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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

No standard carcinogenicity studies are available for Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane. However, data is available for a structural analogue, hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial hexane

 

Carcinogenicity Study (OECD TG 451)

Inhalation NOAEC (rat) = 31743 mg/m3

Inhalation NOAEC (mouse) = 10560 mg/m3(females)/ 31380 mg/m3(males)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-01-23 to 1992-01-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted in accordance with testing guideline OECD 451 and is GLP compliant.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
GLP compliance:
yes (incl. QA statement)
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, NC
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 167 g males, approx. 119 g females
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo
- Diet (e.g. ad libitum): Purina Certified Rodent Chow Brand Animal Diet #5002, ad libitum, except during exposure
- Water (e.g. ad libitum): Elizabethtown Water Company, ad libitum, except during exposure
- Acclimation period: 26 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 53 +/- 14
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: Jan. 23, 1990 To: Jan. 29, 1992
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 10,000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 2000-2130 lpm
- Method of conditioning air: Test substance in a Protectoseal laboratory can passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization generator. Nitrogen was also fed into the volitization generator. A heating element was positioned in the center of the glass coil to aid volatilization. The nitrogen and test substance mixture then entered the exposure chamber.
- Air flow rate: 2000-2130 lpm
- Air change rate: 4.7-5.0 min.
- Method of particle size determination: TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: Air was exhausted through a HEPA filter, charcoal filter, and into a MOCO incinerator. A charcoal drum was used as a back-up in case of incinerator failure.

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: yes, monthly

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hourly samples were taken from the test chamber and analyzed using a MIRAN 1A Ambient Air Analyzer. In addition, samples were taken monthly and analyzed using GC.
Duration of treatment / exposure:
2 yrs, total of 511 exposures
Frequency of treatment:
6 hrs/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
0.043, 900, 3000, 9016 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
50 per sex/per group
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological and pharmacological signs


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: 3 times pretest, weekly for first 13 weeks, monthly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
2 times pretest, weekly for first 13 weeks, monthly thereafter


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest, month 5, termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest, month 12, month 18, termination
- Anaesthetic used for blood collection: No
- Parameters checked: differential leucocyte counts

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
nasal cavity, cranial cavity, brain, spinal cord, thoracic cavity, abdominal cavity, pelvic cavity, and neck

HISTOPATHOLOGY: Yes
lungs, abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, exorbital lacrimal gland, eyes, gonads, heart, intestine, kidneys, larynx, liver, lymph nodes, nasopharyngeal tissues, nerves, pancreas, pituitary, prostate, salivary gland, seminal vesicles, skin, spinal cord, spleen, stomach, thymic region, thyroid, trachea, urinary bladder, uterus, gross lesions, tissue masses
Statistics:
Body weight, body weight change, and mean food consumption were statistically analyzed.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
67% of control males and 76% of control females survived. Results for treatment groups were similar. Excess lacrimation was noticed in all groups, including controls, but was increased in 3000 ppm and 9016 ppm males.

BODY WEIGHT AND WEIGHT GAIN
There was a small dose related decrease (0.8-11.2%) in body weight gain in both sexes. This may have been due to reduced food consumption.

FOOD CONSUMPTION
There was decreased food consumption in treatment groups, however, there was no clear dose related response.

OPHTHALMOSCOPIC EXAMINATION
Some corneal dystrophy was seen, however, this is common in Fischer 344 rats and is not considered treatment related.

HAEMATOLOGY
No treatment related effects were noted.

GROSS PATHOLOGY
No macroscopic abnormalities related to treatment were observed.

HISTOPATHOLOGY:
Hyperplasia of the respiratory epithelium was seen most frequently in males and females exposed to 9000 ppm. The 3000 ppm and 9016 ppm groups had the most frequent hypertrophy/hyperplasia of goblet cells. This effect was more severe in exposure groups, and quite severe in the 9016 ppm group. These effects were likely due to mucosal irritation. Intracytoplasmic eosinophilic material in the respiratory epithelial cells, and sustentacular cells of the olfactory epithelium was seen in almost all animals in the exposure groups. This effect was most severe in the 3000 and 9016 ppm groups, but was also seen in the 900 ppm group. Inflammatory cells debris in the nasal lumen was also observed in most treatment groups, along with subacute /chronic inflammation of the nasal mucosa.

Squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium was seen in animals from both the control and exposure groups. Highest incidence was in the 9016 ppm group, followed by the 3000 ppm group.
Key result
Dose descriptor:
NOAEC
Effect level:
9 016 ppm
Sex:
male/female
Basis for effect level:
other: 31743 mg/m3;
Remarks on result:
other: Effect type: carcinogenicity
Dose descriptor:
NOAEC
Effect level:
9 016 ppm
Sex:
male/female
Remarks on result:
other:
Remarks:
Effect type: other: systemic toxicity
Dose descriptor:
LOAEC
Effect level:
900 ppm
Sex:
male/female
Basis for effect level:
other: Irritation leading to inflammation effects in the nasoturbinal tissue.
Remarks on result:
other:
Remarks:
Effect type: other: local toxicity (nasalturbinal tissue)

Results of Rat Oncogenicity Study - Body Weights (g)     

Dose

Males - 13 Weeks

Females - 13 Weeks

Males - 105 Weeks

Females - 105 Weeks

0

290.2

179.4

345.8

250.6

900 ppm

283.4 (-2.3%)

174.4 (-2.8%)

342.8 (-0.8%)

250.7 (0%)

3000 ppm

281.3 (-3.1%)

174.9 (-2.5%)

327.3 (-5.3%)

243.3 (-2.9%)

9000 ppm

279.3 (-3.8%)

174.3 (-2.8%)

321.3 (-7.1%)

222.5 (-11.2%)

Dose

Kidney Inflammation

Liver Hemorrhage

Liver Inflammation

Male

0 ppm

2

0

0

900 ppm

0

0

0

3000 ppm

4

0

0

9000 ppm

9

3

2

Female

0 ppm

1

0

0

900 ppm

Not examined

Not examined

Not examined

3000 ppm

Not examined

Not examined

Not examined

9000 ppm

1

0

0

Conclusions:
There were no oncogenic effects in rats exposed to the test substance via inhalation at the maximum concentration tested, 9016 ppm (31736 mg/m3).
Executive summary:

The purpose of this study was to determine the oncogenic effect of inhalation exposure of commercial hexane. Groups of 50 male and 50 female rats were exposed to 0, 900, 3000, or 9016 ppm of test substance for 6 hrs/day, 5 days/week, for 2 yrs. During the study, the animals were examined for clinical signs, mortality, body weight, opthomological, and food consumption effects. At study termination, animals were sacrificed and gross pathology and histopathology performed. Mortalities of exposure groups were consistant with control groups. Body weight gain was significantly reduced in exposure groups. Histopathology revealed dose-related effects in the nasoturbinal tissue in all exposure groups. Therefore, there was no NOAEC level for local irritation effects. The LOAEC level for both sexes was 900 ppm. No oncogenic effects were seen in the exposure groups. The NOAEC for systemic effects was 9016 ppm in rats of both sexes.

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-01-23 to 1992-01-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted in accordance with testing guideline OECD 451 and is GLP compliant.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
GLP compliance:
yes (incl. QA statement)
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, MI
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 24 g males, approx. 20 g females
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo
- Diet (e.g. ad libitum): Purina Certified Rodent Chow Brand Animal Diet #5002, ad libitum, except during exposure
- Water (e.g. ad libitum): Elizabethtown Water Company, ad libitum, except during exposure
- Acclimation period: 27 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 53 +/- 14
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: Jan. 23, 1990 To: Jan. 20, 1992
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 10,000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 2000-2130 lpm
- Method of conditioning air: Test substance in a Protectoseal laboratory can passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization generator. Nitrogen was also fed into the volitization generator. A heating element was positioned in the center of the glass coil to aid volatilization. The nitrogen and test substance mixture then entered the exposure chamber.
- Air flow rate: 2000-2130 lpm
- Air change rate: 4.7-5.0 min.
- Method of particle size determination: TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: Air was exhausted through a HEPA filter, charcoal filter, and into a MOCO incinerator. A charcoal drum was used as a back-up in case of incinerator failure.

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: yes, monthly

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hourly samples were taken from the test chamber and analyzed using a MIRAN 1A Ambient Air Analyzer. In addition, samples were taken monthly and analyzed using GC.
Duration of treatment / exposure:
2 yrs, total of 504 exposures
Frequency of treatment:
6 hrs/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
0.039, 900, 3000, 9018 ppm (0, 3168, 10560, 31680 mg/m3)
Basis:
analytical conc.
No. of animals per sex per dose:
50 per sex/per group
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological and pharmacological signs


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: 3 times pretest, weekly for first 13 weeks, monthly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
2 times pretest, weekly for first 13 weeks, monthly thereafter


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest, termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest, month 12, month 18, termination
- Anaesthetic used for blood collection: No
- Parameters checked: differential leucocyte counts

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
nasal cavity, cranial cavity, brain, spinal cord, thoracic cavity, abdominal cavity, pelvic cavity, and neck

HISTOPATHOLOGY: Yes
lungs, abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, exorbital lacrimal gland, eyes, gonads, gall bladder, heart, intestine, kidneys, larynx, liver, lymph nodes, nasopharyngeal tissues, nerves, pancreas, pituitary, prostate, salivary gland, seminal vesicles, skin, spinal cord, spleen, stomach, thymic region, thyroid, trachea, urinary bladder, uterus, gross lesions, tissue masses
Statistics:
Body weight, body weight change, and mean food consumption were statistically analyzed.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
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 MORTALITY
85% of control males and 80% of control females survived. Results for treatment groups were similar.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant differences in body weight or body weight gains in male mice. Females in the 9018 ppm group had significantly reduced weight gain (14%).

FOOD CONSUMPTION AND COMPOUND INTAKE
The 9000 ppm group males had lower food consumption in 29 of 35 measurements. Food consumption was also lower then controls in the 9018 ppm females for 19 of the first 20 measurements.

OPHTHALMOSCOPIC EXAMINATION
No treatment related effects were seen.

HAEMATOLOGY
No treatment related effects were noted.

GROSS PATHOLOGY
Increases in liver masses and nodules were seen in 9018 ppm females. There was also a dose related increase in uterine cysts.

HISTOPATHOLOGY: NON-NEOPLASTIC
Females in the 9018 ppm group had a dose related decrease in the severity and incidence of cystic endometrial hyperplasia, and uterine cysts. There was also an increase in proliferative lesions of the pituitary in all female treatment groups, however, this did not seem to be dose related. These effects may have been due to hormonal imbalances due to treatment.

HISTOPATHOLOGY: NEOPLASTIC
There was a dose related increase in hepatocellular adenomas and carcinomas in females. There was a statistically significant increase in benign tumors, but not in malignant tumors. Incidence in 9018 ppm females was similar to control males.
Key result
Dose descriptor:
NOAEC
Effect level:
3 000 ppm
Sex:
female
Remarks on result:
other: Effect type: carcinogenicity
Key result
Dose descriptor:
LOAEC
Effect level:
9 018 ppm
Sex:
female
Basis for effect level:
other: Increase in liver masses and nodules, however liver masses and tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice (NTP 2004)
Remarks on result:
other: Effect type: carcinogenicity
Key result
Dose descriptor:
NOAEC
Effect level:
9 018 ppm
Sex:
male
Remarks on result:
other: Effect type: carcinogenicity

Significant Results of Oncegenicity Study in Mice

0 ppm

900 ppm

3000 ppm

9018 ppm

Macroscopic Incidence of Uterine Cysts

No. Examined

50

50

49

50

Uterine Cysts

21

18

14

11

Liver Neoplasia Females

No. Examined

50

50

49

50

Hepatocellular Adenomas

4

6

4

10

Hepatocellular Carcinoma

3

2

5

6

Total Neoplasms

7

8

9

16

Liver Neoplasia Males

No. Examined

49

50

50

50

Hepatocellular Adenomas

10

5

7

10

Hepatocellular Carcinoma

7

11

10

3

Total Neoplasms

17

16

17

13

Incidence of Cystic Endometrial Hyperplasia

No. Examined

50

32

32

50

No. of Incidences

48

29

27

44

Trace

3

4

3

10

Mild

14

13

8

19

Moderate

23

10

15

15

Severe

8

2

1

0

Pituitary Proliferative Lesions in Females

No. Examined

45

48

48

49

Hyperplasia

2

4

4

6

Adenoma

0

6

7

5

Adenocarcinoma

0

0

1

0

Total Neoplasms

0

6

8

5

Total Proliferative Lesions

2

10

12

11

Conclusions:
Liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice (NTP 2004). Therefore, the increased incidence of liver masses and nodules in female mice should be interpreted with care. The NOAEC level for oncogenic effects in female mice is 3000 ppm (10560 mg/m3). The LOAEC for female mice was 9018 ppm (31680 mg/m3). No oncogenic effects were seen in male mice. The NOAEC level for oncogenic effects in male mice is 9018 ppm (31680 mg/m3).
Executive summary:

The purpose of this study was to determine the oncogenic effect of inhalation exposure of commercial hexane. Groups of 50 male and 50 female mice were exposed to 0, 900, 3000, or 9018 ppm (0, 3168, 10560, 31680 mg/m3) of test substance for 6 hrs/day, 5 days/week, for 2 yrs. During the study, the animals were examined for clinical signs, mortality, body weight, opthamological, and food consumption effects. At study termination, animals were sacrificed and gross pathology and histopathology performed. Mortalities of exposure groups were consistant with control groups. Histopathology revealed increased liver masses and nodules in female mice at the 9018 ppm exposure group. Liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice (NTP 2004). Therefore, the increased incidence of liver masses and nodules in female mice should be interpreted with care. The NOAEC level for oncogenic effects in female mice is 3000 ppm (10560 mg/m3). The LOAEC for female mice was 9018 ppm (31680 mg/m3). No oncogenic effects were seen in male mice. The NOAEC level for oncogenic effects in male mice is 9018 ppm (31680 mg/m3).

 

NTP. 2004. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Stoddard Solvent IIC (CAS No. 64742-88-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NIH Publication No. 04-4453.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
10 560 mg/m³
Study duration:
chronic
Species:
mouse
Quality of whole database:
2 key read across studies from a structural analogue available for assessment.

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on available read across data, Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane is not classified as carcinogenic under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Additional information

No standard carcinogenicity studies are available for Hydrocarbons, C6-C10 (even numbered), n-hexane, isoalkanes, >5% n-hexane. However, data is available for a structural analogue, hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial hexane

A key study examined the oncogenic effect of inhalation exposure from commercial hexane (API, 1995a). Groups of 50 male and 50 female rats were exposed to 0, 900, 3000, or 9016 ppm of test substance for 6 hrs/day, 5 days/week, for 2 yrs. Mortalities of exposure groups were consistant with control groups. Body weight gain was significantly reduced in exposure groups. Histopathology revealed dose-related effects in the nasoturbinal tissue in all exposure groups. Therefore, there was no NOAEC level for local irritation effects. The LOAEC level for both sexes was 900 ppm. No oncogenic effects were seen in the exposure groups. The NOAEC for systemic effects was 9016 ppm in rats of both sexes.

 

In a key carcinogenic study the oncogenic effect of inhalation exposure of commercial hexane was determined (API, 1995b). Groups of 50 male and 50 female mice were exposed to 0, 900, 3000, or 9018 ppm (0, 3168, 10560, 31680 mg/m3) of test substance for 6 hrs/day, 5 days/week, for 2 yrs. Histopathology revealed increased liver masses and nodules in female mice at the 9018 ppm exposure group. Liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice, as referenced in NTP 2004. Therefore, the increased incidence of liver masses and nodules in female mice should be interpreted with care. The NOAEC level for oncogenic effects in female mice is 3000 ppm (10560 mg/m3). The LOAEC for female mice was 9018 ppm (31680 mg/m3). No oncogenic effects were seen in male mice. The NOAEC level for oncogenic effects in male mice is 9018 ppm (31680 mg/m3).