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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Inhalation NOAEC (Rat): 20000 mg/m3 (according to OECD TG 413)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint:
chronic toxicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Quality of whole database:
No key oral repeat dose toxicity data available. One supporting substance specific and one supporting read across study from a structural analogue available for assessment.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restriction because it was conducted according to OECD guideline 413 and was 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:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: 7 weeks
- Weight at study initiation: Not reported
- Housing: Individual
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 26 °C
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: nitrogen
Remarks on MMAD:
MMAD / GSD: Measured, but not reported
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 litre exposure chamber
- Method of holding animals in test chamber: Cages
- Source and rate of air: 5-gallon container, flushed with nitrogen using laboratory pump
- Method of conditioning air: System of coarse filter, HEPA filter, charcoal filter
- System of generating particulates/aerosols: Volatilization chamber
- Temperature, humidity, pressure in air chamber: Monitored every half hour during exposure; 20 to 24 degrees C, 40 to 60% relative humidity
- Air flow rate: 200 litres per minute
- Method of particle size determination: TSI Aerodynamic Particle Sizer, once each exposure

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography
- Samples taken from breathing zone: yes

VEHICLE (if applicable)
- Composition of vehicle: Nitrogen
- Purity of vehicle: 99.98%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples for determination of analytical exposure levels were withdrawn by vacuum pump from the breathing zone in the exposure chambers three times per exposure for treated groups, and once per exposure for controls. Samples were analyzed using gas chromatography using a flame ionization detector.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Remarks:
Doses / Concentrations:
668 ppm (2.4 mg/m^3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
2220 ppm (8.1 mg/m^3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
6646 ppm (24.3 mg/m^3)
Basis:
analytical conc.
No. of animals per sex per dose:
12
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Highest concentration approximately 75% of the lower explosive limit
- Post-exposure recovery period in satellite groups: 28 days

An extra 12 rats per sex for the high dose and control recovery groups were maintained untreated for 28 days after termination of exposure, to assess reversibility of effects.
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice pretest, weekly during the study period

BODY WEIGHT: Yes
- Time schedule for examinations: Twice pretest, weekly during the study period, prior to sacrifice

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest and prior to sacrifice
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to sacrifice
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen)
- Animals fasted: Yes
- How many animals: 12 per sex per group
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to sacrifice
- Animals fasted: Yes
- How many animals: 12 per sex per group
- Parameters checked in table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Pretest, weeks 5, 9, 14, and 18 (recovery groups)
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity / handling / open-field behaviour / reflexes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Organs weighed: adrenals, brain, heart, kidneys, liver, lung, ovaries, prostate, spleen, testes (with epididymides), thymus, and uterus
Tissues histopathologically examined: 39, preserved, not reported
Statistics:
Statistical evaluations to determine variance and significance were performed on the following parameters: body weights, body weight change from week 0, food consumption, haematology, clinical chemistry, organ weights, organ/terminal body weight ratio, and organ/brain weight ratio.
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):
effects observed, treatment-related
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 treatment-related effects were observed.

BODY WEIGHT AND WEIGHT GAIN: No treatment-related effects were observed.

FOOD CONSUMPTION: No treatment-related effects were observed.

OPHTHALMOSCOPIC EXAMINATION: No treatment-related effects were observed.

HAEMATOLOGY: Statistically significant decreases in haemoglobin, hematocrit, and erythrocytes in blood of high-dose males when compared to controls were not found to be toxicologically relevant, as the values were within the historical range for control animals.

CLINICAL CHEMISTRY: Statistically significant decreases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in blood of high-dose females when compared to controls were not found to be toxicologically relevant, as several control female rats had elevated AST and ALT as well.

NEUROBEHAVIOUR -Motor Activity: There were statistically significant differences in the number and relative pattern of motor activity among the dose groups over the treatment testing periods, but overall, these differences did not occur in a dose-related pattern. The magnitudes of the differences were not large, and none of the treatment-group differences were larger than differences seen during the predose period.
-Functional Operational Battery: No treatment-related effects were observed.

ORGAN WEIGHTS: At terminal sacrifice, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all three treatment groups. High-dose male kidney weights remained elevated after the recovery period. This correlated with microscopic observations indicating light hydrocarbon nephropathy. At terminal sacrifice, there were also statistically significant increases in absolute and relative liver weights in high-dose male and female rats. Liver weights did not remain elevated after the recovery period. There was no microscopic correlation for this condition, so this was considered a functional adaptation to treatment. There were no differences in lung and brain weights when compared to controls.

GROSS PATHOLOGY: No treatment-related effects were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopic observations included hyaline droplet formation in the proximal convoluted tubules, considered to contain an alpha2-microglobulin-hydrocarbon complex, and increase in incidence and severity of nephropathy and dilated tubules at the cortico-medullary junction.
Key result
Dose descriptor:
NOEC
Remarks:
subchronic toxicity
Effect level:
> 2 220 ppm
Sex:
male/female
Basis for effect level:
other: organ weights
Key result
Dose descriptor:
NOEC
Remarks:
neurotoxicity
Effect level:
>= 6 646 ppm
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
The NOEC of the test substance was found to be > 2220 ppm for subchronic toxicity, and >= 6646 ppm for neurotoxicity. The test substance did not cause neurobehavioral or neuropathologic effects in rats after 13 weeks of inhalation exposure at a maximum concentration of 6646 ppm (24.3 mg/m^3). The test substance did induce "light hydrocarbon nephropathy", characterized by increased organ weight and microscopic effects of the kidney (increased incidence of hyaline droplets) in male rats, but since this syndrome is species and sex specific, it is not considered relevant to humans for risk assessment purposes.
Executive summary:

In a 90-day inhalation toxicity study, light alkylate naphtha distillate-2 was administered to 12 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 668, 2220, or 6646 ppm (0, 2.4, 8.1, and 24.3 mg/m^3) for 6 hours per day, 5 days/week for a total of 13 weeks.

 

There were no treatment-related effects in mortality, clinical signs, neurotoxicity, body weight, or food consumption. Significant effects noted in haematology and clinical chemistry were not determined to be toxicologically relevant, and kidney weight increases found in high-dose males were not determined to be relevant to human toxicity risk assessments.  The LOEC for subchronic toxicity is >= 6646 ppm, based on haematology, clinical chemistry and organ weights. The NOEC is > 2220 ppm for subchronic toxicity and >= 6646 ppm for neurotoxicity.

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because it was conducted according to OECD guideline 413 and was GLP compliant.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restriction because it is in compliance with OECD guidelines, as well as U.S. EPA/FIFRA, U.S. EPA/TSCA, and EU guidelines.
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:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Qualifier:
according to guideline
Guideline:
other: U.S. EPA/FIFRA Guidelines §82-4
Qualifier:
according to guideline
Guideline:
EPA OTS 798.2450 (90-Day Inhalation Toxicity)
Qualifier:
according to guideline
Guideline:
other: U.S. EPA/TSCA Guidelines 40 CFR §798.6059, and §798.6059, 798.6200, 798.6400
Qualifier:
according to guideline
Guideline:
other: EU Guideline 87/302/EEC
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
not reported
Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
other: no data
Details on inhalation exposure:
not reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were determined by gas chromatography.
Duration of treatment / exposure:
Rats were exposed to vapours of cyclopentane for 90 days.
Frequency of treatment:
6 hours per workday
Remarks:
Doses / Concentrations:
5, 10, 30 (pure), 30 (technical) mg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
5.0±0.2, 10.0±0.3, 29.8±1.5 (pure), 29.8±1.8 mg/L
Basis:
analytical conc.
No. of animals per sex per dose:
15 males and 15 females per dose group
Control animals:
yes, concurrent no treatment
Details on study design:
not reported
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: yes
- Time schedule: General observation were made twice on weekdays and once on weekends and holidays.
- Cage side observations were not included in a table.

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: Clinical examinations were made once per weekday during preflow and the on the day following exposure.

BODY WEIGHT: yes
- Time schedule for examinations: measured weekly

FOOD CONSUMPTION: not reported

FOOD EFFICIENCY: not reported

WATER CONSUMPTION: not reported
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: yes
- Time schedule for examinations: Examinations were carried out prior to and following exposure.
- Dose groups that were examined: not reported

HAEMATOLOGY: Yes / No / No data: yes
- Time schedule for collection of blood: Examinations of numerous parameters were preformed at the end of the exposure period.
- Anaesthetic used for blood collection: not reported
- Animals fasted: not reported
- How many animals: 10 males and 10 females

CLINICAL CHEMISTRY: yes
- Time schedule for collection of blood: Examinations of numerous parameters were preformed at the end of the exposure period.
- Animals fasted: not reported
- How many animals: 10 males and 10 females

URINALYSIS: not reported

NEUROBEHAVIOURAL EXAMINATION: yes (neurofunctional tests)
- Time schedule for examinations: performed three times during the exposure period (approximately once per month)
- Dose groups that were examined: not reported
- Battery of functions tested: not reported
Sacrifice and pathology:
A complete necropsy was performed on 15 animals per sex, which included weighing of selected organs and gross pathological evaluation.

5 animals per sex, of those subject to neurofunctional testing, were sacrificed by perfusion fixation and examined neuropathologically.
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
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:
no effects observed
Details on results:
No abnormalities were detected during clinical, neurofunctional, and clinico-pathological examinations in any of the test groups. No changes were found during necropsy or in the histo- and neuropathological examinations.
Key result
Dose descriptor:
NOAEC
Effect level:
30 mg/L air
Basis for effect level:
other: Equivalent to 30,000 mg/m3; 29.8 ± 1.5 (pure) or 29.8±1.8 (technical) mg/L air was the actual concentration
Critical effects observed:
not specified
Conclusions:
Subchronic inhalation exposure up to 30 mg/L of cyclopentane vapour (i.e, technical grade or high purity) did not cause a substance-related toxic effect. The NOAEC is 30 mg/L under the conditions of this study.
Executive summary:

Fifteen male and 15 female Wistar rats per test group were exposed to cyclopentane vapour (pure) at concentrations of 5, 10, 30 mg/L and cyclopentane vapour (technical grade) at a concentration of 30 mg/L for 6 hours per weekday for 90 days. A concurrent control group was exposed to clean air. General observation were performed twice during weekdays and once during weekends and holidays. Clinical examinations were performed once every weekday and on the day following exposure. Neurofunctional test were performed in 10 animals per sex, once before the exposure period and three times during the exposure period. A hematological and clinicochemical examination was performed in 10 animals per sex at the end of the exposure period. A complete necropsy was performed on 10 animals per sex, which included weighing of selected organs and gross pathological evaluation. 5 animals per sex, of those subject to neurofunctional testing, were sacrificed by perfusion fixation and examined neuropathologically. Subchronic inhalation exposure to up to 30 mg/L of cyclopentane vapour (i.e., technical grade or high purity) did not cause a substance related toxic effect. The NOAEC is 30 mg/L under the conditions of this study.

This study was given a Kilimsh score of 1, reliable without restriction. The study had minor discrepancies that are listed in the overall remarks/attachments comment box in this robust summary.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1996-10-09 to 1997-02-21
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study is classified as reliable without restriction because it is in compliance with OECD principles of GLP and E.U. Council Decision on GLP, as well as the European Community Dangerous Substance Directive (67/548/EEC), Methods of Determination of Toxicity, Annex VIII.
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
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
Protocol deviations were noted and were not expected to affect the overall study results.
Qualifier:
according to guideline
Guideline:
other: EC, Annex VIII, Sub-chronic inhalation toxicity, 1988
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl: CDBR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Kignstone Facility, Stone Ridge, New York
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: males: 229.8 to 255.8 grams; females: 184.8 to 213.4 grams
- Housing: individually housed in suspended stainless steel and wire mesh cages with absorbent paper below during study period and individually housed in 1.5 cubic meter statinless steel and glass whole body inhalation chambers during exposure
- Diet (e.g. ad libitum): ad libitum during nonexposure periods
- Water (e.g. ad libitum): ad libitum during nonexposure periods
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64 to 72 °F
- Humidity (%): 30 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours dark and 12 hours light

IN-LIFE DATES: From: 1996-11-18 To:1997-02-21
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: not reported
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: vapor generator into a whole body inhalation chamber (1.5 cubic meter)
- Source and rate of air: air flow rate was 300 litres per minute
- Temperature, humidity, pressure in air chamber: 66 to 72°F, 40 to 70% relative humidity, under slightly negative pressure to the room
- Air flow rate: 300 litres per minute

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly measurements from five different locations in the chamber were made by on-line gas chromatography.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
analytical concentrations for the 5000; 10,000; and 20,000 mg/m3 concentrations were as follows: 5097±79; 10,203±151; and 20,483±734 mg/m3
Duration of treatment / exposure:
6 hours a day plus chamber equilibrium time (theoretically=23 minutes)
Frequency of treatment:
5 days a week for 13 weeks; males had three additional treatments during the 14th week and females had four additional treatments
Remarks:
Doses / Concentrations:
5097±79, 10,203±151, and 20,483±734 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes
Details on study design:
- Dose selection rationale: Doses were selected based on a range finding study with concentrations up to 21,000 mg/m3 without any noted effects.
Positive control:
not reported
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily prior to exposure, once a day on nonexposure days, during the first and sixth hour of exposure


BODY WEIGHT: Yes
- Time schedule for examinations: prior to study initiation, weekly thereafter, and at study termination


FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes, specified in grams


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to study initiation and during the final week of the study
- Dose groups that were examined: all dose groups


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at terminal sacrifice
- Anaesthetic used for blood collection: Yes, IP injection of sodium pentobarbital
- Animals fasted: Yes
- How many animals: all 40 animals
- Parameters checked in table were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at terminal sacrifice
- Animals fasted: Yes
- How many animals:all 40 animals
- Parameters checked in table were examined.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table)
Other examinations:
The following organs were weighed: adrenals, brain, epididymis, kidneys, liver, lungs plus trachea, prostate, seminal vesicles (with coagultion gland), spleen, testes or ovaries, thymus, and uterus.
Statistics:
Bartlett's test for equal variance (p<0.01); parametric procedures included a one-way ANOVA with F distribution followed by Dunnett's test and a standard regression analysis for linear response (p<0.05 and p<0.01); nonparametric proceduresincluded the Kruskal-Wallis test followed by Dunn's summed rank test and Jonckheere's test for monotonic trends (p<0.05 and p<0.01)
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 specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
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:
no effects observed
Details on results:
not reported
Key result
Dose descriptor:
NOAEC
Effect level:
20 000 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: lack of any effects
Critical effects observed:
not specified

There were sporadic statistically significant results. However, none of the results were considered clinically significant or related to treatment.

Conclusions:
Inhalation exposure to n-pentane at concentrations ≤20,000 mg/m3 did not cause any observable adverse effects in male or female rats.
Executive summary:

In a subchronic inhalation toxicity study, n-pentane was administered to 10 rats/sex/concentration by whole body exposure at analytical concentrations of 5097±79; 10,203±151; or 20,483±734 mg/m3 6 hours a day, 5 days a week for 13 weeks. Animals were sacrificed in the fourteenth week after 3 (males) or 4 (females) exposures. There were no treatment-related effects observed for clinical signs, body weight, food consumption, hematology, clinical chemistry, ophthalmology, gross pathology, organ weights, or histopathology. This study is classified as reliable without restrictions because it is in compliance with OECD principles of GLP and E.U. Council Decision on GLP, as well as the European Community Dangerous Substance Directive (67/548/EEC), Methods of Determination of Toxicity, Annex VIII. In addition the study was performed according to OECD 413 guidelines.

Endpoint:
chronic toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
20 000 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
30
Species:
rat
Quality of whole database:
Three key and one supporting read across studies from structural analogues along with one supporting short-term substance specific and one supporting short-term read across study from a structural analogue available for assessment.

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

Only supporting oral and inhalation repeated dose toxicity data is available for 2-methylbutane. However, key inhalation toxicity data is available for structural analogues, pentane; cyclopentane; and light alkyl naphtha distillate and presented in the dossier. This data is read across to 2-methylbutane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Oral

Supporting repeated dose toxicity studies via the oral route were identified for 2-methylbutane and n-pentane. However, several study limitations are noted when comparing each of the study’s methods to OECD 407. First, female rates were not used in the study. Second, the selected dose levels did not cover an appropriate range (only two dose groups were used, and both were at fairly high doses for a substance that can be aspirated). Third, the substance was administered 5 days/week instead of 7. Fourth, body weight measurements were only taken twice during the experiment (prior to dosing and at the scheduled sacrifice). Fifth, the only post-necropsy examinations were of the kidney. Finally, functional observations, haematology analysis, urinalysis and other post-necropsy examinations were not conducted. Consequently, these studies were not considered key. 

2-methylbutane

 

The nephrotoxicity of 2-methylbutane was evaluated in male F344 rats over 4 weeks after oral gavage doses of 0.5 g/kg/day and 2.0 g/kg/day (Halder et al., 1985). Clinical examinations were conducted twice daily throughout the study, and nephrotoxicity and histopathology of the kidney were evaluated at termination. The results were compared to positive and negative controls. Statistical methods used were appropriate. 

 

Mortality occurred in 90% of high-dose rats and 10% of low-dose rats. Kidney weights for surviving animals were comparable to controls. 2-methylbutane's ability to cause hydrocarbon nephropathy was comparable to the saline control (not significantly different).

 

Pentane

 

The nephrotoxicity of n-pentane was evaluated in male F344 rats over a period of 4 weeks after oral gavage doses of 0.5 g/kg/day and 2.0 g/kg/day (Halder et al., 1985). Clinical examinations were conducted twice daily throughout the study, and nephrotoxicity and histopathology of the kidney were evaluated at termination. The results were compared to positive and negative controls. Statistical methods used were appropriate. 

 

Mortality occurred in 20% of low dose rats and 40% of high dose rats. Terminal body weights of both treated groups were significantly less than controls. Absolute kidney weights were significantly lower than controls. n-Pentane’s ability to cause hydrocarbon nephropathy was comparable to the saline control (i.e., not significantly different).

Inhalation

Light Alkyl Naphtha Distillate

One key 90-day inhalation toxicity study on light alkylate naphtha distillate-2 (i.e., 33% 2-methylbutane; CAS number64741-66-8) was identified (Schreiner, 1998). In this study, the test substance was administered to 12 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 668, 2220, or 6646 ppm (0, 2.4, 8.1, and 24.3 mg/m3) for 6 hours per day, 5 days/week for a total of 13 weeks. There were no treatment-related effects in mortality, clinical signs, neurotoxicity, body weight, or food consumption. Significant effects noted in haematology and clinical chemistry were not determined to be toxicologically relevant, and kidney weight increases found in high-dose males were not determined to be relevant to human toxicity risk assessments. The LOEC for subchronic toxicity is 6646 ppm, based on haematology, clinical chemistry and organ weights. The NOEC is >2220 ppm (equivalent to 8.1 mg/m3) for subchronic toxicity and 6646 ppm for neurotoxicity. However, because this study tested a substance that is only 33% 2-methylbutane, the results may be of limited value.

Pentane

One read-across subchronic inhalation toxicity study on n-pentane was available. In this study, n-pentane was administered to 10 rats/sex/concentration by whole body exposure at analytical concentrations of 5097±79; 10,203±151; or 20,483±734 mg/m3 6 hours a day, 5 days a week for 13 weeks (ExxonMobil, 1997). Animals were sacrificed in the fourteenth week after 3 (males) or 4 (females) exposures. There were no treatment-related effects observed for clinical signs, body weight, food consumption, hematology, clinical chemistry, ophthalmology, gross pathology, organ weights, or histopathology. Based on this information, an NOAEC was established at 20,000 mg/m3. 

An additional supporting, subacute inhalation study on n-pentane was identified (Stadler et al., 2001). This study was not classified as key because of its short duration (14 days). Overall conclusions regarding the LOAEC and NOAEC values also are in disagreement with the 90-day inhalation study described above. The only finding was a slight, but statistically significant and dose-related, increase in serum calcium accompanied by increased phosphorous levels in 3000- and 10,000-ppm rats. The NOAEC was 1000 ppm (equivalent to 2951 mg/m3) based on the increase in calcium and phosphorus.

 

Cyclopentane

One read-across 90 -day repeated dose inhalation study is available for cyclopentane (BASF, 1998). Fifteen male and 15 female Wistar rats per test group were exposed to cyclopentane vapour (pure) at concentrations of 5, 10, 30 mg/L and cyclopentane vapour (technical grade) at a concentration of 30 mg/L for 6 hours per weekday for 90 days. A concurrent control group was exposed to clean air. General observations were performed twice during weekdays and once during weekends and holidays. Clinical examinations were performed once every weekday and on the day following exposure. Neurofunctional test were performed in 10 animals per sex, once before the exposure period and three times during the exposure period. A hematological and clinicochemical examination was performed in 10 animals per sex at the end of the exposure period. A complete necropsy was performed on 10 animals per sex, which included weighing of selected organs and gross pathological evaluation. Five animals per sex, of those subject to neurofunctional testing, were sacrificed by perfusion fixation and examined neuropathologically. Subchronic inhalation exposure to up to 30 mg/L of cyclopentane vapour (i.e., technical grade or high purity) did not cause a substance related toxic effect. The NOAEC concentration is 30 mg/L (equivalent to 30,000 mg/3) under the conditions of this study.    

2-methylbutane

In a supporting 3-day inhalation toxicity study, 2 -methylbutane was administered to 8WAG/RijCrlBR male rats per dose groupat concentrations of 0, 2, 6.5, or 20 g/m3 for 8 hours per day for 3 consecutive days (CEFIC, 2000).

Behavioural effects in rats were assessed through two experiments. The first experiment evaluated rats by the standardized functional observational battery assessment and automated motor activity assessment; the second experiment evaluated cognitive behaviour through the visual discrimination task. For both experiments, general intoxication was not induced. There were no treatment-related changes in body weight for either experiment. For experiment I, there was a significant increase in foot splay at 2 g/m3 after the first 8 -hour exposure period; however, this effect was not considered treatment-related because it was only observed at the low dose. Consequently, no statistically significant dose-related neurobehavioral effects observed in the rats in either experiment.

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it is compliant with OECD GLPs. It was selected as a supporting study because the duration of exposure was only 3 days, instead of 28 days, and focused on neurobehavioural effects.

Justification for classification or non-classification

Although there were no key repeated dose toxicity studies identified for either oral or dermal exposure, physiochemical data suggests that absorption via the oral or dermal route is not significant and that oral and dermal toxicity is not a significant cause for concern. Additionally, acute oral toxicity data suggests that absorption via the oral route is not significant and that oral toxicity is not a significant cause for concern. Dermal absorption is also expected to be not significant. Based on available substance specific and read-across data from structurally related substances, 2-methylbutane does not meet the criteria for classification for repeated dose toxicity (STOT-RE) under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).