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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (NTP).

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1998
Reference Type:
review article or handbook
Title:
Cobalt und Cobaltverbindungen (in Form atembarer Stäube/Aerosole)
Author:
MAK
Year:
2001
Bibliographic source:
MAK, 33. Lieferung

Materials and methods

Test guideline
Guideline:
other: Standard NTP protocol for Toxicology and Carcinogenesis studies
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): cobalt sulfate heptahydrate
- Molecular formula (if other than submission substance): CoSO4 7H2O
- Molecular weight (if other than submission substance): 281.13 g/mol
- Analytical purity: 99 %
- Impurities (identity and concentrations): 140 ppm nickel, 175 ppm other impurities
- Lot/batch No.: 412092
- Stability: Stability was monitored during the studies; no degradation of the bulk chemical was detected.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 6 wks
- Housing: individually
- Diet (e.g. ad libitum): ad libitum (except exposure periods)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.3-26.6
- Humidity (%): 31-89
- Air changes (per hr): 9-23
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
whole body
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
105 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Post exposure period:
none
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 0.3, 1.0, 3.0 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0.30 ± 0.03, 1.03 ± 0.10, 2.98 ± 0.20 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment: Animals were distributed randomly into groups of approximately equal initial mean body weights

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initially, at weeks 5, 9, and 13 weeks, then in 4-week-intervals up to week 92, then in 2-week-intervals and at the end of the study


BODY WEIGHT: Yes
- Time schedule for examinations: weekly for 13 weeks, then in 4-week-intervals up to week 92, then in 2-week-intervals


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
- Number of animals: Complete histopathology was performed on all mice
- Tissues examined: Gross lesions and tissue masses, adrenal gland, bone with marrow, brain, clitoral gland, oesophagus, gallbladder (mice), harderian gland (rats), heart, large intestine (caecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lungs/bronchi, lymph nodes (mandibular, mesenteric, bronchial, mediastinal), mammary gland (except male mice), nose, oral cavity (rats), ovary, pancreas, pancreatic islets, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, sciatic nerve, seminal vesicle, skin, spinal cord, spleen, stomach (forestomach and glandular), testes/epididymides, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
Survival rates (0, 0.3, 1.0, 3.0 mg/m3):
Male: 17/50, 15/50, 21/50, 15/50
Female: 28/50, 25/49, 26/50, 30/55

BODY WEIGHT AND WEIGHT GAIN
Exposed groups similar to chamber controls


HISTOPATHOLOGY: NON-NEOPLASTIC
Male (0, 0.3, 1.0, 3.0 mg/m3):
- The incidences and severities of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were markedly greater in all exposed groups of male than in the chamber controls. The incidences of alveolar epithelial hyperplasia in all groups of exposed males were significantly greater than those in the chamber control groups.
Lung:
Proteinosis (0/50, 16/50, 40/48, 47/50); alveolar epithelial metaplasia (0/50, 50/50, 48/48, 49/50); granulomatous alveolar inflammation (2/50, 50/50, 48/48, 50/50); interstitial fibrosis (1/50, 50/50, 48/48, 50/50); alveolar epithelial hyperplasia (9/50, 20/50, 20/48, 23/50)

- Hyperplasia of the lateral wall of the nose, atrophy of the olfactory epithelium, and squamous metaplasia of the epiglottis were observed in all exposed groups of males, and the severities of these lesions increased with increasing exposure concentration. The incidences of squamous metaplasia of the lateral wall of the nose and metaplasia of the olfactory epithelium were increased in 3.0 mg/m3 males.
Nose:
Lateral wall hyperplasia (2/50, 14/50, 21/49, 20/50); olfactory epithelial atrophy (8/50, 24/50, 42/49, 48/50); lateral wall squamous metaplasia (1/50, 3/50, 5/49, 8/50); olfactory epithelial metaplasia (5/50, 1/50, 5/49, 30/50)
Larynx:
Epiglottis squamous metaplasia (0/50, 10/49, 37/48, 50/50)

Female (0, 0.3, 1.0, 3.0 mg/m3):
- The incidences and severities of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were markedly greater in all exposed groups of female rats than in the chamber controls. The incidences of alveolar epithelial hyperplasia in females exposed to 3.0 mg/m3 were significantly greater than those in the chamber control groups, as were the incidences of squamous metaplasia in 1.0 mg/m3 females and atypical alveolar epithelial hyperplasia in 3.0 mg/m3 females.
Lung:
Proteinosis (0/50, 36/49, 49/50, 49/50); alveolar epithelial metaplasia (2/50, 47/49, 50/50, 49/50); granulomatous alveolar inflammation (9/50, 47/49, 50/50, 49/50); interstitial fibrosis (7/50, 47/49, 50/50, 49/50); alveolar epithelial hyperplasia (15/50, 7/49, 20/50, 33/50); squamous metaplasia (0/50, 1/49, 8/50, 3/50); atypical alveolar epithelial hyperplasia (0/50, 0/49, 3/50, 5/59)

- Hyperplasia of the lateral wall of the nose, atrophy of the olfactory epithelium, and squamous metaplasia of the epiglottis were observed in all exposed groups of females, and the severities of these lesions increased with increasing exposure concentration. The incidences of squamous metaplasia of the lateral wall of the nose and metaplasia of the olfactory epithelium were increased in 3.0 mg/m3 females
Nose:
Lateral wall hyperplasia (1/50, 8/49, 26/50, 38/50); olfactory epithelial atrophy (5/50, 29/49, 46/50, 47/50), lateral wall squamous metaplasia (1/50, 1/49, 4/50, 10/50); olfactory epithelial metaplasia (2/50, 2/49, 3/50, 40/50)
Larynx:
Epiglottis squamous metaplasia (1/50, 22/49, 39/50, 48/50)


HISTOPATHOLOGY: NEOPLASTIC
Male (0, 0.3, 1.0, 3.0 mg/m3):
In 3.0 mg/m3 males, the combined incidence of alveolar/ bronchiolar neoplasms (adenoma and/or carcinoma) was significantly greater than in the chamber controls. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 1.0 mg/m3 males were significantly greater than those in the chamber controls and exceeded the historical control ranges
Lung:
Alveolar/bronchiolar adenoma (1/50, 4/50, 1/48, 6/50); alveolar/bronchiolar carcinoma (0/50, 0/50, 3/48, 1/50); alveolar/bronchiolar adenoma or carcinoma (1/50, 4/50, 4/48, 7/50)

Female (0, 0.3, 1.0, 3.0 mg/m3):
- In female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were significantly greater than those in the chamber control group and exceeded the NTP historical control ranges. A squamous cell carcinoma was observed in one 1.0 mg/m3 and one 3.0 mg/m3 female. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 3.0 mg/m3 females were significantly greater than those in the chamber controls and exceeded the historical control ranges.
Lung:
Alveolar/bronchiolar adenoma (0/50, 1/49, 10/50, 9/50); alveolar/bronchiolar carcinoma (0/50, 2/49, 6/50, 6/50); alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, or squamous cell carcinoma (0/50, 3/49, 16/50, 16/50)
Adrenal medulla:
Benign, complex, or malignant pheochromocytoma (2/48, 1/49, 4/50, 10/48)


OTHER FINDINGS
Uncertain:
Male (0, 0.3, 1.0, 3.0 mg/m3):
Adrenal medulla:
benign, complex, or malignant pheochromocytoma (15/50, 19/50, 25/49, 20/50)

Effect levels

open allclose all
Dose descriptor:
BMD: Excess Risk 10
Effect level:
0.43 mg/m³ air
Sex:
female
Basis for effect level:
other: histopathology: alveolar/bronchiolar neoplasms
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
BMD: Excess Risk 10%
Effect level:
2.6 mg/m³ air
Sex:
male
Basis for effect level:
other: histopathology: alveolar/bronchiolar neoplasms
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Any other information on results incl. tables

There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in female rats, and some evidence of carcinogenic activity in male rats.

The whole group of soluble cobalt(II)-compounds was classified as Carcinogen Category 2 because in mechanistic studies the cobalt(II)-ion was identified as the active component (MAK, 33. Lieferung, 2001).

Applicant's summary and conclusion