Cobalt molybdate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

- limited documentation of the results

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

10026-24-1

EC Number:

600-050-9

Cas Number:

10026-24-1

IUPAC Name:

10026-24-1

Constituent 2

Reference substance name:

cobalt(II)sulfate heptahydrate

IUPAC Name:

cobalt(II)sulfate heptahydrate

Details on test material:

- Name of test material (as cited in study report): cobalt(II)sulfate heptahydrate
- Molecular formula (if other than submission substance): CoSO4*7H2O
- Molecular weight (if other than submission substance): 281 g/mol
- Analytical purity: 99%
- Other: The pH of aqueous solutions of cobalt(II)sulfate heptahydrate was measured at three concentrations. Solutions of 0.01, 0.1, and 1 M were found to have pH values of 6.3, 6.2 and 5.2, respectively.

Test animals

Species:

rat

Strain:

other: F344/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY, USA)
- Age at study initiation: 6 weeks
- Housing: individual housing
- Diet (e.g. ad libitum): NIH 07 rat and mouse ration (Zeigler Bros., Inc., Gardners, PA); ad libitium except during exposure periods

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7 - 25.2
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: The mass median aerodynamic diameter of the aerosol for all exposures ranged from 0.83 to 1.10 µm.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazleton 2000, Lab Products, Inc.
- System of generating particulates/aerosols: Cobalt sulfate heptahydrate aerosol was generated from an aqueous solution by nebulisation using dried compressed air. The aerosol was diluted to the desired concentration with air from the chamber air-conditioning system.
- Method of particle size determination: Cascade impactor samples were taken to determine aerosol size distribution. The mass median aerodynamic diameter of the aerosol for all exposures ranged from 0.83 to 1.10 µm. Cobalt sulfate hydration in the aerosol distribution line was determined by ultraviolet/visible spectroscopy. Hydration ratios of 7.66 and 7.67 were determined for two samples taken during the studies.

TEST ATMOSPHERE
- Brief description of analytical method used: Three real-time aerosol monitors (Model RAM-1, GCA Environmental Instruments) were used to determine the concentration of the aerosol in the exposure chambers once every 20 minutes throughout the exposure period.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Three real-time aerosol monitors (Model RAM-1, GCA Environmental Instruments) were used to determine the concentration of the aerosol in the exposure chambers once every 20 minutes throughout the exposure period.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.3, 1, 3, 10, 30 mg/m3
Basis:
other: nominal conc.; calculated as the anhydrous salt of cobalt(II)sulfate heptahydrate

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.300±0.029; 0.990±0.087; 2.93±0.275; 9.95±0.579; 30.0±1.64 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

Animals distributed to weight classes and then assigned to cages and groups by a table of random numbers.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weighed initially and once per week thereafter

HAEMATOLOGY: Yes
- Blood was obtained from the retroorbital sinus.

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

OTHER:
- estrous cyclicity
- sperm parameters (testis weight, sperm motility, sperm morphology)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

The analysis of organ weight and male reproductive system data was carried out by using the non-parametric multiple comparison procedures of Dunn (1964) or Shirley (1977) to assess the significance of pairwise comparisons between dosed and chamber control groups. Jonckheere´s test (Jonckheere, 1954) was used to evaluate the significance of dose-response trends and to determine whether Dunn´s or Shirley´s test was more appropriate for pairwise comparisons.
The proportion of time spent in each stage of the estrous cycle was compared by using the Wilks criterion statistic (Wilks, 1932) of the multivariate analysis of variance procedure, which was performed after an arc sine transformation of the data.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
All rats survived to the end of the study.
Compound-related clinical signs included ruffled fur in rats and hunched posture in male rats exposed to 30 mg/m³.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights of rats exposed to 30 mg/m³ were lower than those of controls throughout the study. The final mean body weight of male rats exposed to 30 mg/m³ was 14% lower than that of the controls. Mean body weights of exposed female rats were not related to the exposure.

HAEMATOLOGY
Polycythemia, seen at 10 and 30 mg/m³ for female rats and at 3, 10, 30 mg/m³ for male rats, was indicated by significant increases in erythrocytes, in the mean hemoglobin concentration, and in the hematocrit value. The reticulocyte count was significantly increased in female rats exposed to 30 mg/m³. No significant changes were found in the leukocyte or differential counts.

CLINICAL CHEMISTRY
Mean serum cholesterol values were significantly decreased for males exposed to 10 or 30 mg/m³ and for females exposed to 30 mg/m³. No consistent dose-related effects were seen on the glucose concentration, on total creatine kinase activity, or on serum triglyceride concentration.

URINALYSIS
Granular casts were observed in the urine from many exposed male rats compared to controls. A dose-related increase was seen in the number of epithelial cells in the urine from males that were exposed to 3 mg/m³ or more.
The amount of cobalt excreted in the urine over 16 hours varied from 2.5 µg at 0.3 mg/m³ to 105 µg at 30 mg/m³ for males and from 2.0 µg at 0.3 mg/m³ to 67 µg at 30 mg/m³ for females. The amount of cobalt excreted in the urine of rats exposed to 0.3 mg/m³ was approx. 10 fold increased compared to controls.
ORGAN WEIGHTS
The absolute lung weights and/or the lung weight to body weight ratio were significantly increased for male rats exposed to 0.3 mg/m³ or more and for female rats exposed to 1 mg/m³ or more. Relative kidney weights were increased in male rats at all exposure concentrations.

GROSS PATHOLOGY/HISTOPATHOLOGY:
Compound-related lesions were limited to the respiratory tract of rats of each sex exposed to the test item. Lesions were concentration related and similar in incidence and severity in males and females. In the nose, hyperplasia and squamous metaplasia of the respiratory epithelium were seen primarily at the two highest exposure concentrations. This was most prominent at the tips of the naso- and maxilloturbinates and on the lateral wall of the nasal cavity in the most anterior section of the nose. Degeneration of the olfactory epithelium was characterised by a thinning of the olfactory epithelial cell layer in the dorsal meatus and also on the nasal septum in the ethmoid region (degeneration was slightly more prominent in males).
At 10 and 30 mg/m³, inflammatory polyps were seen in the larynx of most rats. Polyps were consistently located at the base of the epiglottis and extended into the lumen of the larynx. These polyps had a fibrovascular stroma, which was covered by a well-differentiated squamous epithelium. Focal areas of necrosis and ulceration were frequently present in the epithelium of the polyp. Chronic inflammation and mineralisation were prominent in the stroma of the polyp. At 1 and 3 mg/m³, polyps did not occur, but squamous metaplasia of the laryngeal respiratory epithelium and chronic inflammation in the stroma were persisted. At 0.3 mg/m³, the severity of the metaplasia and inflammation was minimal to mild.
Regeneration of bronchiolar epithelium with dilation of bronchioles was observed in the lung of rats exposed to 30 mg/m³; distension or disruption of alveolar septa was also present. Fibrosis was present around bronchioles and within alveolar septae. Histiocytic infiltration, characterised by intraalveolar accumulation of macrophages and infiltration of alveolar septae with inflammatory cells also occurred at 30 mg/m³. At lower concentrations, only intraalveolar histiocytic infiltrates and subacute inflammation were present. Lymphoid hyperplasia was present in the mediastinal lymph nodes of exposed rats, but the incidence was not concentration related.

OTHER:
REPRODUCTIVE FUNCTION: ESTROUS CYCLE
The average estrous cycle of females exposed to 30 mg/m3 was longer (but not statistically) than that of the control animals.

REPRODUCTIVE FUNCTION: SPERM MEASURES
No statistically significant effects on sperm motility, sperm counts, or the incidence of abnormal sperm were observed in exposed rats.

Effect levels

1

Dose descriptor:

LOAEC

Effect level:

0.4 mg/m³ air

Based on:

other: CoMoO4

Sex:

male/female

Basis for effect level:

other: squamous metaplasia in the larynx

2

Dose descriptor:

LOAEC

Effect level:

0.114 mg/m³ air

Based on:

element

Remarks:

Co

Sex:

male/female

Basis for effect level:

other: squamous metaplasia in the larynx

3

Dose descriptor:

LOAEC

Effect level:

0.3 mg/m³ air

Based on:

other: calculated as the anhydrous salt of cobalt(II)sulfate

Sex:

male/female

Basis for effect level:

other: squamous metaplasia in the larynx

Target system / organ toxicity

Critical effects observed:

not specified