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EC number: 203-624-3 | CAS number: 108-87-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Aug 1978 - Jul 1984
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Basic data given.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 985
Materials and methods
- Principles of method if other than guideline:
- Chronic (1-year) inhalation exposure study in rats with additional 1-year post-exposure period; examinations included growth development, haematology, clinical chemistry and pathology
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Methylcyclohexane
- EC Number:
- 203-624-3
- EC Name:
- Methylcyclohexane
- Cas Number:
- 108-87-2
- Molecular formula:
- C7H14
- IUPAC Name:
- methylcyclohexane
- Details on test material:
- - Name of test material (as cited in study report): methylcyclohexane
- Substance type: pure substance
- Physical state: liquid
- Analytical purity: Lot No. A8: 98.57%; Lot No. A9: 98.50%; Lot No. B8: 98.66%
- Impurities (identity and concentrations): Lot No. A8: 0.86% n-Heptane and 0.56% toluene; Lo t No. A9: 0.97% n-Heptane and 0.52% toluene; Lot No. B8: 0.74% n-Heptane and 0.60% toluene
- Lot/batch No.: A8, A9 and B8
- Source: Eastman Organic Chemical Corporation
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: CDF [F344]/CrlBR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratory, Wilmington, MA, USA
- Age at study initiation: 10 weeks
- Weight at study initiation: ca. 170 g
- Diet: available only during non-exposure periods
- Water: ad libitum
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Remarks on MMAD:
- MMAD / GSD: Not applicable.
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dome shaped, 840 cubic foot (ca. 23.79 m³) chambers described by Thomas (1965, AMA Archives Environ Health 11:316-322).
- System of generating vapours: the generation of desired chamber concentrations of the test material was accomplished by metering the liquid test material directly into the chamber inlet air supply stream where vaporization was accomplished in sufficient air volume to prevent formation of an explosive vapour mixture. The liquid was delivered from a drum using 3-5 psig (ca. 0.207-0.345 bar) air pressure with dual regulators to prevent overpressurization. Delivery into the air supply line was metered and controlled with a glass flowmeter and 1° needle valve installed on a manifold from the storage drum and housed in an exhaust hood to prevent leakage into work areas. The stainless steel supply lines were wrapped with electrical heating tape to provide modest heat when necessary to prevent recondensation. Generation of the test material was started at a high rate and then adjusted to a steady rate to achieve 95% of the nominal chamber concentration within 15 minutes of daily start-up of animal exposures.
TEST ATMOSPHERE
- Brief description of analytical method used: air samples were continuously drawn from the chambers during animal exposures for analysis using a total hydrocarbon analyzer. Each pair of chambers with the same nominal concentration was sampled alternately on a 15-minute cycle with a single analyzer.
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- -Nominal concentration: 400 ppm
Measured concentration in Chamber 1 (± SD): 401.5 ± 4.5 ppm (range: 393-312 ppm; No. of sampling days: 243)
Measured concentration in Chamber 2 (± SD): 398.9 ± 2.5 ppm (range: 395-402 ppm; No. of sampling days: 243)
-Nominal concentration: 2000 ppm
Measured concentration in Chamber 3 (± SD): 2009 ± 46.6 ppm (range: 1878-2080 ppm; No. of sampling days: 243)
Measured concentration in Chamber 4 (± SD): 1998 ± 52.4 ppm (range: 1847-2047 ppm; No. of sampling days: 243) - Duration of treatment / exposure:
- 12 months
- Frequency of treatment:
- 6 h/day, 5 days/week (excluding holidays)
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
400 and 2000 ppm
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
389.9 or 401.5 and 1998 or 2009 ppm
Basis:
analytical conc.
- Remarks:
- Doses / Concentrations:
ca. 1600 and 8000 mg/m³
Basis:
nominal conc.
- No. of animals per sex per dose:
- 65
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale: animal exposure concentrations of the test material for this study were selected on the basis of the current threshold limit value TLV (400 ppm) and the maximum tolerated level for repeated exposures which appeared to be 2000 ppm.
- Post-exposure recovery period in satellite groups: at the end of the 12-month exposure period, 10 animals per sex per group were sacrificed. The remaining animals were held for additional 12 months of post-exposure observation.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: hourly during the one-year exposure phase and at least six times daily during a one-year post-exposure period.
BODY WEIGHT: Yes
- Time schedule for examinations: at biweekly intervals during exposure and monthly during the post-exposure period.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy following the one-year exposure.
- How many animals: 9 males and females of the control group; 10 males and females of the low-concentration group; 9 males and 10 females of the high-concentration group.
- Parameters examined: red blood cell count (RBC), white blood cell count (WBC), haematocrit level (HCT), haemoglobin concentration (HGB).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy following the one-year exposure.
- How many animals: 9 male and female control animals; 10 males and females of the low-concentration group; 9 males and 10 females of the high-concentration group.
- Parameters examined: electrolytes, glucose, creatinine, bilirubin, serum protein, albumin, and three enzymes, alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT) and alkaline phosphatase. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. No details reported.
HISTOPATHOLOGY: Yes. A battery of approx. 33 tissues was sampled. Results were reported for selected organs: adrenals, brain, clitorial gland, heart, kidneys, liver, lungs, mammary gland, mediastinal lymph nodes, nose, ovaries, pancreas, parathyroid, pituitary, preputial gland, skin, stomach, testes, thyroid, urinary bladder, uterus, Zymbal's gland. - Statistics:
- Body weight, haematology and clinical chemistry values were presented as group mean values without reporting statistical deviations. Histopathological findings were reported as incidences (number of lesions observed/number of animals examined). Statistically significant differences were reported where applicable, but the method(s) of analysis was (were) not specified.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 2000 ppm: 1 male died during the 12-month exposure period.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 2000 ppm: 1 male died during the 12-month exposure period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 400 and 2000 ppm: depressed body weight in males of both treatment groups throughout the whole study period (not concentration-related, non-adverse).
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 400 ppm (males): increase in haematocrit level and decrease in white blood cell count (non-adverse); 2000 ppm: decrease in white blood cell count in males and females and haemoglobin concentration in males (non-adverse).
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 400 ppm (males): increase in potassium and creatinine and decrease in sodium concentrations (non-adverse); 2000 ppm (males): decrease in sodium concentrations (non-adverse).
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Description (incidence and severity):
- no information reported.
- Gross pathological findings:
- not specified
- Description (incidence and severity):
- no information reported.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 2000 ppm: slight increase in the incidence of renal tubular dilatation at the end of the exposure period; statistically significant increase in the incidence of medullary mineralization and hyperplasia of the renal papilla after the post-exposure period.
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Several neoplastic lesions were found in the control and in both treatment groups. These foundings were reported as being commonly found in the strain used and/or not considered related to exposure due to the even distribution between groups.
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- Mortality: number, time and cause of death were not explicitly reported. Mortality occurring during the 12-month exposure period was deduced from the number of animals used for histopathological examinations.
Controls: 1/65 males and 1/65 females died.
400 ppm: no mortality occurred.
2000 ppm: 1/65 males died.
- Clinical signs: not reported.
BODY WEIGHT AND WEIGHT GAIN
Body weight data were presented as plot and not tabulated. No statistical analysis on body weight data was presented. Differences in mean body weight values were estimated from the plotted data.
Male rats exposed to both levels of the test material showed depressed growth throughout the study period. At the end of the 12-month exposure period, the mean body weight of the test animals was decreased by about 7% compared with the control group. Although the male rats showed an increase in weight gain after removal from the exposure chambers, they still did not attain the mean weight of the unexposed control group. At this time point, the mean body weight of the treated animals was decreased by ca. 4% when compared with the control animals.
Despite the differences in mean body weight values between control and treated groups at each time point, the body weight gain rate was comparable among groups from Month 2-12 of exposure. Due to the lack of a concentration dependence and of information on statistical significance, this effect was considered non-adverse.
The female rat weights were unaffected during exposure as well as during the post-exposure observation period.
HAEMATOLOGY (see Tables 1 and 2)
There were no biologically significant differences between rats exposed to the test material and control rats.
Low white blood cell counts (WBC's) were found in all exposed groups, both male and female.
CLINICAL CHEMISTRY (see Table 1)
There were no biologically significant differences between rats exposed to the test material and control rats.
An increase in creatinine, blood urea nitrogen (BUN) and potassium along with a decrease in sodium was seen in the male group exposed to 400 ppm but only the decrease in sodium was evident in the 2000 ppm exposure group. Because of haemolysis in most samples of female rat blood, no clinical chemistry comparisons could be made.
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological tissue changes seen in male and female animals that were sacrificed at the end of the 12-month exposure as well as in those which died during the exposure period are presented in Table 3. Since only a small number of lesions were observed in these animals, both tumours and non-tumorous lesions are tabulated together (see below).
There appeared to be a slight increase in dilatation of renal tubules in the 2000 ppm exposed male rats but no other indication of kidney injury was seen at the end of the 12-month exposure.
The results of examination of tissue from the animals that died during the post-exposure observation period or were killed at the study termination are listed in Table 4. According to the authors, the table of non-neoplastic lesions was abbreviated to exclude lesions of very low incidence.
In male rats, the major target organ was the kidney where two types of lesions were associated with exposure. Virtually all of the male rats had lesions consistent with progressive renal nephropathy, common in older male rats. In the male rats exposed to the higher level, there was a statistically significant increase in the occurrence of medullary mineralization and epithelial hyperplasia of the renal papilla. However, no increase of these lesions over controls was seen in the group exposed to 400 ppm. No concentration-related lesions were noted in the exposed female rats when compared to the control group.
HISTOPATHOLOGY: NEOPLASTIC
At the end of the 12-month exposure period, only one tumour, a benign endometrial stromal polyp, was found in any female rat and this was seen in an animal exposed to 400 ppm (see Table 3). The tumours seen in the male rats are commonly found in this strain.
The results of examination of tissue from the animals that died during the post-exposure observation period or were killed at the study termination are listed in Table 5.
Interstitial cell tumours of the testes, seen at study termination, appeared to be equally distributed between the test and control groups and not related to exposure. No concentration-related lesions were noted in the exposed female rats when compared to the control group.
Neoplastic changes seen in rats were those expected in aging animals of this species. According to the authors, statistical analysis of the data failed to indicate any significant increase in tumour formation in the exposed animals when compared to the controls.
Effect levels
open allclose all
- Dose descriptor:
- NOAEC
- Effect level:
- 1 600 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Non-adverse depression of body weight in males. Equivalent to a nominal concentration of 400 ppm based on a MW of 98.2.
- Dose descriptor:
- NOAEC
- Effect level:
- 8 000 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Overall effects. Equivalent to a nominal concentration of 2000 ppm based on a MW of 98.2.
- Dose descriptor:
- LOAEC
- Effect level:
- 8 000 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Histopathology: progressive renal nephropathy. Equivalent to a nominal concentration of 2000 ppm based on a MW of 98.2.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1. Mean haematology and clinical chemistry values of male rats (a) after a one-year inhalation exposure to methylcyclohexane vapour.
Parameter |
Control |
400 ppm |
2000 ppm |
RBC (106) |
9.7 |
9.8 |
9.7 |
WBC (103) |
6.7 |
5.4 b |
5.3 b |
HCT (%) |
47.7 |
48.9 b,e |
47.0 |
HGB (g/dl) |
15.2 |
15.4 |
14.7 c,e |
Total Pro. (g/dL) |
7.2 |
7.3 |
7.3 |
Albumin (g/dL) |
4.2 |
4.2 |
4.1 |
Globulin (g/dL) |
3.0 |
3.1 |
3.1 |
Glucose (mg/dL) |
162.8 |
170.3 |
165.8 |
Potassium (mEq/L) |
5.3 |
6.0 b,d |
5.4 |
Calcium (mg/dL) |
9.6 |
9.7 |
10.5 |
Sodium (mEq/L) |
154.9 |
151.6 b |
150.1 c |
Bilirubin (mg/dL) |
0.38 |
0.40 |
0.38 |
BUN (mg/dL) |
14.2 |
15.4 |
14.4 |
Creatinine (mg/dL) |
0.55 |
0.64 c,e |
0.58 |
SGPT (IU/L) |
62.8 |
60.9 |
58.2 |
SGOT (IU/L) |
91.6 |
94.7 |
86.4 |
Alk. Phos. (IU/L) |
12.5 |
11.8 |
9.7 |
a N = 9 or 10.
b Significantly different from controls, p < 0.05.
c Significantly different from controls, p < 0.01.
d Significantly different from other test group, p < 0.05.
e Significantly different from other test group, p < 0.01.
Table 2. Mean haematology values of female rats after a one-year inhalation exposure to methylcyclohexane vapour, N = 10.
Parameter |
Control |
400 ppm |
2000 ppm |
RBC (106) |
7.8 |
7.8 |
7.9 |
WBC (103) |
5.4 |
4.8 |
3.6 a |
HCT (%) |
44.1 |
43.1 |
44.0 |
HGB (g/dl) |
14.5 |
14.4 |
14.3 |
a Significantly different from controls, p < 0.01.
Table 3. Tissue changes seen in male and female rats at the end of 12-month intermittent exposure to inhaled methylcyclohexane.
|
Controls |
400 ppm |
2000 ppm |
Males |
|||
Pituitary Adenoma |
2 |
0 |
1 |
Testicular Tumor |
0 |
5a |
2 |
Adrenal Pheochromocytoma |
1 |
1 |
0 |
Bile Duct Hyperplasia |
1 |
2 |
0 |
Renal Tubular Dilatation |
1 |
2 |
4 |
Lungs: |
|||
- Lymphocytic Infiltrates |
2 |
0 |
1 |
- Arterial Mineralization |
2 |
1 |
0 |
Myocardial Fibrosis |
2 |
3 |
0 |
Number of Animals Examined |
11 |
10 |
11 |
|
|
|
|
Females |
|||
Ovarian Cyst |
0 |
4 |
2 |
Lungs: |
|||
Lymphocytic Infiltrates |
6 |
0 |
3 |
- Arterial Mineralization |
1 |
1 |
1 |
- Endometrial Stromal Polyp |
0 |
1 |
0 |
Number of Animals Examined |
11 |
10 |
10 |
a Statistically different from control incidence at p ≤ 0.05.
Table 4. Selected non-neoplastic lesions (a) seen in rats held for post-exposure observation after 12-month intermittent inhalation exposure to methylcyclohexane.
|
Controls |
400 ppm |
2000 ppm |
Males |
|||
Liver |
|||
Bile Duct Hyperplasia |
32/53 |
22/55 |
19/52 |
Necrosis |
2/53 |
0/55 |
1/52 |
Circulatory System |
|||
Myocardial Fibrosis |
11/53 |
3/55 |
14/52 |
Pulmonary Artery Mineralization |
6/53 |
3/55 |
0/52
|
Kidney |
|||
Medullary Mineralization |
1/53 |
2/55 |
19/52 b |
Nephropathy |
49/53 |
52/55 |
52/52 |
Papillary Hyperplasia |
1/53 |
1/55 |
23/52 b |
Tubular Degeneration |
1/53 |
0/55 |
2/52 |
Testes |
|||
Atrophy |
4/53 |
2/55 |
1/52 |
Lungs |
|||
Adenomatosis |
1/53 |
2/55 |
0/52 |
Females |
|||
Liver |
|||
Bile Duct Hyperplasia |
5/52 |
2/50 |
3/54 |
Necrosis |
4/52 |
0/50 |
1/54 |
Circulatory System |
|||
Myocardial Fibrosis |
1/52 |
3/51 |
4/53 |
Pulmonary Artery Mineralization |
6/52
|
2/51 |
3/54 |
Kidney |
|||
Medullary Mineralization |
4/52 |
0/51 |
1/54 |
Nephropathy |
15/52 |
7/51 |
15/54 |
Reproductive |
|||
Ovarian Cysts |
6/50 |
2/51 |
3/52 |
Uterine Dilatation |
5/52 |
9/51 |
4/52 |
Mammary Gland |
|||
Cystic Hyperplasia |
10/47 |
17/53 |
17/53 |
Lungs |
|||
Adenomatosis |
2/52 |
0/51 |
1/54 |
a Number of lesions observed/number of animals examined.
b Statistically different from control incidence at p ≤ 0.01.
Table 5. Neoplastic lesions (a) seen in rats held for post-exposure observation after 12-month intermittent inhalation exposure to methylcyclohexane.
|
Control |
400 ppm |
2000 ppm |
Males |
|||
Skin/Subcutaneous |
|||
Keratoacanthoma |
0/51 |
1/55 |
3/52 |
Fibroma |
3/53 |
4/55 |
0/52 |
Fibroadenoma |
0/53 |
1/55 |
0/52 |
Osteosarcoma |
1/53 |
0/55 |
0/52 |
Basal Cell Tumor |
0/53 |
1/55 |
1/52 |
Mammary Gland Fibroadenoma |
0/46 |
0/47 |
2/52 |
Myxoma |
1/53 |
0/55 |
0/52 |
Lungs |
|||
Squamous Cell Carcinoma |
0/54 |
1/55 |
0/52 |
Nasal |
|||
Squamous Cell Carcinoma |
1/53 |
0/55 |
0/52 |
Liver |
|||
Mononuclear Cell Leukemia |
0/53 |
0/55 |
0/52 |
Pituitary |
|||
Adenoma |
17/51 |
11/54 |
16/48 |
Carcinoma |
2/51 |
1/54 |
0/48 |
Neoplasm |
1/51 |
0/54 |
0/48 |
Thyroid |
|||
Adenoma |
4/52 |
5/54 |
5/51 |
Carcinoma |
0/52 |
1/54 |
2/51 |
Kidney |
|||
Renal Cell Adenoma |
0/54 |
0/55 |
1/52 |
Renal Cell Carcinoma |
0/54 |
1/55 |
0/52 |
Adrenals |
|||
Adenoma |
1/54 |
1/55 |
5/52 |
Carcinoma |
0/54 |
1/55 |
0/52 |
Pheochromocytoma |
3/54 |
0/55 |
2/52 |
Stomach |
|||
Leiomyoma |
0/53 |
0/54 |
1/52 |
Pancreas |
|||
Islet Cell Adenoma |
1/53 |
1/54 |
1/51 |
Testis |
|||
Interstitial Cell Tumor |
49/54 |
49/55 |
50/52 |
Zymbal's Gland |
|||
Squamous Cell Carcinoma |
0/54 |
0/55 |
1/52 |
Preputial Gland |
|||
Adenocarcinoma |
0/54 |
0/55 |
1/52 |
Parathyroid |
|||
Adenoma |
1/54 |
0/55 |
0/52 |
Multiple Organ |
|||
Mesothelioma |
1/54 |
1/55 |
1/52 |
Malignant Lymphoma |
1/54 |
2/55 |
0/52 |
Bronchial Mucous Gland |
|||
Adenoma |
0/54 |
1/55 |
0/52 |
Circulatory System |
|||
Histiocytic Leukemia |
0/54 |
3/55 |
2/52 |
Females |
|||
Skin |
|||
Keratoacanthoma |
0/49 |
0/54 |
2/51 |
Fibroma |
1/52 |
0/51 |
3/51 |
Trichoepithelioma |
1/52 |
0/51 |
0/51 |
Fibroadenoma |
1/52 |
3/51 |
3/51 |
Adenoma |
1/52 |
0/51 |
0/51 |
Sarcoma, Undifferentiated |
0/52 |
1/51 |
0/51 |
Sarcoma |
0/52 |
1/51 |
0/51 |
Mammary Gland Fibroadenoma |
0/47 |
4/50 |
6/48 |
Lungs |
|||
Alveolar/Bronchiolar Carcinoma |
0/52 |
1/54 |
0/54 |
Osteosarcoma |
0/52 |
0/54 |
1/54 |
Sarcoma |
0/52 |
1/54 |
0/54 |
Pituitary |
|||
Adenoma |
11/50 |
16/50 |
17/54 |
Carcinoma |
3/50 |
4/50 |
5/54 |
Thyroid |
|||
Adenoma |
1/52 |
1/52 |
2/51 |
Carcinoma |
2/52 |
3/52 |
1/51 |
Parathyroid |
|||
Adenoma |
0/31 |
1/40 |
0/35 |
Mediastinal Lymph Node |
|||
C-Cell Carcinoma |
0/52 |
1/54 |
0/54 |
Adrenals |
|||
Adenoma |
0/52 |
1/53 |
1/54 |
Adenocarcinoma |
1/52 |
0/53 |
0/54 |
Pancreas |
|||
Adenocarcinoma |
1/51 |
0/54 |
0/50 |
Uterus |
|||
Endometrial Stromal Polyp |
7/52 |
4/54 |
0/52 |
Adenocarcinoma |
3/52 |
0/54 |
0/52 |
Leiomyosarcoma |
0/52 |
1/54 |
0/52 |
Urinary Bladder |
|||
Adenocarcinoma |
1/45 |
0/53 |
0/51 |
Brain |
|||
Astrocytoma |
0/52 |
1/54 |
0/53 |
Clitoral Gland |
|||
Adenoma |
2/52 |
0/54 |
0/53 |
Abdominal Cavity |
|||
Lipoma |
1/52 |
0/54 |
1/53 |
Adenocarcinoma |
1/52 |
0/54 |
3/53 |
Mesothelioma |
0/52 |
1/54 |
0/53 |
Myxosarcoma |
0/52 |
0/54 |
1/53 |
Circulatory System |
|||
Histiocytic Leukemia |
2/52 |
2/54 |
5/53 |
Malignant Lymphoma |
1/52 |
0/54 |
0/53 |
a Number of lesions observed/number of animals examined.
Applicant's summary and conclusion
- Conclusions:
- Groups of rats (65 per sex and group) were whole body-exposed to air or methylcyclohexane concentrations of 400 and 2000 ppm (corresponding to ca. 1600 and 8000 mg/m³), 6 h/day, 5 days/week, for 12 months. At the end of the exposure period, 10 rats per sex and group were sacrificed and subjected to necropsy. The remaining animals were maintained for a post-exposure observation period of further 12 months.
No clinical signs were reported and mortalities (number, time and cause of death) were not explicitly mentioned. From the number of animals used for histopathological examinations, it can be deduced that 1 male and 1 female in the control and 1 male in the 8000 mg/m³ group died during the 12-month exposure period.
Male rats exposed to both levels of the test material showed depressed growth throughout the study period. At the end of the 12-month exposure period, the mean body weight of the test animals was decreased by about 7% compared with the control group. Although the male rats showed an increase in weight gain after removal from the exposure chambers, they still did not attain the mean weight of the unexposed control group. At this time point, the mean body weight of the treated animals was decreased by ca. 4% when compared with the control animals. Despite the differences in mean body weight values between control and treated groups at each time point, the body weight gain rate was comparable among groups from Month 2-12 of exposure. Due to the lack of concentration dependence and of information on statistical significance, this effect was considered non-adverse. The female rat weights were unaffected during exposure as well as during the post-exposure observation period.
Haematological and clinical chemistry analyses showed no biologically significant differences between rats exposed to the test material and control rats. Statistically significant differences from control values were seen in white blood cell count (WBC) in both male groups (both ca. 20% decrease) and in the 8000 mg/m³ female group (ca. 30% decrease). Males in the 1600 mg/m³ group showed slight but statistically significant changes in haematocrit value (2% increase), potassium level (13% increase), sodium level (2% decrease) and creatinine (16% increase). In 8000 mg/m³ males, sodium levels were also statistically significantly decreased by ca. 2%. Because of haemolysis in most samples of female rat blood, no clinical chemistry comparisons could be made.
Histopathological examination of tissues from animals that were sacrificed at the end of the 12-month exposure as well as from those which died during the exposure period showed no differences between female control and exposure groups. In males rats, a statistically significant increase in the incidence of testicular tumours was observed in the 1600 mg/m³ group (control: 0/11; 1600 mg/m³: 5/10; 8000 mg/m³: 2/11). The authors stated that tumours seen in the male rats are commonly found in this strain. A dose-related but not statistically significant increase in the incidence of renal tubular dilatation was observed (controls: 1/11; 1600 mg/m³: 2/10; 8000 mg/m³: 4/11). No other indication of kidney injury was seen at the end of the 12-month exposure.
At the end of the 12-month post-exposure period, no statistically significant differences in the incidences of neoplastic and non-neoplastic lesions were seen between female control and exposure groups. Only one tumour, a benign endometrial stromal polyp, was found in any female rat and this was seen in an animal exposed to 1600 mg/m³. In male rats, the major target organ was the kidney where two types of lesions were associated with exposure. Virtually all of the male rats had lesions consistent with progressive renal nephropathy, common in older male rats. In the male rats exposed to 8000 mg/m³, there was a statistically significant increase in the occurrence of medullary mineralization (control: 1/53; 1600 mg/m³: 2/55; 8000 mg/m³: 19/52) and epithelial hyperplasia of the renal papilla (control: 1/53; 1600 mg/m³: 1/55; 8000 mg/m³: 23/52). Interstitial cell tumours of the testes, seen at study termination, appeared to be equally distributed between the test and control groups and not related to exposure. In general, neoplastic changes seen in rats were those expected in aging animals of this species. According to the authors, statistical analysis of the data failed to indicate any significant increase in tumour formation in the exposed animals when compared to the controls.
In conclusion, based on the progressive renal nephropathy observed at histopathological examination of male rats, 8000 mg/m³ (2000 ppm) was considered the LOAEC. Thus, in this study, 1600 mg/m³ (400 ppm) was identified as the NOAEC, at which only a non-adverse depression of body weight was observed in male rats. No adverse effects were seen in female rats up to the highest concentration tested. Therefore the NOAEC for females was 8000 mg/m³.
Based on the study results, methylcyclohexane does not fulfil the classification criteria for toxicity after repeated exposure according to Regulation (EC) No 1272/2008 and Directive 67/548/EEC.
CLP: not classified
DSD: not classified
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