kidney lesions observed at 4,000 ppm in a previous 13-week rat study.
- Rationale for animal assignment (if not random): animals were distributed using a table of random numbers
- Rationale for selecting satellite groups: no satellite groups
- Interim groups: 10 male and 10 female rats per group were randomly selected for interim evaluations after 15 months of chemical administration.
- Sentinel groups: 15 male and 15 female rats were maintained with the study animals to serve as sentinel animals. At 6, 12 and 18 months, five male and five female were bled from the external jugular vein. Additional blood was collected from the artery of these or other animals at 5, 7, 8 and 19 months to better evaluate the viriological burden of this study. Samples for viral screening at 24 months were collected from five male and female rats.

Positive control:
No positive control
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initially weekly for 13 weeks, then monthly and at interim evaluations (after 15 months).

BODY WEIGHT: Yes
- Time schedule for examinations: initially weekly for 13 weeks, then monthly and at interim evaluations (after 15 months).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

FOOD EFFICIENCY: No

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes.
- Time schedule for collection of blood: after 15 months (interim groups).
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 male and 10 female rats per group
- Parameters examined: Hemoglobin, hematocrit, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, platelets, reticulocytes, nucleated erythrocytes and leukocyte count and differential.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 15 months (interim groups).
- Animals fasted: No data
- How many animals: 10 male and 10 female rats per group
- Parameters examined: Urea nitrogen, creatinine, calcium, phosphorus, alanine aminotransferase, creatinine kinase, lactate dehydrogenase, sorbitol dehydrogenase and gamma-glutamyltransferase.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: plasma barium levels were determined in blood samples from 15-months interim groups. Bone density, barium, calcium and phosphorus levels in bone were determined in the left femur from eight male and eight female rats in control and high-dose groups.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. At necropsy, all organs and tissues were examined for gross lesions. Organs weighed were adrenal gland, brain, heart, right kidney, liver, lung, ovary, right testis, spleen, thymus and uterus.
All major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned and stained with hematoxylin and eosin for microscopic examination.

HISTOPATHOLOGY: Yes.
Complete histopathology was performed on all rats. In addition to gross lesions, tissue masses and associated lymph nodes, the tissues examined included: adrenal, gland, brain, bone and marrow, clitoral gland, large intestine (cecum, colon, rectum), epididymis, esophagus, heart, kidney, liver, lung, mandibular and mesenteric lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostrate gland, salivary gland, seminal vesicle, skin, small intestine (duodenum, jejunum, ileum), spleen, stomach (forestomach and glandular), testis, thymus, thyroid gland, trachea, urinary bladder and uterus.
Statistics:
SURVIVAL ANALYSIS: the probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analysis for possible dose-related effects on survival used Cox's (1972) method for testing equality and Tarone's (1975) life table test to identify dose-related trends.

ANALYSIS of NEOPLASM INCIDENCES: The primary statistical method used was logistic regression analysis. In addition, other methods of statistical analysis were used. These include the life table test (Cox, 1972; Tarone, 1975), appropriate for rapidly lethal neoplasms, and the Fisher exact test and the Cochran-Armitage trend test (Armitage, 1971; Gart et al., 1979), procedures based on the overall proportion of neoplasm-bearing animals.

ANALYSIS of NON-NEOPLASTIC LESION INCIDENCES: the primary statistical analysis used was the logistic regression analysis. For lesions detected at the interim evaluation, the Fisher exact test was used.

ANALYSIS OF CONTINUOUS VARIABLES: Organ and body weight data, which have approximately normal distributions, were analysed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971,1972). Clinical chemistry and hematology, which are typically skewed distributions, were analysed using nonparametric multiple comparison methods of Dunn (1964) and Shirley (1977). Jonckheere's tests (Jonckheere, 1954) was used to asses the significance of the dose-response trends and to determine whether a trend-sensitive test (Williams' or Shirley's test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose-response trend (Dunnett's or Dunn's test). Average severity values were analysed for significance using Mann-Whitney U test (Hollander and Wolfe, 1973).
Clinical signs:
no effects observed
Description (incidence and severity):
The two-year survival of exposed male and female rats was similar to that of the controls. There were no chemical-related clinical findings in male and female rats.
Mortality:
no mortality observed
Description (incidence):
The two-year survival of exposed male and female rats was similar to that of the controls. There were no chemical-related clinical findings in male and female rats.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose groups body-weights were lower than control in both male (5%) and female (10%) rats.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
From week 5, water consumption of the high-dose groups was lower (males: 11% to 30%; females: 19% to 33%) than control groups.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Parameters measured at the 15-month interim evaluation.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Parameters measured at the 15-month interim evaluation
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Description (incidence and severity):
No conclusion reported
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
there were no increased incidences of lesions that could be attributed to barium chloride dihydrate.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
there were no increased incidences of lesions that could be attributed to barium chloride dihydrate.
Details on results:
CLINICAL SIGNS AND MORTALITY: The two-year survival of exposed male and female rats was similar to that of the controls. There were no chemical-related clinical findings in male and female rats

BODY WEIGHT AND WEIGHT GAIN: High dose groups body-weights were lower than control in both male (5%) and female (10%) rats.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not applicable.

FOOD EFFICIENCY: not applicable.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): From week 5, water consumption of the high-dose groups was lower (males: 11% to 30%; females: 19% to 33%) than control groups.

OPHTHALMOSCOPIC EXAMINATION: not examined.

HAEMATOLOGY: Parameters measured at the 15-month interim evaluation.

CLINICAL CHEMISTRY: Parameters measured at the 15-month interim evaluation.

URINALYSIS: not examined.

NEUROBEHAVIOUR: not examined.

ORGAN WEIGHTS: not reported

GROSS PATHOLOGY: No findings reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no increased incidences of lesions that could be attributed to barium chloride dihydrate.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
There were no increased incidences of lesions that could be attributed to barium chloride dihydrate.

HISTORICAL CONTROL DATA (if applicable): no historical data reported.

OTHER FINDINGS:
- At the 15-month interim evaluation, the plasma barium concentrations (mg/L) were significantly increased in males receiving 1,250 and 2,500 ppm and in all exposed groups of females (male: 0 ppm, 0.98; 500 ppm, 1.00; 1,250 ppm, 1.23; 2,500 ppm 1.68; female: 0 ppm, 0.74; 500 ppm, 0.99; 1,250 ppm, 0.97; 2,500 ppm 1.43). Barium levels in bone in rats from the 2,500 ppm groups were about 400 times greater than those in the controls.
- Mononuclear cell leukemia was not observed in males at 15 months. However, at 2 years, there was a significant negative trend in the incidence of mononuclear cell leukemia in males and the incidences in exposed male groups were significantly decreased. The decreased incidence of this lethal neoplasm may account for the marginal increase in survival of exposed males. The incidences of mononuclear leukemia in exposed females were similar to that in the controls (0 ppm, 15/50; 500 ppm, 13/50; 1,250 ppm, 9/50; 2,500 ppm, 9/50).
- Adrenal gland: A significant negative trend in the incidence of adrenal medulla phenochromocytoma (bening or malignant) was observed in male rats (13/49, 11/50, 12/49, 6/50). The incidence of this neoplasm in the 2.500 ppm males was significantly decreased. The incidences of adrenal medulla hyperplasia in exposed male rats were similar to that in the controls. Incidences of adrenal medulla pheochromocytoma and hyperplasia in exposed females were similar to those in controls.
- Mammary gland: a significant negative trends in the incidence of mammary gland neoplasms was observed in female rats.
Dose descriptor:
other: no descriptor defined
Conclusions:
Under the conditions of these 2-year drinking water study, there was no evidence of carcinogenic activity of barium chloride dihydrate in male or female F344/N rats that received 500, 1250, or 2500 ppm.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
114.2 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

There was no evidence of carcinogenic activity (showing no chemical related increase of malignant or benign neoplasms) of barium chloride dehydrate in both sexes of rats that received 500, 1250 and 2500 ppm. Thus, the concentration of 2500 ppm represents a NOAEL (corresponding to Ba doses of 60 and 75 mg/kg bw/d to male and female rats, respectively) (U.S. National Toxicology program, 1994). The recalculated NOAEL for barium nitrate is 114.2 and 142.7 mg/kg bw/day (for male and female animals resp.).


Justification for selection of carcinogenicity via oral route endpoint:
Well documented read-across study from barium chloride dihydrate.

Justification for classification or non-classification

Based on the available data and according to the criteria of the DSD and CLP regulation, barium nitrate should not be classified for carcinogenicity.