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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1990-08-30 to 1992-09-4
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Although no guideline is stated for this study it is reliable without restriction, because it was conducted according to GLP requirements under the National Toxicology Program.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1998
Reference Type:
publication
Title:
Inhalation toxicity and carcinogenicity studies of cobalt sulfate
Author:
Bucher, J.R.; et al.
Year:
1999
Bibliographic source:
Toxicol. Sci. 49, 56-67

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of 50 male and 50 female rats were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m³ cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
cobalt sulfate heptahydrate
IUPAC Name:
cobalt sulfate heptahydrate
Constituent 2
Reference substance name:
10026-24-1
Cas Number:
10026-24-1
IUPAC Name:
10026-24-1
Details on test material:
- Name of test material (as cited in study report): Cobalt sulfate heptahydrate (CoSO4 * 7H2O) (From Curtin mMatheson Scientific (Kansas City, MO)
- Physical state: red, crystalline solid
- Molecular weight: 281.13 g
- Analytical purity: approx. 99 %; Elemental analyses for sulfur and hyfrogen were in agreement with the theoretical values for cobalt sulfate heptahydrate, but results for cobalt wer slightly low. Karl Fischer water analysis indicated 44.6 % +/- 0.5% water
- Impurities (identity and concentrations): Spark source mass spectroscopy indicated 140 ppm nickel present as impurity; all other impurities had a combined total of less than 175 ppm.
- Lot No.: 412092
- Storage condition of test material: To ensure stability, the bulk chemical was stored in its original shipping containers, metal cans, at room temperature.
- Other: Cobalt sulfate heptahydrate is stable as a bulk chemical when stored protected from light at normal tempertures. The heptahydrate dehydrates to the hexahydrate at 41.5 °C and to the monohydrate when heated to 71°C, with no further changes expected below the decomposition temperature (708°C). Therefore, an accelerated stability study was not conducted. Stability was monitored during the study using elemental analysis by inductively coupled plasma/atomic emission spectroscopy (ICP/AES) normalized against a cobalt standard (National Institute of Standards and Technology, Gaithersburg, MD); no degradation of the bulk chemical was detected.
No further information on the test material was stated.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Simonsen Laboratories (Gilroy, CA)- Age at study initiation: approx. 6 weeks- Housing: Rats were housed individually. Cages (stainless-steel wire-bottom (Hazleton System, Inc., Aberdeen, MD)) and racks were rotated weekly. Cages were changed weekly. Bedding: cageboard (Bunzl Cincinnati Paper Co., Cincinnati, OH), changed daily (15 October 1990 to study termination)- Chamber Air supply filters: Single HEPA (Flanders Filters, Inc., San Rafael, CA)- Chambers: Stainless-steel with excreta pan suspended below each cage unit (Harford System Division of Lab Products, Inc., Aberdeen, MD), changedweekly- Diet (ad libitum except during exposure period): NIH-07 open formula pellet diet (Zeigler Brothers, Inc., Gardners, PA), changed weekly- Water (ad libitum): Tap water (Richland municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI)- Quarantine period: 14 days before beginning of the study. Five male and five females rats were selected for parasite evaluation and gross observation of disease. Serology samples were collected for viral screening. The health of the animals was monitored during the study according to the protocols of the NTP Sentinel Animal Program.ENVIRONMENTAL CONDITIONS OF CHAMBERS FOR EXPOSURE- Temperature (°C): 21.3°C–26.6° C- Relative humidity: 31%–89%:- Air changes (per hr): 9-23/hour- Photoperiod (hrs dark / hrs light): 12 hours/dayNo further information on the test animals was stated.

Administration / exposure

Route of administration:
other: particulated aerosol from solution; see details on inhalation exposure below
Type of inhalation exposure:
whole body
Vehicle:
other: see details on inhalation exposure below
Remarks on MMAD:
MMAD / GSD: 0.3 mg/m³ concentration: MMAD = 1.5 +/- 0.10 µm (GSD = 2.2 +/- 0.14)1.0 mg/m³ concentration: MMAD = 1.4+/- 0.12 µm (GSD = 2.1 +/- 0.13)3.0 mg/m³ concentration: MMAD = 1.6 +/- 0.12 µm (GSD = 2.2 +/- 0.13)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION- Exposure apparatus: Hazleton 2000 inhalation exposure chambers (Harford Systems Division of Lab Products, Inc., Aberdeen, MD); The inhalation exposure chambers were designed so that uniform aerosol concentrations could be maintained throughout each chamber with the catch pans in place. The total active mixing volume of each chamber was 1.7 m³.- System of generating particulates/aerosols: Cobalt sulfate heptahydrate aerosol was generated and delivered from an aqueous solution by a system composed of three main components: a compressed-air-driven nebulizer (Model PN7002; RETEC Development Laboratory, Portland, OR), an aerosol charge neutralizer, and an aerosol distribution system. The nebulizer consisted of two orifices of different sizes aligned on opposite sides of a small chamber. Compressed air entered the chamber through the small orifice and, on entering the larger orifice, induced a negative pressure.Cobalt sulfate heptahydrate in deionized water (approx. 400 g/L) was siphoned from the bulk reservoir to the nebulizer reservoir and then aspirated into the nebulizer chamber and expelled as a stream through the larger orifice. Shear forces broke the stream into droplets that were evaporated to leave dry particles of cobalt sulfate heptahydrate. The aerosol generation and delivery system included primary and secondary compressed-air-driven nebulizers. The aerosol generated by the compressed-air-driven nebulizer was passed through the aerosol charge neutralizer to remove static charge that formed on the aerosol particles during generation, reducing adhesion of the droplets to the walls of the delivery system. This neutralizer consisted of a length of plastic duct with two 10-mCi 63Ni-plated foils suspended in the center of the tube. The activity of the foils was matched to the diameter of the duct to allow adequate time for the aerosol to approach Boltzmann equilibrium at the system flow rate.A distribution line carried aerosol (20 mg/m³) to exposure chambers on both sides of the exposure room. Aerosol was siphoned from the branches of the distribution line by pneumatic pumps (one pump per exposure chamber). The flow rate in each branch of the distribution line was controlled by an Air-Vac pump (Air-Vac Engineering, Milford, CT) and monitored by a photohelic differential pressure gauge (Dwyer Instruments, Inc., Michigan City, IN) coupled to a Venturi tube. At each chamber, aerosol moving through the chamber inlet was further diluted with HEPA-filtered air to the appropriate concentration for the chamber. - Temperature, humidity, pressure in air chamber: see above under "Details on test animals and environmental conditions"- Method of particle size determination: Aerosol size distribution was determined monthly for each exposure chamber with a Mercer-style sevenstageimpactor (In-Tox Products, Albuquerque, NM). Samples were analyzed for cobalt sulfate heptahydrate with ICP/AES. The relative mass on each impactor stage was analyzed by probit analysis; the mass median aerodynamic diameter for the aerosol was within the specified range of 1 to 3 μm.TEST ATMOSPHERE- Brief description of analytical method used: The chamber aerosol concentrations of cobalt sulfate heptahydrate were monitored by real-time aerosol monitors (Model RAM-1; MIE, Inc., Bedford, MA) controlled by a Hewlett-Packard HP-85B computer (Hewlett-Packard Company, Palo Alto, CA). The RAM-1s detected aerosol particles ranging from 0.1 to 20 μm in diameter. Three RAM-1s were employed in the monitoring system; these monitorswere exchanged with different RAM-1s when the on-line monitor performance deteriorated. Chamber aerosol concentrations were sampled at least once per hour during each exposure day. Sample lines connecting the exposure chambers to the RAM-1s were designed to minimize aerosol particle losses due to settling or impaction. Throughout the 2-year studies, the background concentrations of total suspended particles in the control chambers were less than the limit of detection.The RAM-1 voltage output was calibrated against cobalt sulfate heptahydrate concentrations of chamber filter samples. Samples were collected on Teflon®-coated, glass-fiber filters with a calibrated flow sampler. Equations for the calibration curves contained in the HP-85B computer converted the RAM-1 voltages into exposure concentrations. Solutions of filter samples in 2% nitric acid were analyzed quantitatively for cobalt sulfate heptahydrate by inductively coupled plasma/atomic emission spectroscopy (ICP/AES). Calibration samples were collected every 2 weeks. Additional samples for monitoring the accuracy of calibration were collected daily from at least one chamber monitored by each RAM-1 and were analyzed two to three times per week. The ICP/AES was calibrated with a solution of standard cobalt diluted with nitric acid.The stability of aerosol concentrations in the 0.3 and 3.0 mg/³ chambers was monitored by analyzing samples collected on Gelman A/E glass fibers using a calibrated flow sampler. X-ray diffraction analyses were performed by a Philips 3600 diffraction unit with Cu Ka radiation. Results indicated that cobalt sulfate hexahydrate was the primary species delivered to the chambers.The time required for the chamber concentration to reach 90% of the target value following the beginning of exposure (T90) and the time required for the chamber concentration to reach 10% of the target value following termination of the exposure (T10) were determined for each exposure chamber. Without animals present, T90 values ranged from 9 to 11 minutes and T10 ranged from 8 to 9 minutes for rats. With animals present, T90 values ranged from 11 to 16 minutes and T10 ranged from 12 to 13 minutes for rats. A T90 of 12 minutes was selected for the 2-year studies.Studies of cobalt sulfate heptahydrate degradation and monitoring for impurities were conducted throughout the 2-year studies with ICP/AES. No degradation of cobalt sulfate heptahydrate was observed during the studies. Cageboards were used after the first 8 weeks of the studies to control ammonia in the exposure chambers.No further information on the inhalation exposure was stated.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see "Details on inhalation exposure" above
Duration of treatment / exposure:
6 hours plus T90 (12 minutes) per day
Frequency of treatment:
5 days per week, for 105 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:0, 0.3, 1.0 or 3.0 mg/m³ cobalt sulfate heptahydrateBasis:nominal conc.
Remarks:
Doses / Concentrations:0.31 +/- 0.03 mg/m³, 1.03 +/-0.10 mg/m³ or 2.98 +/- 0.20 mg/m³Basis:analytical conc.
No. of animals per sex per dose:
50 males / 50 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The exposure concentrations for the 2-year cobalt sulfate heptahydrate studies were based on the findings of 16-day and 13-week studies. The most sensitive tissue was the larynx, with squamous metaplasia observed in rats the lowest exposure concentration of 0.3 mg/m³. A NOAEL was not reached for this tissue. Inflammatory polyps, some nearly obstructing the esophagus, were observed at 10 and 30 mg/m³ in rats, while these lesions at the 0.3 and 1.0 mg/m³ exposure concentrations were composed of mild orminimal squamous metaplasia and/or chronic inflammation in rats. The severity of the laryngeal changes and other lesions in the respiratory tract at 3.0 mg/m³ was not considered life threatening, and, therefore, exposure concentrations of 0.3, 1.0, and 3.0 mg/m³ were chosen for the 2-year study with rats.No further information on the study design was stated.
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: All animals were observed twice daily. Clinical findings were recorded initially, at weeks 5, 9, and 13, monthly through week 92, every 2 weeks thereafter, and at the end of the studies.DETAILED CLINICAL OBSERVATIONS: No dataBODY WEIGHT: Yes- Time schedule for examinations: Body weights were recorded initially, weekly for 13 weeks, monthly through week 92, every 2 weeks thereafter, and at the end of the studies.FOOD CONSUMPTION:- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No dataFOOD 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 dataWATER CONSUMPTION: No dataOPHTHALMOSCOPIC EXAMINATION: No dataHAEMATOLOGY:No dataCLINICAL CHEMISTRY: No dataURINALYSIS: No dataNEUROBEHAVIOURAL EXAMINATION: No dataNo further information on the observations and examinations performed and frequency were stated.
Sacrifice and pathology:
GROSS PATHOLOGY: YesA complete necropsy and microscopic examination were performed on all rats. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 to 6 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (i.e., adrenal gland, kidney, ovary), samples from each organ were examined. HISTOPATHOLOGY: YesComplete histopathology was performed on all rats. In addition to gross lesions and tissue masses, the tissues examined included:adrenal gland, bone with marrow, brain, clitoral gland, esophagus, harderian gland, heart, large intestine (cecum,colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lungs/bronchi, lymph nodes (mandibular, mesenteric,bronchial, mediastinal), mammary gland, nose, oral cavity, ovary, pancreas, pancreatic islets, parathyroid gland,pituitary gland, preputial gland, prostate gland, salivary gland, sciatic nerve, seminal vesicle, skin, spinal cord, spleen, stomach (forestomachand glandular), testes/epididymides, thymus, thyroid gland, trachea, urinary bladder, and uterus.No further information on the sacrifice and pathology was stated.
Statistics:
- Survival analyses: The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Animals found dead of other than natural causes or pregnant were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.- Analysis of continuous variables: Average severity values were analyzed for significance using the Mann-Whitney U test (Hollander and Wolfe, 1973).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITYSurvival of exposed males and females was similar to that of the chamber controls. Irregular breathing was observed more frequently in female ratsexposed to 3.0 mg/m³ than in the chamber controls or other exposed groups.BODY WEIGHT AND WEIGHT GAINMean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study.GROSS PATHOLOGY AND HISTOPATHOLOGY(NON-NEOPLASTIC AND NEOPLASTIC)Lung: In all exposed groups of male and female rats, the incidences of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were significantly greater than those in the chamber controls. In general, these lung lesions increased in incidence and severity with increased exposure to cobalt sulfate heptahydrate. The incidence of squamous metaplasia in 1.0 mg/m³ females was significantly greater than in the chamber control group. Multifocally, throughout the lungs, pulmonary architecture was distorted by a combination of inflammatory cells, fibrosis, and epithelial metaplasia. Lesions tended to be subpleural, peripheral, and/or along larger blood vessels and airways. Granulomatous inflammation was characterized by accumulations of alveolar macrophages with foamy cytoplasm, occasional multinucleated giant cells and cholesterol clefts, cell debris and few neutrophils. In these areas, the alveolar interstitium and occasionally the overlying pleura were variably thickened by dense fibrous connective tissue which often effaced alveoli Although a diffuse change, aggregates of homogeneous to granular eosinophilic material within alveolar lumens (alveolar proteinosis) were often pronounced within the areas of chronic inflammation. Metaplasia of the alveolar epithelium in alveoli within and at the periphery of foci of inflammation was characterized by replacement of normal Type I epithelial cells with plump cuboidal or ciliated columnar epithelial cells. The incidences of alveolar epithelial hyperplasia in all groups of exposed males and in females exposed to 3.0 mg/m³ and atypical alveolar epithelial hyperplasia in 3.0 mg/m³ females were significantly greater than those in the chamber control groups.The combined incidence of alveolar/bronchiolar neoplasms (adenoma and/or carcinoma) was significantly greater in 3.0 mg/m³ males than that in the chamber controls and exceeded the historical control range. In females 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 historical control ranges. Although the incidences of alveolar/bronchiolar adenoma in 3.0 mg/m³ males and alveolar/bronchiolar carcinoma in 1.0 mg/m³ males were not significantly increased, they exceeded the historical control ranges for inhalation studies. The spectrum of alveolar/bronchiolar neoplasms and nonneoplastic proliferative lesions observed within the lungs of exposed rats was broad. While many of these lesions were highly cellular and morphologically similar to those observed spontaneously, others were predominantly fibrotic, squamous, or mixtures of alveolar/bronchiolar epithelium and squamous or fibrous components. Hyperplasia generally represented an increase in numbers of epithelial cells along alveolar walls with maintenance of normal alveolar architecture. Multiple hyperplastic lesions were often observed in animals receiving higher concentrations of cobalt sulfate heptahydrate. The benign neoplasms typical of those observed spontaneously were generally distinct masses that often compressed surrounding tissue. Component epithelial cells were often arranged in acinar and/or irregular papillary structures and occasionally in a solid cellular pattern. These epithelial cells were typically uniform and similar to hyperplastic counterparts. Malignant alveolar/bronchiolar neoplasms had similar cellular patterns but were generally larger and had one or more of the following histologic features: heterogeneous growth pattern, cellular pleomorphism and/or atypia, and local invasion or metastasis. In addition to these more typical proliferative lesions, there were “fibroproliferative” lesions ranging from less than 1 mm to greater than 1 cm in diameter. Generally, these lesions had a rounded outline and a central fibrous core containing dispersed glandular (alveolar) structures lined by uniformly cuboidal epithelial cells. Aggregates of mostly necrotic inflammatory cells were also present in adjacent pheoalveoli and often within the glandular structures. Peripherally, the fibroproliferative lesions had one to several layers of epithelium which coursed along and often extended into adjacent alveoli, frequently forming papillary projections. These epithelial cells were often slightly pleomorphic with occasional mitotic figures. The smallest of these lesions were usually observed adjacent to areas of chronic inflammation. Small lesions with modest amounts of peripheral epithelial proliferation were diagnosed as atypical hyperplasia, while larger lesions with florid epithelial proliferation, marked cellular pleomorphism, and/or local invasion were diagnosed as alveolar/bronchiolar carcinomas.While squamous epithelium is not normally observed within the lung, squamous metaplasia of alveolar/ bronchiolar epithelium is a relatively common response to pulmonary injury and occurred in a number of rats in this study. Squamous metaplasia was a minor change consisting of a small cluster of alveoli in which the normal epithelium was replaced by multiple layers of flattened squamous epithelial cells that occasionally formed keratin. One 3.0 mg/m³ male and one 1.0 mg/m³ female had a large cystic squamous lesion rimmed by a variably thick (a few to many cell layers) band of viable squamous epithelium with a large central core of keratin. These were diagnosed as cysts. In one 1.0 mg/m³ and one 3.0 mg/m³ female, proliferative squamous lesions had cystic areas but also more solid areas of pleomorphic cells and invasion into the adjacent lung; these lesions were considered to be squamous cell carcinomas. In general, diagnoses of squamous lesions were made only when the lesion composition was almost entirely squamous epithelium. However, squamous metaplasia/ differentiation was a variable component of other alveolar/bronchiolar proliferative lesions, including the fibroproliferative lesions, and was clearly a part of the spectrum of lesions resulting from exposure to cobalt sulfate heptahydrate.Adrenal medulla: The incidence of benign pheochromocytoma in 3.0 mg/m³ females was significantly greater than that in the chamber controls and exceeded the historical range for inhalation studies. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 1.0 mg/m³ males and in 3.0 mg/m³ females were significantly greater than those in the chamber controls and exceeded the historical control ranges.The incidences of bilateral pheochromocytoma in exposed males slightly exceeded that in the chamber control group. The incidence of hyperplasia was not significantly increased in exposed males or females. Focal hyperplasia and pheochromocytoma are considered to constitute a morphological continuum in the adrenal medulla. Focal hyperplasia consisted of irregular, small foci of small- to normal-sized medullary cells arranged in packets or solid clusters slightly larger than normal; compression of surrounding parenchyma was minimal or absent. Benign pheochromocytomas were well-delineated masses often with altered architecture and variable compression of surrounding parenchyma. Neoplastic cells were arranged in variably sized aggregates, clusters, and/or variably thick trabecular cords. Larger neoplasms usually exhibited greater cellular pleomorphism and atypia than smaller neoplasms. Malignant pheochromocytomas were identified when there was invasion of or beyond the adrenal capsule or when distant metastases were observed. Although a very common spontaneous neoplasm in male F344/N rats, pheochromocytomas have a lower spontaneous occurrence in females. In this study, the incidence of pheochromocytoma in 3.0 mg/m³ females was considered related to the administration of cobalt sulfate heptahydrate. The marginally increased incidence of pheochromocytoma in males was considered an uncertain finding because it occurred only in the 1.0 mg/m³ group and was not supported by increased incidence or severity of hyperplasia.Nose: The incidences of hyperplasia of the lateral wall of the nose and atrophy of the olfactory epithelium in all exposed groups of males and females were significantly greater than those in the chamber controls, 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 in 3.0 mg/m³ males and females were significantly greater than those in the chamber controls.Although the incidence and severity of nasal lesions increased with increased exposure to cobalt sulfate heptahydrate, they involved limited portions of nasal epithelium and none were severe. Hyperplasia and squamous metaplasia were minimal to mild, unilateral or bilateral, and involved the transitional epithelium along the walls and turbinates of the anterior nasal passage. Hyperplasia was characterized by an increase in thickness of the epithelium from the normal one to two layers to two or more layers, while squamous metaplasia represented areas where the normal transitional epithelium was replaced by multiple layers of flattened epithelial cells. More posterior in the nose, along the dorsal meatus, atrophy of the olfactory epithelium was characterized by loss of cell layers and disorganization of remaining epithelium, and in some instances, increased prominence of sensory cell nuclei. Metaplasia was characterized by replacement of olfactory epithelium with respiratory-type ciliated columnar epithelium.Larynx: The incidences of squamous metaplasia of the epiglottis in all exposed groups of males and females were significantly greater than those in the chamber controls, and the severity of this lesion increased with increasing exposure concentration. Squamous metaplasia was limited to the base of the epiglottis and was not a severe lesion in exposed rats. It was characterized by replacement of the ciliated respiratory epithelium by one or more layers of flattened epithelial cells overlying a basal layer of cuboidal cells. Keratinization was sometimes observed.

Effect levels

open allclose all
Dose descriptor:
BMCL10
Effect level:
0.414 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: squamous metaplasia lesions in the larynx
Dose descriptor:
LOAEC
Effect level:
0.31 mg/L air (analytical)
Based on:
test mat.
Basis for effect level:
other: squamous metaplasia lesions in the larynx

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Under the conditions of the 2-year inhalation study, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms. Marginal increases in incidences of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. Exposure to cobalt sulfate heptahydrate caused a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tract of male and female rats.

Applicant's summary and conclusion

Conclusions:
Under the conditions of the 2-year inhalation study, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms. Marginal increases in incidences of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. Exposure to cobalt sulfate heptahydrate caused a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tract of male and female rats.