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Toxicological information

Repeated dose toxicity: inhalation

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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:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985

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
Name:
Unnamed
Type:
Constituent
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

Test animals

Species:
rat
Strain:
other: CDF [F344]/CrlBR
Sex:
male/female
Details on test animals 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