Pent-1-ene

Endpoint summary

Description of key information

OECD 422 (read-across, GLP, Key, rel.1): NOAEC = 8000 ppm (18359 mg of but-1-ene /m3), ca. 22947 mg of pent-1-ene /m3

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

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

Combined repeated exposure toxicity, reproduction and neurotoxicity screening in rats via whole-body inhalation exposures

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1 July to 25 August 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP compliant, guideline study, available as unpublished report, fully adequate for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD® (Sprague-Dawley) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Laboratories, Kingston, New York, USA.
- Age at study initiation: c.a. 8 weeks
- Weight at study initiation: Males 200-300g, females 150-250 g
- Housing: Individually in stainless steel, wire mesh cages within a 1.0 m3 glass and stainless steel whole body exposure chamber except during the mating period when one male and one female were housed together in a cage of suitable size.
- Diet: Certified Rodent Diet No. 5002 (PMI Nutrition International, St. Louis, MO, USA) ad libitum except during exposure
- Water: Mains water ad libitum except during exposure.
- Acclimation period: Approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 20-25°C
- Humidity: 36-82%
- Air changes: Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 1 July 2002 To: 25 August 2002

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: MMAD: 0.822 ± 0.1, 0.893 ± 0.2, 0.7986 ± 0.0343 and 3.6503 ± 7.0 for 0, 500, 2000 and 8000 ppm respectively.
GSD: 2.019 ± 0.4, 1.869 ± 0.3, 1.893 ± 0.3 and 2.181 ± 0.8 for 0, 500, 2000 and 8000 ppm respectively.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The whole-body exposure chambers each had a volume of approximately 1000 L. The chambers were operated at a minimum flow rate of 200 L/minute. The final airflow was set to provide at least one air change in 5.0 minutes (12 air changes/hour) and a T99 equilibrium time of at most 23 minutes. At the end of the 6-hour exposure, all animals remained in the chambers for a minimum of 30 minutes. During this time, the chambers were operated at approximately the same flow rate using clean air only. The chambers were exhausted through the in housed filtering system, which consisted of a coarse filter, a HEPA filter and activated charcoal.
For the treated groups, the test article was delivered from the cylinder via a regulator with a backpressure gauge via 1/4" tubing through a flowmeter via 1/4" tubing. The outlet of the flowmeter was regulated by a built-in metering valve. The test article laden airstream was directed into the turret of a 1.0 m3 glass and stainless steel exposure chamber via 1/4" tubing, where it was diluted with room air as it was drawn into the chamber. For controls, room air was drawn into the turret of the 1.0 m3 glass and stainless steel exposure chamber.

TEST ATMOSPHERE
During each exposure, measurements of airborne concentrations were performed in the animals' breathing zone at least 4 times using an appropriate sampling procedure and on-line GC analytical method. During each week of exposure, particle size determinations were performed using a TSI Aerodynamic Particle Sizer to characterize the aerodynamic particle size distribution of any aerosol present.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The mean (± standard deviation) analytical (GC) concentrations for the control and the exposure groups were as follows: 0 ± 0, 524 ± 40, 2062 ± 126 and 8271 ± 683 ppm. The analytically measured exposure levels of the airborne test article were reasonably close to the targeted exposure levels.

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 hours/day, 7 days/week

Dose / conc.:

500 ppm (nominal)

Remarks:

524 ± 40 ppm (analytical concentration)

Dose / conc.:

2 000 ppm (nominal)

Remarks:

2062 ± 126 ppm (analytical concentration)

Dose / conc.:

8 000 ppm (nominal)

Remarks:

8271 ± 683 ppm (analytical concentration)

No. of animals per sex per dose:

12

Control animals:

yes, sham-exposed

Details on study design:

The study design included the main study for repeated dose toxicity end points and reproductive/ developmental toxicity satellite groups (summarized separately). The reproductive and developmental toxicity satellite groups (12 females per exposure level) were exposed for two weeks prior to breeding, during breeding, and continuing through day 19 of gestation. Males from the main study were used to breed these females.

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice/day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to randomisation and then once/week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen)
- Animals fasted: Yes
- How many animals: 12/sex/group
- Parameters examined: erythrocyte count, haematocrit, haemoglobin, MCV, MCHC, leucocyte count (total and differential), platelet count, reticulocyte count, erythrocyte morphology, prothrombin time, activated partial thromboplastin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen)
- Animals fasted: Yes
- How many animals: 12/sex/group
- Parameters examined: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, urea nitrogen, creatinine, glucose, total cholesterol, triglycerides, total protein, albumin, globulin, albumin/globulin ratio, total bilirubin, sodium, potassium, chloride, calcium, phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: pre-test and during final week of exposure
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity / rectal temperature

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all animals including those dying spontaneously or killed moribund). The nasal pharynx was preserved but not examined microscopically.

ORGAN WEIGHTS: Yes (testes, epididymides, ovaries with oviducts, uterus with vagina, adrenals, brain with brain stem, heart, kidneys, liver, lungs, spleen, thymus)

HISTOPATHOLOGY: Yes (control and high dose only initially. Tissues examined: adrenals, bone marrow (femur), brain (medulla/pons, cerebrum and cerebellum), epididymides, heart, kidneys, large intestine (caecum, colon and rectum), liver, lungs (with mainstem bronchi), lymph nodes (mesenteric and mediastinal), mammary gland, ovary with oviduct, prostate, seminal vesicles, small intestine (duodenum, ileum and jejunum), spinal cord, spleen, stomach, testes, thymus, thyroid with parathyroids, tibial nerve, trachea, urinary bladder, uterus with vagina, all macroscopic lesions and tissue masses.

Other examinations:

None

Statistics:

Mean values of all exposure groups were compared to the mean value for the control group at each time interval. For all parameters except for organ weights, the standard one-way analysis of variance (ANOVA) using the F ratio to assess significance was used. If significant differences among the means were indicated, additional testing was performed using Dunnett's t-test to determine which means were significantly different from the control. Organ weight data was analyzed only by parametric methods. Bartlett's test was performed to determine if groups had equal variances. The standard one-way analysis of variance (ANOVA) using the F ratio to assess significance was used. If significant differences among the means were indicated, additional tests were used to determine which means were significantly different from the control: Dunnett's t-test for homogeneous data, or Cochran and Cox's modified t-test for non-homogeneous data. All t-tests were conducted at the 5% and 1% significance levels. Motor Activity Data was analyzed using split-plot repeated measures ANOVA with model terms for group, animal within group, interval and group by interval interaction. If the group x interval interaction was statistically significant (p=0.05), indicating non-parallelism in the behavioural profile between groups, a separate one-way ANOVA for group effects was performed at each interval. If the response data passed on the parallel hypothesis, an ANOVA (using summed responses over intervals) was used to test for the overall treatment effect which constituted the level hypothesis. If any significant overall treatment group effect was found by any of the above ANOVAs, Dunnett's t-test was used to find groups that differed from control. Analyses were performed for sexes separately and combined. Treatment group effects were deemed significant at the p=0.05 level. Plots, tables, listings, and analyses were generated using SAS version 6.12 for WINDOWS.

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 examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

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

Other effects:

not specified

Details on results:

There were no microscopic findings considered to be related to exposure to 1-butene. In comparison with controls, there was a slightly increased incidence and severity of mixed inflammatory cells in the caecal mucosa of rats exposed to 1-butene at exposure levels of 2000 ppm and above. The caecal mucosa normally contains a small population of mixed inflammatory cells, which acts as a natural defence mechanism against ingested substances or organisms. Increased numbers of inflammatory cells are sometimes seen as a normal spontaneous finding, and this was evident in a few males and females from the control group in this study. Since the finding was present in the control group and there was no clear exposure level response relationship in the treated groups, the increased incidence is considered to be fortuitous and unlikely to be related to treatment with 1 -butene. Other microscopic findings occurred sporadically or showed a similar incidence in control and 1-butene-treated animals. None were considered to be associated with exposure to 1-butene.

Key result

Dose descriptor:

NOAEC

Effect level:

8 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: there were no adverse effects at 8000 ppm, the highest concentration tested

Remarks on result:

other: 18359 mg/m3, 18 mg/L

Key result

Critical effects observed:

not specified

None

Conclusions:

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m3) in rats.

Executive summary:

In a repeated dose toxicity performed according to OECD Guideline 422 and in compliance with GLP, Crl:CD® (Sprague-Dawley) IGS BR rats (12/sex/dose) were exposed to 1-butene via whole body inhalation (gas) at target concentrations of 500, 2000, 8000 ppm (approximately 1147, 4589, 18359 mg/m³) for 28 days for subchronic evaluations (males and females) or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. Then, the dams and the pups were observed on day 1-4 of lactation. A similarly constituted Control group received “air” throughout the treatment period. Examinations during the study included: clinical signs, body weight, food consumption, haematology, clinical chemistry, neurobehavioural examination, organ weights, gross and histopathology.

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. No treatment-related effects on body weight, food consumption, haematology, clinical chemistry, organ weights or gross/histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery.

Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m³) in rats.

Reference 2

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

Combined repeated exposure toxicity, reproduction and neurotoxicity screening in rats via whole-body inhalation exposures

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See RAAF document.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

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 examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

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

Other effects:

not specified

Details on results:

There were no microscopic findings considered to be related to exposure to 1-butene. In comparison with controls, there was a slightly increased incidence and severity of mixed inflammatory cells in the caecal mucosa of rats exposed to 1-butene at exposure levels of 2000 ppm and above. The caecal mucosa normally contains a small population of mixed inflammatory cells, which acts as a natural defence mechanism against ingested substances or organisms. Increased numbers of inflammatory cells are sometimes seen as a normal spontaneous finding, and this was evident in a few males and females from the control group in this study. Since the finding was present in the control group and there was no clear exposure level response relationship in the treated groups, the increased incidence is considered to be fortuitous and unlikely to be related to treatment with 1 -butene. Other microscopic findings occurred sporadically or showed a similar incidence in control and 1-butene-treated animals. None were considered to be associated with exposure to 1-butene.

Key result

Dose descriptor:

NOAEC

Effect level:

8 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: there were no adverse effects at 8000 ppm, the highest concentration tested

Remarks on result:

other: ca. 22947 mg/m3 of pent-1-ene based on its MW of 70.1329 g/mol

Key result

Critical effects observed:

not specified

None

Conclusions:

Under the test conditions and based on the read across approach, repeated inhalation exposure of male and female rats to target concentrations of 0, 500, 2000 and 8000 ppm of pent-1-ene is expected to produce no general systemic effects. Under the test conditions, the NOAEC is 8000 ppm, ca. 22947 mg/m3 of pent-1-ene in rats.

Executive summary:

In a repeated dose toxicity performed according to OECD Guideline 422 and in compliance with GLP, Crl:CD® (Sprague-Dawley) IGS BR rats (12/sex/dose) were exposed to 1-butene via whole body inhalation (gas) at target concentrations of 500, 2000, 8000 ppm (approximately 1147, 4589, 18359 mg/m³) for 28 days or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. A similarly constituted Control group received “air” throughout the treatment period. Examinations during the study included: clinical signs, body weight, food consumption, haematology, clinical chemistry, neurobehavioural examination, organ weights, gross and histopathology.

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. No treatment-related effects on body weight, food consumption, haematology, clinical chemistry, organ weights or gross/histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery.

Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m³ of 1 -butene), and ca. 22947 mg/m³ of pent-1-ene in rats by read-across.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

22 947 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP-compliant and of high quality (Klimisch score = 1), performed on the analogue substance, 1-butene. Based on the read across approach, this study was considered sufficiently robust to cover this endpoint.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

Combined repeated exposure toxicity, reproduction and neurotoxicity screening in rats via whole-body inhalation exposures

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1 July to 25 August 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP compliant, guideline study, available as unpublished report, fully adequate for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD® (Sprague-Dawley) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Laboratories, Kingston, New York, USA.
- Age at study initiation: c.a. 8 weeks
- Weight at study initiation: Males 200-300g, females 150-250 g
- Housing: Individually in stainless steel, wire mesh cages within a 1.0 m3 glass and stainless steel whole body exposure chamber except during the mating period when one male and one female were housed together in a cage of suitable size.
- Diet: Certified Rodent Diet No. 5002 (PMI Nutrition International, St. Louis, MO, USA) ad libitum except during exposure
- Water: Mains water ad libitum except during exposure.
- Acclimation period: Approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 20-25°C
- Humidity: 36-82%
- Air changes: Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 1 July 2002 To: 25 August 2002

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: MMAD: 0.822 ± 0.1, 0.893 ± 0.2, 0.7986 ± 0.0343 and 3.6503 ± 7.0 for 0, 500, 2000 and 8000 ppm respectively.
GSD: 2.019 ± 0.4, 1.869 ± 0.3, 1.893 ± 0.3 and 2.181 ± 0.8 for 0, 500, 2000 and 8000 ppm respectively.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The whole-body exposure chambers each had a volume of approximately 1000 L. The chambers were operated at a minimum flow rate of 200 L/minute. The final airflow was set to provide at least one air change in 5.0 minutes (12 air changes/hour) and a T99 equilibrium time of at most 23 minutes. At the end of the 6-hour exposure, all animals remained in the chambers for a minimum of 30 minutes. During this time, the chambers were operated at approximately the same flow rate using clean air only. The chambers were exhausted through the in housed filtering system, which consisted of a coarse filter, a HEPA filter and activated charcoal.
For the treated groups, the test article was delivered from the cylinder via a regulator with a backpressure gauge via 1/4" tubing through a flowmeter via 1/4" tubing. The outlet of the flowmeter was regulated by a built-in metering valve. The test article laden airstream was directed into the turret of a 1.0 m3 glass and stainless steel exposure chamber via 1/4" tubing, where it was diluted with room air as it was drawn into the chamber. For controls, room air was drawn into the turret of the 1.0 m3 glass and stainless steel exposure chamber.

TEST ATMOSPHERE
During each exposure, measurements of airborne concentrations were performed in the animals' breathing zone at least 4 times using an appropriate sampling procedure and on-line GC analytical method. During each week of exposure, particle size determinations were performed using a TSI Aerodynamic Particle Sizer to characterize the aerodynamic particle size distribution of any aerosol present.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The mean (± standard deviation) analytical (GC) concentrations for the control and the exposure groups were as follows: 0 ± 0, 524 ± 40, 2062 ± 126 and 8271 ± 683 ppm. The analytically measured exposure levels of the airborne test article were reasonably close to the targeted exposure levels.

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 hours/day, 7 days/week

Dose / conc.:

500 ppm (nominal)

Remarks:

524 ± 40 ppm (analytical concentration)

Dose / conc.:

2 000 ppm (nominal)

Remarks:

2062 ± 126 ppm (analytical concentration)

Dose / conc.:

8 000 ppm (nominal)

Remarks:

8271 ± 683 ppm (analytical concentration)

No. of animals per sex per dose:

12

Control animals:

yes, sham-exposed

Details on study design:

The study design included the main study for repeated dose toxicity end points and reproductive/ developmental toxicity satellite groups (summarized separately). The reproductive and developmental toxicity satellite groups (12 females per exposure level) were exposed for two weeks prior to breeding, during breeding, and continuing through day 19 of gestation. Males from the main study were used to breed these females.

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice/day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to randomisation and then once/week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen)
- Animals fasted: Yes
- How many animals: 12/sex/group
- Parameters examined: erythrocyte count, haematocrit, haemoglobin, MCV, MCHC, leucocyte count (total and differential), platelet count, reticulocyte count, erythrocyte morphology, prothrombin time, activated partial thromboplastin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen)
- Animals fasted: Yes
- How many animals: 12/sex/group
- Parameters examined: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, urea nitrogen, creatinine, glucose, total cholesterol, triglycerides, total protein, albumin, globulin, albumin/globulin ratio, total bilirubin, sodium, potassium, chloride, calcium, phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: pre-test and during final week of exposure
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity / rectal temperature

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all animals including those dying spontaneously or killed moribund). The nasal pharynx was preserved but not examined microscopically.

ORGAN WEIGHTS: Yes (testes, epididymides, ovaries with oviducts, uterus with vagina, adrenals, brain with brain stem, heart, kidneys, liver, lungs, spleen, thymus)

HISTOPATHOLOGY: Yes (control and high dose only initially. Tissues examined: adrenals, bone marrow (femur), brain (medulla/pons, cerebrum and cerebellum), epididymides, heart, kidneys, large intestine (caecum, colon and rectum), liver, lungs (with mainstem bronchi), lymph nodes (mesenteric and mediastinal), mammary gland, ovary with oviduct, prostate, seminal vesicles, small intestine (duodenum, ileum and jejunum), spinal cord, spleen, stomach, testes, thymus, thyroid with parathyroids, tibial nerve, trachea, urinary bladder, uterus with vagina, all macroscopic lesions and tissue masses.

Other examinations:

None

Statistics:

Mean values of all exposure groups were compared to the mean value for the control group at each time interval. For all parameters except for organ weights, the standard one-way analysis of variance (ANOVA) using the F ratio to assess significance was used. If significant differences among the means were indicated, additional testing was performed using Dunnett's t-test to determine which means were significantly different from the control. Organ weight data was analyzed only by parametric methods. Bartlett's test was performed to determine if groups had equal variances. The standard one-way analysis of variance (ANOVA) using the F ratio to assess significance was used. If significant differences among the means were indicated, additional tests were used to determine which means were significantly different from the control: Dunnett's t-test for homogeneous data, or Cochran and Cox's modified t-test for non-homogeneous data. All t-tests were conducted at the 5% and 1% significance levels. Motor Activity Data was analyzed using split-plot repeated measures ANOVA with model terms for group, animal within group, interval and group by interval interaction. If the group x interval interaction was statistically significant (p=0.05), indicating non-parallelism in the behavioural profile between groups, a separate one-way ANOVA for group effects was performed at each interval. If the response data passed on the parallel hypothesis, an ANOVA (using summed responses over intervals) was used to test for the overall treatment effect which constituted the level hypothesis. If any significant overall treatment group effect was found by any of the above ANOVAs, Dunnett's t-test was used to find groups that differed from control. Analyses were performed for sexes separately and combined. Treatment group effects were deemed significant at the p=0.05 level. Plots, tables, listings, and analyses were generated using SAS version 6.12 for WINDOWS.

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 examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

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

Other effects:

not specified

Details on results:

There were no microscopic findings considered to be related to exposure to 1-butene. In comparison with controls, there was a slightly increased incidence and severity of mixed inflammatory cells in the caecal mucosa of rats exposed to 1-butene at exposure levels of 2000 ppm and above. The caecal mucosa normally contains a small population of mixed inflammatory cells, which acts as a natural defence mechanism against ingested substances or organisms. Increased numbers of inflammatory cells are sometimes seen as a normal spontaneous finding, and this was evident in a few males and females from the control group in this study. Since the finding was present in the control group and there was no clear exposure level response relationship in the treated groups, the increased incidence is considered to be fortuitous and unlikely to be related to treatment with 1 -butene. Other microscopic findings occurred sporadically or showed a similar incidence in control and 1-butene-treated animals. None were considered to be associated with exposure to 1-butene.

Key result

Dose descriptor:

NOAEC

Effect level:

8 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: there were no adverse effects at 8000 ppm, the highest concentration tested

Remarks on result:

other: 18359 mg/m3, 18 mg/L

Key result

Critical effects observed:

not specified

None

Conclusions:

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m3) in rats.

Executive summary:

In a repeated dose toxicity performed according to OECD Guideline 422 and in compliance with GLP, Crl:CD® (Sprague-Dawley) IGS BR rats (12/sex/dose) were exposed to 1-butene via whole body inhalation (gas) at target concentrations of 500, 2000, 8000 ppm (approximately 1147, 4589, 18359 mg/m³) for 28 days for subchronic evaluations (males and females) or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. Then, the dams and the pups were observed on day 1-4 of lactation. A similarly constituted Control group received “air” throughout the treatment period. Examinations during the study included: clinical signs, body weight, food consumption, haematology, clinical chemistry, neurobehavioural examination, organ weights, gross and histopathology.

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. No treatment-related effects on body weight, food consumption, haematology, clinical chemistry, organ weights or gross/histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery.

Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m³) in rats.

Reference 2

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

Combined repeated exposure toxicity, reproduction and neurotoxicity screening in rats via whole-body inhalation exposures

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See RAAF document.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

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 examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

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

Other effects:

not specified

Details on results:

There were no microscopic findings considered to be related to exposure to 1-butene. In comparison with controls, there was a slightly increased incidence and severity of mixed inflammatory cells in the caecal mucosa of rats exposed to 1-butene at exposure levels of 2000 ppm and above. The caecal mucosa normally contains a small population of mixed inflammatory cells, which acts as a natural defence mechanism against ingested substances or organisms. Increased numbers of inflammatory cells are sometimes seen as a normal spontaneous finding, and this was evident in a few males and females from the control group in this study. Since the finding was present in the control group and there was no clear exposure level response relationship in the treated groups, the increased incidence is considered to be fortuitous and unlikely to be related to treatment with 1 -butene. Other microscopic findings occurred sporadically or showed a similar incidence in control and 1-butene-treated animals. None were considered to be associated with exposure to 1-butene.

Key result

Dose descriptor:

NOAEC

Effect level:

8 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: there were no adverse effects at 8000 ppm, the highest concentration tested

Remarks on result:

other: ca. 22947 mg/m3 of pent-1-ene based on its MW of 70.1329 g/mol

Key result

Critical effects observed:

not specified

None

Conclusions:

Under the test conditions and based on the read across approach, repeated inhalation exposure of male and female rats to target concentrations of 0, 500, 2000 and 8000 ppm of pent-1-ene is expected to produce no general systemic effects. Under the test conditions, the NOAEC is 8000 ppm, ca. 22947 mg/m3 of pent-1-ene in rats.

Executive summary:

In a repeated dose toxicity performed according to OECD Guideline 422 and in compliance with GLP, Crl:CD® (Sprague-Dawley) IGS BR rats (12/sex/dose) were exposed to 1-butene via whole body inhalation (gas) at target concentrations of 500, 2000, 8000 ppm (approximately 1147, 4589, 18359 mg/m³) for 28 days or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. A similarly constituted Control group received “air” throughout the treatment period. Examinations during the study included: clinical signs, body weight, food consumption, haematology, clinical chemistry, neurobehavioural examination, organ weights, gross and histopathology.

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. No treatment-related effects on body weight, food consumption, haematology, clinical chemistry, organ weights or gross/histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery.

Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m³ of 1 -butene), and ca. 22947 mg/m³ of pent-1-ene in rats by read-across.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

22 947 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP-compliant and of high quality (Klimisch score = 1), performed on the analogue substance 1-butene. Based on the read across approach, this study was considered sufficiently robust to cover this endpoint.

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

A Key study was identified (Huntingdon, 2003). In a repeated dose toxicity performed according to OECD Guideline 422 and in compliance with GLP, Crl:CD® (Sprague-Dawley) IGS BR rats (12/sex/dose) were exposed to 1-butene (gas) at target concentrations of 500, 2000, 8000 ppm (approximately 1147, 4589, 18359 mg/m³) via whole-body inhalation for 28 days (male and female) or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. The dam and the pups were sacrificed at day 4 of lactation. similarly constituted Control group received “air” throughout the treatment period.Examinations during the study included:clinical signs, body weight, food consumption, haematology, clinical chemistry, neurobehavioural examination,organ weights,gross and histopathology.

Exposure of male and female rats to target concentrations of 500, 2000 and 8000 ppm of 1-butene resulted in no general systemic effects. No treatment-related effects on body weight, food consumption,haematology, clinical chemistry, organ weights orgross/histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery.

Under the test conditions, the NOAEC was 8000 ppm (18359 mg/m³of 1 -butene), and ca. 22947mg/m³of pent-1-ene in rats by read-across.

Moreover, in the NTP 14 -week studies (NTP, 1998), mice and rats were exposed by whole body inhalation to the analogue substance isobutene at concentrations up to 8,000 ppm (6 hours per day, 5 days per week). There were no adverse effects observed and the NOAEC was 8000 ppm (ca. 22947 mg/m3 of pent-1 -ene).

In the 2 -year carcinogenicity studies, the NOAEC was also 8000 ppm (ca. 22947 mg/m3 of pent-1 -ene) in mice as no advserse effects was observed. However, in rats, the NOAEC was established at 2000 ppm (ca. 5736 mg/m3 of pent-1-ene) based on increased goblet cell hypertrophy in males at 8000 ppm. These effects are a common occurrence in long-term inhalation studies and are observed at the site of entry into the body and were not considered to be adverse.

Also, male rats given 8000 ppm developed thyroid follicular cell tumours. However, in the summary of technical reports review subcommittee comments, it is mentioned that there was no apparent precursor lesion, hyperplasia, for the thyroid gland neoplasms. Indeed , this lesion can be considered a preneoplastic lesion for thyroid gland neoplasms and that this has been seen in other studies. In this study, the incidences of follicular cell hyperplasia were not significantly increased. Under the conditions of these studies, the proposed conclusions were some evidence of carcinogenicity activity in male F344/N rats and no evidence of carcinogenic activity in female F344/N rats or male or female B6C3F1 mice.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No 1272/2008.

Self-classification:

Based on the available data, no self-classification is proposed regarding the specific target organ toxicity after a dose-repeated exposure by inhalation according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

There were no data regarding the oral and dermal route.