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Repeated dose toxicity: inhalation

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sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2005-03-07 to 2005-06-08
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study
Reason / purpose for cross-reference:
reference to same study

Data source

Reference Type:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Version / remarks:
adopted 2009-09-07
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
solid: particulate/powder
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Cobalt metal (produced by OMG Kokkola Chemicals Oy (Kokkola, Finland))- Physical state: silver-gray powder- Analytical purity: 98.2% ± 0.6% (ICP/AES); Overall purity of cobalt metal: >98%- Composition of test material, percentage of components: chromium: approximately 84 ppm- Lot No.: P32 3040-1- Storage condition of test material: at room temperature in safety-coated amber glass containers with Teflon®-lined caps under a nitrogen headspace- Carbon content: 0.09% ± 0.01%- Periodic reanalyses of the bulk chemical: no degradation of the bulk chemical was detected

Test animals

other: F344/N
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Taconic Farms, Inc. (Germantown, NY)- Age at study initiation: 5 to 6 weeks old- Weight at study initiation: Males0 mg/m³: 102 ± 2 g2.5 mg/m³: 102 ± 2 g4.9 mg/m³: 102 ± 3 g9.7 mg/m³: 100 ± 3 g19.7 mg/m³: 103 ± 3 g40.1 mg/m³: 101 ± 3 gFemales0 mg/m³: 88 ± 4 g2.5 mg/m³: 88 ± 2 g4.9 mg/m³: 86 ± 3 g9.7 mg/m³: 87 ± 4 g19.7 mg/m³: 86 ± 3 g40.1 mg/m³: 86 ± 3 g- Housing: housed individually; cages: stainless steel wire bottom (Lab Products, Inc., Seaford, DE), changed weekly, rotated weekly in chambers; cageboard: untreated paper cage pan liner (Techboard, Shepherd Specialty Papers, Kalamazoo, MI), changed daily- Diet (ad libitum, except feed was withheld during exposure periods): irradiated NTP-2000 wafer diet (Zeigler Brothers, Inc., Gardners, PA), changed weekly- Water (ad libitum): tap water (Richland, WA municipal supply)- Acclimation period: 12 or 13 (male rats) daysBefore the study began, five male and five female rats were randomly selected for parasite evaluation and gross observation for evidence of disease.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Remarks on MMAD:
MMAD / GSD: 0.61 mg/m³: MMAD: 1.61 to 1.69 µm / GSD: 1.94 to 1.971.23 mg/m³: MMAD: 1.71 to 1.73 µm / GSD: 1.81 to 1.842.5 mg/m³: MMAD: 1.76 to 1.96 µm / GSD: 1.75 to 1.785.0 mg/m³: MMAD: 1.77 to 1.90 µm / GSD: 1.74 to 1.78
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION- Exposure apparatus: the inhalation exposure chambers was designed so that uniform aerosol concentrations could be maintained throughout the chambers with the catch pans in place. The total volume of the chamber was 2.3 m³ with an active mixing volume of 1.7 m³. Tests showed that aerosol concentration could be reliably maintained homogenous within 8% throughout the chambers, provided the aerosol was uniformly mixed before passing through the chamber inlet and provided the test material did not react to a significant extent with animals, animal excrement, or the chamber interior (Griffis et al., 1981)*.Chamber environment:Temperature: 20.6 to 23.9°CRelative humidity: 55% ± 15%Room fluorescent light: 12 hours/dayChamber air changes: 15 ± 2/hour- System of generating particulates/aerosols: the generation system used a linear feed device to meter cobalt metal into the Trost jet mill. Initial particle size reduction was accomplished within the Trost jet mill. From the jet mill, aerosol was directed to the main distribution line where it was diluted with humidified air then conveyed from the exposure control center to the exposure room where it passed through a cyclone separator to further reduce particle size. On exiting the cyclone, the aerosol-laden air was directed to either of two smaller branch lines. From the branch lines, aerosol was delivered to each exposure chamber by a sampling tube. The flow through the sampling tube was induced by a stainless steel ejector pump. The aerosol then entered the chamber inlet duct where it was further diluted with conditioned chamber air to achieve the desired exposure concentration.- Method of particle size determination: particle size distribution was determined once prior to the 3-month study and twice during the 3-month studies. Impactor samples were taken from each exposure chamber using a Mercer-style seven-stage impactor and the stages (glass coverslips lightly coated with silicone to prevent particle bounce) were analyzed using ICP/AES after cobalt was extracted from the slides. The relative mass collected on each stage was analyzed by the CASPACT impactor analysis program developed at Battelle based on probit analysis (Hill et al., 1977)*.TEST ATMOSPHERE- Brief description of analytical method used: the concentration of cobalt metal in the exposure chambers and room air was monitored using three real-time aerosol monitors (RAMs). Each RAM was calibrated by constructing a response curve using the measured RAM voltages (voltage readings were corrected by subtracting the RAM zero-offset voltage from measured RAM voltages) and cobalt metal concentrations that were determined by analyzing tandem Teflon®-coated, glass-fiber filters collected daily from the exposure chambers. Cobalt was extracted from the filters and analyzed using ICP/AES.Buildup and decay rates for chamber aerosol concentrations were determined with and without animals present in the chambers. At a chamber airflow rate of 15 air changes per hour, the theoretical value for the time to achieve 90% of the target concentration after the beginning of aerosol generation (T90) and the time for the chamber concentration to decay to 10% of the target concentration after aerosol generation was terminated (T10) was approximately 9.4 minutes. A T90 value of 12 minutes was selected.The uniformity of aerosol concentration in the inhalation exposure chambers without animals was evaluated before the 3-month study began; in addition, concentration uniformity with animals current in the chambers was measured once during 3-month study. Chamber concentration uniformity was maintained throughout the studies. The persistence of cobalt metal in the exposure chambers after aerosol delivery ended was determined by monitoring the concentration overnight in the 5 mg/m³ rat chambers in the 3-month studies with and without animals current in the chambers. The average cobalt metal concentration decreased to 1% of the target concentration within 17 to 18 minutes.Stability studies of the test material in the generation and exposure system were performed before and during the study. In this studiy, XRD analyses consistently indicated two primary phases of cobalt in the samples, cubic and hexagonal, and minimal detectable concentrations of cobalt oxides. Low and acceptable levels of trace element inorganic impurities were detected in these stability samples using PIXE and ICP/AES assays.*References- Griffis, L.C., Wolff, R.K., Beethe, R.L., Hobbs, C.H., and McClellan, R.O. (1981). Evaluation of a multitiered inhalation exposure chamber. Fundam. Appl. Toxicol. 1, 8-12.- Hill, M.A., Watson, C.R., and Moss, O.R. (1977). An Interactive Computer Program for Particle Size Analysis, PNL-2405, UC-32. Pacific Northwest Laboratory, Richland, WA.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Please refer to "Details on inhalation exposure" above.
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
6 hours plus T90 (12 minutes) per day, 5 days per week
Doses / concentrationsopen allclose all
Doses / Concentrations:0.61 ± 0.04 mg/m³Basis:analytical conc.
Doses / Concentrations:1.23 ± 0.07 mg/m³Basis:analytical conc.
Doses / Concentrations:2.5 ± 0.1 mg/m³Basis:analytical conc.
Doses / Concentrations:5.0 ± 0.3 mg/m³Basis:analytical conc.
No. of animals per sex per dose:
Core study: 10 males / 10 femalesClinical pathology study: 10 malesSpecial study: 32 to 36 females
Control animals:
Details on study design:
- Dose selection rationale: based on significant mortality in male and female rats exposed to 20 and 40 mg/m³ and body weight reductions in the 10 mg/m³ groups coupled with reduced urine volumes with concomitant increases in urine creatinine at the end of the 2-week study (please refer to the endpoint study record k_NTP_2013_rats_16 days), 5 mg/m³ was selected as the highest exposure concentration for the 3-month inhalation study in rats. The lesions in the nose were minimal in the 5 mg/m³ group and were not considered sufficiently severe to preclude the use of this concentration. When exposure concentrations for the 3-month studies are different for two species, the NTP has elected to have one less exposure concentration for one species as opposed to adding an extra chamber to accommodate the differences in species. Hence, only four concentrations were used in the 3-month rat studies.- Rationale for animal assignment (if not random):- Rationale for selecting satellite groups:- Post-exposure recovery period in satellite groups:- Section schedule rationale (if not random):
Positive control:
no data


Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: observed twice daily; weekly beginning day 9 (male rats) or 10 and at the end of the studies.DETAILED CLINICAL OBSERVATIONS: No dataBODY WEIGHT: Yes- Time schedule for examinations: core study animals were weighed initially, weekly beginning day 9 (male rats) or 10, 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: Yes- Time schedule for collection of blood: blood was collected from the retroorbital sinus of male clinical pathology rats and 10 female special study rats on days 3 and 23 and from core study rats at the end of the study.- Anaesthetic used for blood collection: No data- Animals fasted: No data- Parameters examined: hematocrit; packed cell volume; hemoglobin; erythrocyte, reticulocyte, and platelet counts; total nucleated cells; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentialsCLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: blood was collected from the retroorbital sinus of male clinical pathology rats and 10 female special study rats on days 3 and 23 and from core study rats at the end of the study.- Animals fasted: No data- Parameters examined: urea nitrogen, creatinine, glucose, total protein, albumin, globulin, cholesterol, triglyceride, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile saltsURINALYSIS: No dataNEUROBEHAVIOURAL EXAMINATION: No dataOTHER:For tissue burden studies, lungs and blood (retroorbital sinus) were collected from three special study female rats per exposure group on days 5, 12, 26, 40, 61, and 89 and on days 7, 14, 28, and 42 postexposure. Liver (right lateral and caudate lobes) was also collected on days 26 and 40. Liver and lungs were weighed; blood, liver, and lungs were analyzed for cobalt metal concentration.On days 26 and 40, liver samples from special study rats not used for the tissue burden studies were collected and acetanilide-4-hydroxylase, 7-ethoxyresorufin-O-deethylase, and 7-pentoxyresorufin-O-deethylase activities were determined in order to analyse cytochrome P450 activities.At the end of the 3-month studies, samples were collected for sperm motility and vaginal cytology evaluations on rats exposed to 0, 1.23, 2.5, or 5 mg/m³. The following parameters were evaluated: spermatid heads per testis and per gram testis, sperm motility, and sperm per cauda epididymis and per gram cauda epididymis. The left cauda, left epididymis, and left testis were weighed. For 12 consecutive days prior to scheduled terminal kill samples of vaginal fluid and cells were collected and stained. Relative numbers of leukocytes, nucleated epithelial cells, and large squamous epithelial cells were determined and used to ascertain oestrous cycle stage.
Sacrifice and pathology:
GROSS PATHOLOGY: YesHISTOPATHOLOGY: YesNecropsies were performed on all core study and special study animals. The heart, right kidney, liver, lung, right testis, thymus, and thyroid gland of core study animals were weighed. Tissues for microscopic examination were fixed and preserve , processed and trimmed, embedded in paraffin, sectioned, and stained. Complete histopathologic examinations were performed on core study 0 and 5 mg/m³ groups of rats. In addition to gross lesions and tissue masses, the following tissues were examined to a no-effect level: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eye, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung, lymph nodes (bronchial, mandibular, mesenteric, and mediastinal), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus.
Please refer to the field "Any other information on materials and methods incl. tables" below.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
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:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY- all male and female rats survived to the end of the study.- no clinical signs related to cobalt metal exposure.BODY WEIGHT AND WEIGHT GAIN- the final mean body weights of males and females exposed to 5 mg/m³ were significantly less than those of the chamber controls, and the mean body weight gain of 5 mg/m³ males was significantly less than that of the chamber controlsHAEMATOLOGY- erythrocytosis characterized by exposure concentration-related increases in the hemoglobin concentration, erythrocyte count, hematocrit value, and manual packed cell volume occurred in males exposed to 2.5 and 5 mg/m³ on days 3 and 23 and all exposed groups by week 14; at week 14, female rats also had increases in these parameters. Animals in the lower exposure groups demonstrated these increases but less consistently.- reticulocyte counts were increased in 5 mg/m³ males at all three time points, while in the female rats, reticulocyte counts were increased in all exposed groups on day 23 and in the 2.5 and 5 mg/m³ groups at week 14. - at week 14, platelet counts were mildly (<18%) decreased in all of the exposed groups of females and in males exposed to 1.23 mg/m³ or greater. These platelet count changes may represent an altered peripheral distribution or decreased production. - all other hematology changes observed were considered within biological variability and not toxicologically relevant.CLINICAL CHEMISTRY- at week 14, total protein concentrations were mildly decreased (<10%) in 2.5 and 5 mg/m³ females, as well as 5 mg/m³ males. This change was paired with mild decreases in albumin and globulin concentrations in 5 mg/m³ females and a mild decrease in globulin concentration in 5 mg/m³ males. These changes are most likely related to altered food intake compared to concurrent chamber controls and are supported by the mild decreases (7%) in body weights of 5 mg/m³ males and females. - exposure concentration-dependent decreases in cholesterol concentrations were observed at all three time points in both males and females. While this change was not always observed with the lower exposure concentrations, these decreases were consistently observed in the 2.5 and 5 mg/m³ groups of both sexes on day 23 and at week 14.- glucose concentration was decreased in 1.23 mg/m³ or greater males at week 14.- all other biochemical changes were transient or inconsistent and not considered toxicologically relevant.ORGAN WEIGHTS- absolute and relative lung weights of all exposed groups of males and females were significantly greater than those of the chamber controls. The increased lung weights are related to the histopathological changes observed in the lungs.GROSS PATHOLOGY- pale foci were noted in the lungs of most exposed male and female rats.HISTOPATHOLOGY: NON-NEOPLASTIC- lung: a spectrum of nonneoplastic lesions was observed that included chronic active inflammation, alveolar proteinosis, bronchiole epithelium hyperplasia, and alveolus epithelium hyperplasia. Minimal to mild chronic active inflammation and generally minimal to mild alveolar proteinosis occurred in all exposed males and females, and minimal to mild bronchiole epithelium hyperplasia occurred in all males and females exposed to 1.23 mg/m³ or greater. The severities of these lesions generally increased with increasing exposure concentration. Chronic active inflammation consisted of a mixture of macrophages, neutrophils, and lymphocytes in the alveolar spaces and was sometimes associated with minimal hyperplasia of the alveolar epithelium and minimal fibrosis of the alveolar interstitium. At higher exposure concentrations, the inflammatory cells were more diffusely distributed throughout the lung. However, at the lower exposure concentrations, the inflammatory cells tended to occur in focal, subpleural aggregates. The pale foci noted grossly at necropsy correlated with subpleural inflammation. There were also perivascular and peribronchiolar infiltrates of macrophages, neutrophils, and lymphocytes with extension into the adjacent alveoli. Some males and females exposed to 5 mg/m³ had minimal infiltrates of inflammatory cells in the walls of bronchioles with minimal proliferation of fibrovascular tissue into the lumen. Alveolar proteinosis consisted of clumps of dense amorphous eosinophilic material or less dense, more dispersed accumulations of proteinaceous debris within the alveolar spaces. Alveoli also contained increased numbers of macrophages that contained eosinophilic material similar to that in the alveolar spaces. Hyperplasia of bronchiolar epithelium was characterized by proliferation of the epithelial cells lining terminal bronchioles and alveolar ducts. The hyperplastic cells were cuboidal with increased cytoplasm that sometimes contained poorly defined cytoplasmic vacuoles.Minimal alveolar epithelium hyperplasia occurred in low numbers of males and females exposed to 5 mg/m³, but the increased incidences of this lesion were not statistically significant. Alveolar epithelium hyperplasia was characterized by randomly scattered, focal, irregular proliferations of cuboidal sometimes ciliated alveolar epithelial cells. Alveolar epithelial hyperplasia is frequently observed in inhalation studies with particulates and may be considered a reparative response and sometimes occurs as a component of inflammatory changes in the lung.- nose: a spectrum of nonneoplastic lesions were observed that included olfactory epithelium degeneration and hyperplasia, respiratory epithelium hyperplasia, and turbinate atrophy. The incidences of olfactory epithelium degeneration and minimal to mild respiratory epithelium hyperplasia were significantly increased in males and females exposed to 2.5 or 5 mg/m³; the incidence of olfactory epithelium degeneration was also significantly increased in 1.23 mg/m³ females. In addition, the incidences of olfactory epithelium hyperplasia were significantly increased in 2.5 mg/m³ males and 5 mg/m³ males and females. Degeneration of the olfactory epithelium was a focal or multifocal lesion that variably involved the epithelium lining the dorsal meatus, ethmoid turbinates, and nasal septa. In affected sites, there was vacuolization and disorganization of the epithelium with variable individual cell necrosis and/or loss of epithelial cells. Olfactory epithelium hyperplasia was characterized by clusters or nests of cells proliferating within or just adjacent to the olfactory epithelium, sometimes with extension into the lamina propria around glandular ducts. The proliferating cells sometimes formed rosettes and had scant cytoplasm and large, round to oval nuclei. Increased incidences of minimal turbinate atrophy occurred in males and females exposed to 2.5 or 5 mg cobalt metal/m³; the increases were statistically significant in 2.5 mg/m³ females and 5 mg/m³ males and females. Respiratory epithelium hyperplasia involved the turbinates and/or lateral walls of the Level I and II nasal sections. Hyperplasia appeared as increased numbers of cells in the respiratory or transitional epithelium resulting in crowding of the cells or an increase in the number of cell layers. The epithelial cells were squamous to cuboidal, usually not ciliated, and some cells were hypertrophied. Turbinate atrophy occurred in all three sections of the nose and was characterized by short and blunt turbinates that had attenuation and/or loss of turbinate bone and interstitial tissue in the lamina propria including the glands, vessels, nerve bundles, and connective tissue, and as a result, the nasal passages appeared wider than normal.OTHER FINDINGS- Cytochrome P450 activities: there were no consistent trends in acetanilide-4-hydroxylase, 7-ethoxyresorufin-O-deethylase, or 7-pentoxyresorufin-O-deethylase activities relative to exposure concentrations at either time point.- sperm motility was significantly decreased in males exposed to 1.23, 2.5, or 5 mg/m³, and the decrease in the 5 mg/m³ group was approximately 8%.- females in the 5 mg/m³ group had a significantly higher probability of extended diestrus than the chamber control females. The toxicologic significance of this subtle alteration in the oestrous cycle is unclear and there were no cobalt-related histopathological findings observed in the female reproductive organs.OTHER FINDINGS - Tissue burden studies- lung and liver weights and lung, blood, and liver cobalt concentrations were determined in female rats. Lung weights were increased in all exposed groups starting on day 40 (5 mg/m³) or day 61 (2.5 mg/m³ or less) and remained greater than those in the chamber controls throughout the exposure and postexposure periods. Because of the significant changes in lung weights with exposure concentration, lung cobalt burdens rather than lung cobalt concentrations were evaluated for toxicokinetic parameters.- liver weights of exposed groups of females were either decreased or similar to chamber controls at each time point.- lung cobalt concentrations and burdens increased with increasing exposure concentration and were significantly increased over chamber controls with all exposure concentrations at all time points. By day 26, the concentrations and burdens of cobalt in the lung of all exposed groups appeared to reach steady state and did not change significantly through the end of exposure (day 89) before decreasing rapidly during the first week of the postexposure period and then more slowly until the end of the postexposure period. Lung cobalt concentrations in chamber control animals were at or below the limit of detection (LOD) at all time points. Lung cobalt burden data normalized to exposure concentration indicated increases in burden that were proportional to exposure concentration.- during the 3-month exposure, blood cobalt concentrations in chamber control animals were at or below the LOD at all time points and concentrations in the exposed groups generally increased in proportion to exposure concentration at all time points. Within each exposure concentration, blood cobalt concentrations appeared to be at or near steady state starting from the earliest time point and continuing throughout the exposure period. However, during the recovery period, blood cobalt concentrations fell very rapidly; the largest declines occurred during the first week postexposure. Accordingly, because of the extensive elimination of cobalt from the blood, it was not possible to demonstrate dose proportionality from blood concentration data collected during the recovery period. In addition, it was not possible to fit the blood data to a two-compartment model due to the lack of early sampling times; however, it appears that there were both rapid and slow clearance phases from the blood.- liver cobalt concentrations in the chamber control group were at or below the LOD and concentrations and burdens in the exposed groups increased with increasing exposure concentration at both time points (days 26 and 40). Cobalt concentrations and burdens in the liver of exposed animals were generally lower on day 26 compared to day 40. The normalized liver cobalt burdens were similar across the exposed groups at both time points. At both time points liver cobalt burdens were similar to and in some cases greater than the corresponding lung cobalt burdens.- pulmonary clearance of cobalt during the recovery period showed a well-defined two-phase elimination profile. The rapid phase exhibited half-lives ranging from 1.8 to 2.6 days and was followed by a slower lung clearance phase with half-lives of 19 to 23 days. A two-compartment clearance model could not be fit to the lung cobalt burden data collected during the 3-month study due to the lack of data collected prior to 5 days of exposure, but a one-compartment model provided an adequate fit to these data. The results indicated that half-lives ranged from 4.7 to 9.0 days.

Effect levels

Dose descriptor:
Effect level:
0.61 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

The predominant findings in this study are related to the respiratory tract of the test animals, i.e. pale foci in the lung, increased lung weights, chronic inflammation in the lung, alveolar proteinosis in the lung, bronchiole epithelium hyperplasia in the lung, olfactory epithelium degeneration in the nose, respiratory epithelium hyperplasia in the nose, olfactory epithelium hyperplasia in the nose and turbinate atrophy in the nose.The LOAEC for both sexes was determined to be 0.61 mg/m³ (air)(analytical).