Registration Dossier

Administrative data

Description of key information

There is no data available for Methylcyclopentane. Data available from a structural analogues, n-Hexane, mixed hexanes, and 2-methylpentane, is used as read across.

Two key 90 day repeat dose inhalation studies were conducted for commercial hexane (API, 1990b,c; Klimisch score = 1).

Key results:

Repeat dose toxicity: oral - no studies available

Repeat dose toxicity: inhalation - OECD 413 in rats using commercial hexane (40-55% n-hexane) -LOAEC of 2984 ppm (10504mg/m3)

Repeat dose toxicity: dermal - no studies available

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989-04-10 to 1989-07-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it is well documented and follows OECD Guideline 413.
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 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
yes
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, Raleigh, NC
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 181 g male, approx. 123 g female
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo
- Diet (e.g. ad libitum): Purina Rodent Chow Brand Animal Diet#5002, ad libitum
- Water (e.g. ad libitum): ad libitum, Elizabethtown Water Company
- Acclimation period: 20 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-75 degree F
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: April 10, 1989 To: July 12, 1989
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Particle size measurements showed that there was no measurable amount of test substance present as aerosol.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 200-216 lpm
- Method of conditioning air: Test substance in a 5-gallon drum passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization chamber. Nitrogen was also fed into the volitization chamber. 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: 200-216 lpm
- Air change rate: 4.6-5.0 min.

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

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Air samples were drawn from the chamber via teflon tubing into charcoal tubes.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hrs/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 900, 3,000, 9000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 904, 2,984, 8,992 ppm (0, 3182, 10504, 31652 mg/m3)
Basis:
analytical conc.
No. of animals per sex per dose:
10 animals of each sex per dose
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 effects


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and week during the test


BODY WEIGHT: Yes
- Time schedule for examinations: twice prior to test, weekly during test and at termination


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Weekly beginning one week prior to test

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to test and prior to sacrifice


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to test on 10 animals per sex, and at sacrifice
- Animals fasted: Yes
- Anaesthetic used for blood collection: Yes, ether
- Parameters checked: erythrocyte count, hemoglobin count, hematocrit, total and differential leucocyte count, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to test on 10 animals per sex, and at sacrifice
- Animals fasted: Yes
- Parameters checked: glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, creatinine, blood urea nitrogen, fasting glucose, total protein, alkaline phosphatase, albumin, potassium, sodium, calcium, chloride, inorganic phophorus, gamma glutamyl transpeptidase, total bilirubin, creatine phosphokinase, lactic acid dehydrogenase


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

ORGAN WEIGHTS: Yes
adrenals, ovaries, testes with epididymides, kidneys, liver, brain, lungs, heart, spleen


HISTOPATHOLOGY: Yes
abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, eyes, optic nerve, larynx, ovaries, testes with epididymus, heart, kidneys, liver, intestine, gall bladder, lungs, lymph nodes, nerve, skeletal muscle, trachea, nasopharyngeal tissues, pancreas, pituitary, prostate, salivary gland, thymus, spinal cord, seminal vesicles, spleen, skin, stomach, thyroid, urinary bladder, uterus, exorbital lacrimal glands, Zymbal gland
Statistics:
Statistical analysis was done on body weight, body weight gain, change in body weight, food consumption, change in food consumption, hematology, clinical chemistry, organ weights, organ/body and organ/brain weight ratios.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
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:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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 examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No rats died during the study. Transient excess lacrimation was observed in the female rats. No other effects attibutable to exposure were noted.

BODY WEIGHT AND WEIGHT GAIN
Females in the high exposure group had sporadic reduced weight gain. As there was no consistant overall effect, this was not considered treatment related.

FOOD CONSUMPTION
There was no effect on food consumption.


OPHTHALMOSCOPIC EXAMINATION
Two males in the high exposure group showed corneal dystrophy. As this is not uncommon in males of this strain of rat, it is not considered treatment related.

HAEMATOLOGY
There were increased platelets in high exposure males. High and medium exposure males also had increased mean corpuscular volume. The significance of these changes are uncertain.

CLINICAL CHEMISTRY
High exposure males had increased creatinine, total protein, and albumin. They had decreased serum chloride. The significance of these changes are also uncertain.

ORGAN WEIGHTS
High exposure males had increased organ/body and organ/brain weight ratios. High exposure males and females had increased relative spleen weights. Liver weights were also increased in high exposure males. The liver effects appeared to be treatment related.

GROSS PATHOLOGY
No treatment related effects were noted.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was hemorrhage and inflammation in male rat livers at the high dose level. There was also inflammation in the kidneys of males in the high and middle exposure groups. The significance of these effects are uncertain.



Key result
Dose descriptor:
NOAEC
Effect level:
2 984 ppm
Sex:
male
Basis for effect level:
other: 10504 mg/m3
Key result
Dose descriptor:
LOAEC
Effect level:
8 992 ppm
Sex:
male
Basis for effect level:
other: 31652 mg/m3; liver and kidney effects
Key result
Dose descriptor:
NOAEC
Effect level:
8 992 ppm
Sex:
female
Basis for effect level:
other: 31652 mg/m3
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
8 992 ppm
System:
other: Hepatobiliary and urinary
Organ:
kidney
liver
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The NOAEC for male rats exposed via inhalation was 2984 ppm based on liver and kidney effects. The LOAEC for male rats was 8992 ppm. The NOAEC for female rats was 8992 ppm.
Executive summary:

The purpose of this study was to determine the sub-chronic toxicity of commercial hexane via inhalation. Groups of 10 male and 10 female rats were exposed to concentrations of 0, 904, 2,984, and 8,992 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. During the exposure period, animals were examined for mortality, body weight, clinical signs, opthamological effects, and food consumption. At the end of the exposure period, the animals were sacrificed and examined for hematological parameters, clinical chemistry, gross pathology, organ weights, and histopathology.

There was no mortality among the exposed groups, and no treatment related effects to body weight gain. At sacrifice, the only possible treatment related effects were hemorrhage and inflammation in high dose male livers. The significance of this effect is uncertain. The NOAEC for male rats in 2984 ppm, and the LOAEC is 8992 ppm (10504 mg/m3). The NOAEC for female rats in 8992 ppm (31652 mg/m3).

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989-04-11 to 1989-07-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it is well documented and follows OECD Guideline 413.
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 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
yes
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, NC
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 25 g male, approx. 19 g female
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo or cage card
- Diet (e.g. ad libitum): Purina Rodent Chow Brand Animal Diet#5002, ad libitum
- Water (e.g. ad libitum): ad libitum, Elizabethtown Water Company
- Acclimation period: 22 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-75 degree F
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: April 11, 1989 To: July 13, 1989
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Particle size measurements showed that there was no measurable amount of test substance present as aerosol.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 200-216 lpm
- Method of conditioning air: Test substance in a 5-gallon drum passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization chamber. Nitrogen was also fed into the volitization chamber. 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: 200-216 lpm
- Air change rate: 4.6-5.0 min.

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

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Air samples were drawn from the chamber via teflon tubing into charcoal tubes.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hrs/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 900, 3,000, 9000 ppm
Basis:
other: target concentrations
Remarks:
Doses / Concentrations:
904, 2,984, 8,992 ppm (0, 3182, 10504, 31652 mg/m3)
Basis:
analytical conc.
No. of animals per sex per dose:
10 animals of each sex per dose
Control animals:
yes, sham-exposed
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological and pharmacological effects


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and week during the test


BODY WEIGHT: Yes
- Time schedule for examinations: twice prior to test, weekly during test and at termination


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Weekly beginning one week prior to test

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to test and prior to sacrifice


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to test on 10 animals per sex, and at sacrifice
- Animals fasted: Yes
- Anaesthetic used for blood collection: Yes, ether
- Parameters checked: erythrocyte count, hemoglobin count, hematocrit, total and differential leucocyte count, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to test on 10 animals per sex, and at sacrifice
- Animals fasted: Yes
- Parameters checked: glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, creatinine, blood urea nitrogen, fasting glucose, total protein, alkaline phosphatase, albumin, potassium, sodium, calcium, chloride, inorganic phophorus, gamma glutamyl transpeptidase, total bilirubin, creatine phosphokinase, lactic acid dehydrogenase


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

ORGAN WEIGHTS: Yes
adrenals, ovaries, testes with epididymides, kidneys, liver, brain, lungs, heart, spleen


HISTOPATHOLOGY: Yes
abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, eyes, optic nerve, larynx, ovaries, testes with epididymus, heart, kidneys, liver, intestine, gall bladder, lungs, lymph nodes, nerve, skeletal muscle, trachea, nasopharyngeal tissues, pancreas, pituitary, prostate, salivary gland, thymus, spinal cord, seminal vesicles, spleen, skin, stomach, thyroid, urinary bladder, uterus, exorbital lacrimal glands, Zymbal gland
Statistics:
Statistical analysis was done on body weight, body weight gain, change in body weight, food consumption, change in food consumption, hematology, clinical chemistry, organ weights, organ/body and organ/brain weight ratios.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
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:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Seven mice died during the study, 3 from drawing blood, and 4 others died accidently. None of these deaths were attributed to treatment. There was sporadic excessive lacrimation due to exposure, no other clinical signs were considered treatment related.

BODY WEIGHT AND WEIGHT GAIN
There was no effect on body weight observed.

FOOD CONSUMPTION
There was no effect on food consumption.


OPHTHALMOSCOPIC EXAMINATION
No effects were observed.

HAEMATOLOGY
High exposure males had increased mean corpuscular volume. The significance of these changes are uncertain.

CLINICAL CHEMISTRY
No treatment related effects were observed.

ORGAN WEIGHTS
No effects to organ weights were noted.

GROSS PATHOLOGY
No treatment related effects were noted.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment related effects were noted.

Key result
Dose descriptor:
NOAEC
Effect level:
>= 8 992 ppm
Sex:
male/female
Basis for effect level:
other: 31652 mg/m3
Key result
Critical effects observed:
no
Conclusions:
The NOAEC for male and female mice exposed via inhalation is 8992 ppm (31652 mg/m3).
Executive summary:

The purpose of this study was to determine the sub-chronic toxicity of commercial hexane via inhalation. Groups of 10 male and 10 female mice were exposed to concentrations of 0, 904, 2,984, and 8,992 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. During the exposure period, animals were examined for mortality, body weight, clinical signs, opthamological effects, and food consumption. At the end of the exposure period, the animals were sacrificed and examined for hematological parameters, clinical chemistry, gross pathology, organ weights, and histopathology.

Seven animals died during the study, however, all deaths were accidental and not considered treatment related. The NOAEC for mice is 8992 ppm (31652 mg/m3).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
10 504 mg/m³
Study duration:
subchronic
Species:
rat
System:
other: Hepatobiliary and Urinary
Organ:
kidney
liver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There is no data available for Methylcyclopentane. Data available from a structural analogues, n-Hexane, mixed hexanes, and 2-methylpentane, is used as read across.

Oral Toxicity:

There is no key data available for Methylcyclopentane

In a supporting neurotoxicity study (Ono et al., 1981), an experiment was performed to evaluate the neurotoxicity of 4 different substances by measuring the nerve conduction velocity in the rat's tail. Thirty rats were divided into five groups of 5-7 rats. n-Hexane, 2 -methylpentane, 3-methylpentane and methylcyclopentane were diluted with olive oil and orally administered daily for eight weeks. The body weight, motor nerve conduction velocity, motor distal latency and mixed nerve conduction velocity were measured before administration, after two, four, six and eight weeks' administration.

 

The n-hexane group showed a distinct impairment of the functional states of the peripheral nerve Methylcyclopentane, 2-methylpentane and

3-methylpentane group had some significant differences in comparison with the control in the experiment, although these differences were not so distinct as those in n-hexane group. The results revealed that the neurotoxicity of the three chemicals was not so severe as that of n-hexane and were in the order of n-hexane > methylcyclopentane > 2-methylpentane = 3-methylpentane.

A supporting article (Galvin and Bond, 1999) reports that Halder et al. (1985) carried out a series of 28-d gavage (oral) screening studies in male F344 rats to identify the major contributors to nephropathy. Tested were PS-6 reference gasoline, some fractions of this gasoline, and 15 individual components of gasoline, including 2-methylpentane. In all, 0.5 or 2 g/kg of 22 different hydrocarbon materials was administered once a day by gavage for 5 d/wk for 28 d. 2-Methylpentane showed a statistically significant elevation in nephropathy scores when compared with the saline control animals.

It has been determined that the kidney lesions occurring in F344 rats with wholly vaporized gasoline occur only in male rats, and not in female rats. The gasoline was also tested using the same protocol in male and female mice. The kidney lesion was not found at all in this species. The kidney

lesions were found only in male rats. Considerable research has established that with gasoline and a number of other substances the effect is due to the accumulation of the alpha-2μ-globulin protein in the male rat (Short et al., 1989; Dietrich & Swenberg, 1991). Since alpha-2μ-globulin is a species (rat) and sex (male) specific protein that is causal for kidney cytotoxicity, extrapolation of the data from rat studies to other species, including humans, is not warranted (Hard et al., 1993).

Inhalation Toxicity:

In a sub-chronic toxicity study of commercial hexane, groups of 10 male and 10 female rats were exposed to concentrations of 0, 904, 2984, and 8992 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks via the inhalation route (API, 1990b; Klimisch score =1).

There was no mortality among the exposed groups, and no treatment related effects to body weight gain. At sacrifice hemorrhage and inflammation in high dose male livers were considered the only possible treatment related effects. The significance of this effect is uncertain. The NOAEC for male rats in 2984 ppm, and the LOAEC is 8992 ppm (10504 mg/m3). The NOAEC for female rats in 8992 ppm (31652 mg/m3).

In a similar sub-chronic toxicity study of commercial hexane, groups of 10 male and 10 female mice were exposed to concentrations of 0, 904, 2,984, and 8,992 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks, via inhalation (API, 1990c; Klimisch score =1). Seven animals died during the study, however, all deaths were accidental and not considered treatment related. The NOAEC for mice is 8992 ppm (31652 mg/m3).

Justification for classification or non-classification

There is no data available for Methylcyclopentane. Data available from a structural analogues, n-Hexane, mixed hexanes, and 2-methylpentane, is used as read across. Based on available read across data, Methylcyclopentane is Not classified for repeated dose toxicity under the Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP).