Pentane

Endpoint summary

Description of key information

Repeated Dose Inhalation 90d – NOAEC = 20,000 mg/m³ for rats (OECD TG 413)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Data waiving:

other justification

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Critical effects observed:

not specified

Reference 2

Endpoint:

chronic toxicity: oral

Data waiving:

other justification

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

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 - systemic effects

Link to relevant study records

Reference

Reference 1

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 g/m^3)
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
2220 ppm (8.1 g/m^3)
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
6646 ppm (24.3 g/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 g/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 g/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.

Reference 2

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.

Reference 3

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

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.

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.

Reference 4

Endpoint:

chronic toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

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:

Two supporting, short-term substance specific, One key and two supporting sub-chronic substance specific, and two key sub-chronic read across studies from structural analogues available for assessment.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Critical effects observed:

not specified

Reference 2

Endpoint:

sub-chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Reference 3

Endpoint:

chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity data is available for Normal-Pentane. Additionally, data is available for structural analogues, naphtha (petroleum), light alkylate, 2-methylbutane and cyclopentane. This data is read across to 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:

 

Normal-Pentane

In a supporting study (Halder, 1985), 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. 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).

 

2-methylbutane

In a supporting study (Halder, 1985), 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. 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).

 

The physicochemical and toxicological properties of pentanes do not suggest potential for oral toxicity. The results from acute oral studies as well as an oral developmental toxicity study in rats with pentanes confirm that Normal-Pentane is not toxic by oral administration either under acute or repeated dose conditions.

 

Inhalation:

 

Normal-Pentane

In a 14-day inhalation study (Stadler, 2001), n-pentane was administered to 10 male Crl:CDBR rats by whole body exposure at concentrations of 1000, 3000, or 10,000 ppm for 6 hours a day, 5 days a week for 2 weeks. Five of the rats were sacrificed after the last dose while 5 rats were sacrificed after a 14 -day recovery period. There were no unusual clinical observations, abnormal neurobehavior, changes in body weight, changes in haematology, change in organ weight, or abnormal tissues observed during gross or microscopic observation. 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. This study is classified as reliable with restrictions because there is no statement as to whether the study was compliant with GLPs or equivalent; however, details regarding test parameters were sufficient to accept the data.

In a 3 -day inhalation toxicity study (Lammers, 1999), n-pentane was administered to 8 WAG/RijCrlBR male rats per dose group at concentrations of 0, 2, 6.5, or 20 g/m³ for 8 hours per day for 3 consecutive days. 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.  Neither experiment induced general intoxication, and there were no treatment-related changes in body weight. Short-term exposure to n-pentane showed mild and reversible differences in learned performance. Differences were observed during or after 3 consecutive 8-hour periods of exposure at 2 and 6.5 g n-pentane/m³. There were no neurobehavioral effects observed at 20 g n-pentane/m³ and the effects in the lower exposure groups were reversible.

In a sub-chronic inhalation toxicity study (Whitman, 1997), 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, haematology, clinical chemistry, ophthalmology, gross pathology, organ weights, or histopathology. Inhalation exposure to n-pentane at concentrations ≤20,000 mg/m³ did not cause any observable adverse effects in male or female rats.

In a 90-day inhalation toxicity study (Aranyi, 1986), n-butane:n-pentane was administered to 20 male and 10 female rats at concentrations of 4500 or 1000 ppm by dynamic whole-body exposure for 6 hours per day, 5 days/week for 13 weeks. The exposure period totalled 66 days. Forty control male rats and 20 control female rats were exposed to filtered air under otherwise identical conditions. No animals died during the study. Possible treatment-related clinical signs included transient hunched posture and/or lethargy and intermittent tremors. Significant decreases in body weights were observed during weeks 3 and 4 for both sexes. Male body weights recovered near the end of the exposure period, however, female body weights did not. At the 28 -day interim sacrifice, there was a treatment-related effect in male kidneys with an increase in kidney scores for lesion characteristic of hydrocarbon-induced nephropathy; however, these values did not reach statistical significance. Characteristic lesions that were scored included: increase in hyaline droplet accumulation in the proximal tubule epithelial cells; foci of regenerative tubular epithelium in the cortical region of the kidney; and the presence of dilated tubules filled with granular material located at the junction between the inner and outer stripes of the medulla. Based on the study results, the authors concluded that the rats were not significantly affected by the exposures, and there was no evidence of hydrocarbon-induced nephropathy in either sex at termination. At the 28-day interim sacrifice period, male rats exhibited mild, transient treatment-related but not exposure related kidney effects.

Naphtha (petroleum), light alkylate

A key 13-week inhalation toxicity study (Schreiner, 1998) was conducted using wholly vaporized light alkylate naphtha distillate-2 generated in nitrogen. Male and female rats were exposed by inhalation in whole-body exposure cages 6 hours/day, 5 days/week for 13 weeks at analytical concentrations of 0, 668, 2220, and 6646 ppm. All animals survived the treatment period and were sacrificed according to study design at the end of week 13 or 18 (recovery group). No test-related observations were noted in the exposure chambers during any exposure period for any treatment groups or during non-exposure periods. From weekly clinical observations, the only apparent treatment-related finding was an increased incidence of red facial staining in both male and female rats in the high dose group. At week 13, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all 3 treatment groups. The kidney weights of high-dose males remained elevated after the recovery period. These increases correlated with microscopic observations of hyaline droplet formation in the proximal convoluted tubules considered to contain an alpha2-microglobulin-hydrocarbon complex as well as an increase in incidence and severity of nephropathy and dilated tubules at the corticomedullary junction. These microscopic finding are characteristic of ‘light hydrocarbon nephropathy” also known as hyaline droplet nephropathy and are male rat specific. Therefore, these effects are not considered to be relevant to humans. Statistically significant increases in absolute and relative liver weights were observed in high-dose male and female rats at week 13 after sacrifice. Differences were not present after the recovery period and had no microscopic correlate. Thus, the NOAEC for systemic toxicity was 24,300 mg/m³ corresponding to 6646 ppm.

 

Cyclopentane

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 (Gamer, 1998). 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 haematological 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. Sub-chronic 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.

Justification for classification or non-classification

Based on available substance specific and read across data, Normal-Pentane 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).