Registration Dossier

Administrative data

Description of key information

Only one stream of the Other Petroleum Gases category has been tested but this and the main components of the category (C1-C4 alkanes and propene) indicate low sub-chronic toxicity by the inhalation route of exposure, the most relevant route. No significant exposure-related toxicological effects or target organ toxicity have been observed in inhalation studies up to 90 days duration on the C2-C4 alkanes, as well as Liquefied Petroleum Gas, the composition of which is mainly propane and propene. Propene has also been thoroughly tested for repeated exposure toxicity up to very high exposure concentrations in sub-chronic and chronic studies. Overall, only minimal local irritation effects to the nasal cavity (mild rhinitis) were observed and only following chronic lifetime exposure to high doses in rats and mice. The mammalian toxicity effects of this category will be not driven by the content of benzene as the latter is present at levels of <1%, however, the category may contain carbon monoxide which could trigger classification. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP; predates implementation of GLP and/or development of study guidelines but otherwise acceptable for assessment
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
only mortality/morbidity, clinical observations, body weight and histopathology were assessed
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 9-10 weeks
- Weight at study initiation: mean bw per group for males 159-169 g; mean bw per group for females 115-121 g
- Fasting period before study: none
- Housing: Individually housed in stainless steel wire cages (Lab Products, Rochelle Pk, NJ, USA)
- Diet: Wayne Lab-Blox® (Allied Mills, Inc., Chicago, IL, USA); freely available except during inhalation exposure
- Water: tap water available ad libitum
- Acclimation period: 5 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: Average of 70°F (equivalent to 21.1 C) (during exposure 75 ± 2°F) (equivalent to 23.9 C)
- Humidity: During non-exposure 54-57 % (during exposure 57 ± 7 %)
- Air changes: 20/hour
- Photoperiod: 12 hrs dark /12 hrs light

IN-LIFE DATES: From: 29 October 1979 To: 28 October 1981
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Propene gas, at an operating pressure of 54 psi, was metered to the exposure chambers and diluted in the chamber fresh-air inlets. The animals were individually housed in mesh cages (6 cages/exposure chamber). Since the exposure chambers were being operated with concentrations of propene close to the lower explosive limit (LEL) of the gas (25% and 50% of the LEL), safety devices were incorporated in the polyethylene vapour hood (vented to the room exhaust) to minimize the hazard to animals and personnel in the event of a leak. The gas was then piped to a second hood containing four double-pattern metering valves. Since the upstream pressure to these valves was well regulated, these valves provided stable control of the gas flow rate and ultimately of the concentration in the chambers. To provide the proper chamber concentration, the valves were set and periodically checked, by matching the calculated with the actual flow measured by a bubble meter. From the double-pattern metering valves, the gas was piped to each exposure chamber. A shut-off valve at the entrance to the chamber permitted easy, rapid termination of gas flow. All materials in the gas distribution system were stainless steel, Teflon®, viton, or brass.

TEST ATMOSPHERE
The vapour concentration uniformity in the chamber was measured with a portable photoionization detector at 12 positions (2 positions, one at the front and one at the back, for each of the six animal cage units per chamber). The sample point was just above and about 10 cm in from the front or back centre of each cage unit. Propene concentrations in the exposure chambers, control chambers, and exposure room were automatically monitored approximately 10 times during each exposure day by gas chromatography.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Throughout the studies, samples taken from the chambers several times each day indicated that average daily chamber concentrations were usually within 5 %-6 % of the target concentrations. However, wider variations in exposures were observed during the first 40 weeks of the studies as compared with the remainder of the studies.
Atmospheric samples were obtained from the control and 10000 ppm chambers during an exposure period during week 30 and were analyzed by gas chromatography. No peaks were observed in the air from the control chamber. Only those impurities present in the bulk propene at the pretest analysis were observed in the air from the 10000 ppm chamber
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Remarks:
Doses / Concentrations:
0, 5000, 10000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 4985±274, 9891±515 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: No compound-related effects were seen in a 14 week inhalation study following exposure at 0, 625, 1250, 2500, 5000, or 10000 ppm. Based on these results even though no propene-related toxicity was observed, concentrations of 5000 and 10000 ppm propene were selected for rats in the 2-year studies. Concentrations higher than 10000 ppm propene could not be selected because of the risk of explosion
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice per day for signs of moribundity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once per month

BODY WEIGHT: Yes
- Time schedule for examinations: Once per week for 14 weeks, once per month for 76 weeks and then biweekly thereafter.

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Complete necropsy exam performed on all animals.

HISTOPATHOLOGY: Yes. Complete histopathological examination performed on all animals. The following tissues were examined: gross lesions, skin, mandibular lymph node, mammary gland, sternebrae, vertebrae or femur including marrow, thymus, trachea (2 sections), lungs and bronchi, heart, thyroid gland, parathyroids, oesophagus, stomach, colon, small intestine, liver (2 sections), pancreas, spleen, kidneys and adrenal glands (2 sections), urinary bladder, prostate/testes (2 sections) or ovaries/uterus (2 sections), nasal cavity and nasal turbinates (3 sections), brain (3 sections), pituitary gland, and (if abnormal) spinal cord, eyes, and pharynx.
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) life table test for a dose-related trend. All reported P values for the survival analysis are two-sided.
The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Three statistical methods are used to analyze tumour incidence data (Life table analysis, incidental tumour analysis and unadjusted analyses). The two that adjust for intercurrent mortality employ the classical method for combining contingency tables developed by Mantel and Haenszel (1959). Tests of significance included pairwise comparisons of high dose and low dose groups with chamber controls and tests for overall dose-response trends.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY; No clinical signs were recorded. No significant differences in survival were observed between any groups of either sex.

BODY WEIGHT AND WEIGHT GAIN: The mean bodyweights of exposed male and female rats were comparable to those of the controls throughout the study. The fluctuations in weight gain were not dose-related.

HISTOPATHOLOGY: NON-NEOPLASTIC: Several non-neoplastic effects were observed. Squamous metaplasia of the respiratory epithelium of the nasal cavity occurred in females exposed to propene at both concentrations and in males exposed at the high concentration. Inflammatory changes of the nasal cavity occurred in both males. The changes were characterized as unspecified inflammation and suppurative inflammation. The former lesion, consisting of a mild submucosal influx of lymphocytes, macrophages, and a few granulocytes, occurred in males exposed at the low concentration. The latter lesion was more severe and contained macrophages that migrated through the epithelium and accumulated in the lumen, occurring in male and females exposed at the high concentration. The combined incidence of these nasal cavity lesions was higher in male rats exposed at both
concentrations and in female rats exposed at the high concentration than in controls. These changes may reflect local tissue responses to long-term inhalation exposure to propene.

HISTOPATHOLOGY: NEOPLASTIC: No evidence was found for a carcinogenic effect of propene in rats. C-cell adenomas and C-cell adenomas or carcinomas (combined) of the thyroid gland occurred in female rats with a negative trend, and the incidence of C-cell adenomas in the high concentration group was significantly lower than that in the controls. The incidences in the controls (13%-15%) were higher than those observed in unexposed chamber control F344/N female rats in a propene oxide inhalation study (NTP, 1985) and in untreated control F344/N female rats in other studies. The incidences of C-cell hyperplasia occurred with a positive trend. In rats, C-cell hyperplasia, C-cell adenoma, and C-cell carcinoma appear to represent a continuous spectrum of progressive lesions. When hyperplasia, adenoma, and carcinoma are combined, the negative trend disappears. These comparisons suggest that the lower incidence of thyroid gland neoplasms is not related to administration of propene.
Dose descriptor:
LOAEC
Effect level:
5 000 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: (8,600 mg/m3). No NOAEC identified for local effects. Mild rhinitis (nasal inflammation) and associated epithelial alterations without obvious dose response relationship - refer to expert report of Harkema (2002)
Critical effects observed:
not specified

Inflammation of the nasal cavity, characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and by granulocytes into the lumen, occurred at increased incidences in low concentration and high concentration male rats and in high concentration female rats.

Incidences of nasal inflammatory changes in rats in the two-year inhalation studies of propene

 

Control

5000 ppm

10000 ppm

Males

Inflammation, unspecified

4/60 (8%)

14/50 (28%)

5/60 (10%)

Inflammation, suppurative

7/60 (14%)

7/50 (14%)

14/60 (28%)

Inflammation, unspecified or suppurative

11/60 (22%)

21/50 (42%)

19/50 (38%)

Females

Inflammation, unspecified

0/49 (0%)  

2/60 (4%)

2/60 (4%)

Inflammation, suppurative

8/49 (16%)

7/60 (14%)

11/60 (22%)

Inflammation, unspecified or suppurative

8/49 (16%)

10/60 (20%)

13/60 (26%)

Conclusions:
A NOAEC was not achieved. The LOAEC was 5000 ppm (lowest dose tested) for males and females based on mild rhinitis (nasal inflammation) and associated epithelial alteration suggesting chronic, low-grade irritation in these rodents. There was no obvious dose response relationship for this effect.
Executive summary:

Toxicology and carcinogenesis studies of propene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats of each sex to propene in air by inhalation at concentrations of 5000 or 10000 ppm, 6 hours per day, 5 days per week, for 103 weeks. Other groups of 50 rats of each sex received air only on the same schedule and served as chamber controls. The highest concentration of propene that was considered safe for these studies was 10000 ppm because of the risk of explosion that can occur at higher concentrations.

A NOAEC was not reported. The LOAEC reported was 5000 ppm (lowest dose tested) for males and females based on mild rhinitis.

The survival of exposed and control rats was comparable. Throughout most of the studies, mean body weights of exposed male and female rats were slightly lower (0%-5%) than those of the controls, but the decrements were not concentration-related. No compound-related adverse clinical signs were observed. An increased incidence of squamous metaplasia of the nasal cavity was observed in female rats exposed at 5000 and 10000 ppm (control, 0/49; low, 15/50; high, 6/50) and in male rats exposed at 5000 ppm (2/50; 19/50; 7/50). Epithelial hyperplasia of the nasal cavity was increased in female rats exposed at the 10000 ppm concentration (0/49; 4/50; 9/50); the incidences in male rats were 2/50, 2/50, and 5/50. Inflammation of the nasal cavity, characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and by granulocytes into the lumen, occurred at increased incidences in low concentration and high concentration male rats and in high concentration female rats. In the nasal cavity, propene induced squamous metaplasia of the respiratory epithelium in male and female rats and epithelial hyperplasia in female rats.

The nasal findings reported in this study were further investigated by re-evaluation of the archived tissue specimens (Harkema, 2002).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
8 600 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
Adequate for assessment.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP; predates implementation of GLP and/or development of study guidelines but otherwise acceptable for assessment
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
only mortality/morbidity, clinical observations, body weight and histopathology were assessed
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 9-10 weeks
- Weight at study initiation: mean bw per group for males 159-169 g; mean bw per group for females 115-121 g
- Fasting period before study: none
- Housing: Individually housed in stainless steel wire cages (Lab Products, Rochelle Pk, NJ, USA)
- Diet: Wayne Lab-Blox® (Allied Mills, Inc., Chicago, IL, USA); freely available except during inhalation exposure
- Water: tap water available ad libitum
- Acclimation period: 5 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: Average of 70°F (equivalent to 21.1 C) (during exposure 75 ± 2°F) (equivalent to 23.9 C)
- Humidity: During non-exposure 54-57 % (during exposure 57 ± 7 %)
- Air changes: 20/hour
- Photoperiod: 12 hrs dark /12 hrs light

IN-LIFE DATES: From: 29 October 1979 To: 28 October 1981
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Propene gas, at an operating pressure of 54 psi, was metered to the exposure chambers and diluted in the chamber fresh-air inlets. The animals were individually housed in mesh cages (6 cages/exposure chamber). Since the exposure chambers were being operated with concentrations of propene close to the lower explosive limit (LEL) of the gas (25% and 50% of the LEL), safety devices were incorporated in the polyethylene vapour hood (vented to the room exhaust) to minimize the hazard to animals and personnel in the event of a leak. The gas was then piped to a second hood containing four double-pattern metering valves. Since the upstream pressure to these valves was well regulated, these valves provided stable control of the gas flow rate and ultimately of the concentration in the chambers. To provide the proper chamber concentration, the valves were set and periodically checked, by matching the calculated with the actual flow measured by a bubble meter. From the double-pattern metering valves, the gas was piped to each exposure chamber. A shut-off valve at the entrance to the chamber permitted easy, rapid termination of gas flow. All materials in the gas distribution system were stainless steel, Teflon®, viton, or brass.

TEST ATMOSPHERE
The vapour concentration uniformity in the chamber was measured with a portable photoionization detector at 12 positions (2 positions, one at the front and one at the back, for each of the six animal cage units per chamber). The sample point was just above and about 10 cm in from the front or back centre of each cage unit. Propene concentrations in the exposure chambers, control chambers, and exposure room were automatically monitored approximately 10 times during each exposure day by gas chromatography.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Throughout the studies, samples taken from the chambers several times each day indicated that average daily chamber concentrations were usually within 5 %-6 % of the target concentrations. However, wider variations in exposures were observed during the first 40 weeks of the studies as compared with the remainder of the studies.
Atmospheric samples were obtained from the control and 10000 ppm chambers during an exposure period during week 30 and were analyzed by gas chromatography. No peaks were observed in the air from the control chamber. Only those impurities present in the bulk propene at the pretest analysis were observed in the air from the 10000 ppm chamber
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Remarks:
Doses / Concentrations:
0, 5000, 10000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 4985±274, 9891±515 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: No compound-related effects were seen in a 14 week inhalation study following exposure at 0, 625, 1250, 2500, 5000, or 10000 ppm. Based on these results even though no propene-related toxicity was observed, concentrations of 5000 and 10000 ppm propene were selected for rats in the 2-year studies. Concentrations higher than 10000 ppm propene could not be selected because of the risk of explosion
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice per day for signs of moribundity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once per month

BODY WEIGHT: Yes
- Time schedule for examinations: Once per week for 14 weeks, once per month for 76 weeks and then biweekly thereafter.

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Complete necropsy exam performed on all animals.

HISTOPATHOLOGY: Yes. Complete histopathological examination performed on all animals. The following tissues were examined: gross lesions, skin, mandibular lymph node, mammary gland, sternebrae, vertebrae or femur including marrow, thymus, trachea (2 sections), lungs and bronchi, heart, thyroid gland, parathyroids, oesophagus, stomach, colon, small intestine, liver (2 sections), pancreas, spleen, kidneys and adrenal glands (2 sections), urinary bladder, prostate/testes (2 sections) or ovaries/uterus (2 sections), nasal cavity and nasal turbinates (3 sections), brain (3 sections), pituitary gland, and (if abnormal) spinal cord, eyes, and pharynx.
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) life table test for a dose-related trend. All reported P values for the survival analysis are two-sided.
The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Three statistical methods are used to analyze tumour incidence data (Life table analysis, incidental tumour analysis and unadjusted analyses). The two that adjust for intercurrent mortality employ the classical method for combining contingency tables developed by Mantel and Haenszel (1959). Tests of significance included pairwise comparisons of high dose and low dose groups with chamber controls and tests for overall dose-response trends.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY; No clinical signs were recorded. No significant differences in survival were observed between any groups of either sex.

BODY WEIGHT AND WEIGHT GAIN: The mean bodyweights of exposed male and female rats were comparable to those of the controls throughout the study. The fluctuations in weight gain were not dose-related.

HISTOPATHOLOGY: NON-NEOPLASTIC: Several non-neoplastic effects were observed. Squamous metaplasia of the respiratory epithelium of the nasal cavity occurred in females exposed to propene at both concentrations and in males exposed at the high concentration. Inflammatory changes of the nasal cavity occurred in both males. The changes were characterized as unspecified inflammation and suppurative inflammation. The former lesion, consisting of a mild submucosal influx of lymphocytes, macrophages, and a few granulocytes, occurred in males exposed at the low concentration. The latter lesion was more severe and contained macrophages that migrated through the epithelium and accumulated in the lumen, occurring in male and females exposed at the high concentration. The combined incidence of these nasal cavity lesions was higher in male rats exposed at both
concentrations and in female rats exposed at the high concentration than in controls. These changes may reflect local tissue responses to long-term inhalation exposure to propene.

HISTOPATHOLOGY: NEOPLASTIC: No evidence was found for a carcinogenic effect of propene in rats. C-cell adenomas and C-cell adenomas or carcinomas (combined) of the thyroid gland occurred in female rats with a negative trend, and the incidence of C-cell adenomas in the high concentration group was significantly lower than that in the controls. The incidences in the controls (13%-15%) were higher than those observed in unexposed chamber control F344/N female rats in a propene oxide inhalation study (NTP, 1985) and in untreated control F344/N female rats in other studies. The incidences of C-cell hyperplasia occurred with a positive trend. In rats, C-cell hyperplasia, C-cell adenoma, and C-cell carcinoma appear to represent a continuous spectrum of progressive lesions. When hyperplasia, adenoma, and carcinoma are combined, the negative trend disappears. These comparisons suggest that the lower incidence of thyroid gland neoplasms is not related to administration of propene.
Dose descriptor:
LOAEC
Effect level:
5 000 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: (8,600 mg/m3). No NOAEC identified for local effects. Mild rhinitis (nasal inflammation) and associated epithelial alterations without obvious dose response relationship - refer to expert report of Harkema (2002)
Critical effects observed:
not specified

Inflammation of the nasal cavity, characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and by granulocytes into the lumen, occurred at increased incidences in low concentration and high concentration male rats and in high concentration female rats.

Incidences of nasal inflammatory changes in rats in the two-year inhalation studies of propene

 

Control

5000 ppm

10000 ppm

Males

Inflammation, unspecified

4/60 (8%)

14/50 (28%)

5/60 (10%)

Inflammation, suppurative

7/60 (14%)

7/50 (14%)

14/60 (28%)

Inflammation, unspecified or suppurative

11/60 (22%)

21/50 (42%)

19/50 (38%)

Females

Inflammation, unspecified

0/49 (0%)  

2/60 (4%)

2/60 (4%)

Inflammation, suppurative

8/49 (16%)

7/60 (14%)

11/60 (22%)

Inflammation, unspecified or suppurative

8/49 (16%)

10/60 (20%)

13/60 (26%)

Conclusions:
A NOAEC was not achieved. The LOAEC was 5000 ppm (lowest dose tested) for males and females based on mild rhinitis (nasal inflammation) and associated epithelial alteration suggesting chronic, low-grade irritation in these rodents. There was no obvious dose response relationship for this effect.
Executive summary:

Toxicology and carcinogenesis studies of propene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats of each sex to propene in air by inhalation at concentrations of 5000 or 10000 ppm, 6 hours per day, 5 days per week, for 103 weeks. Other groups of 50 rats of each sex received air only on the same schedule and served as chamber controls. The highest concentration of propene that was considered safe for these studies was 10000 ppm because of the risk of explosion that can occur at higher concentrations.

A NOAEC was not reported. The LOAEC reported was 5000 ppm (lowest dose tested) for males and females based on mild rhinitis.

The survival of exposed and control rats was comparable. Throughout most of the studies, mean body weights of exposed male and female rats were slightly lower (0%-5%) than those of the controls, but the decrements were not concentration-related. No compound-related adverse clinical signs were observed. An increased incidence of squamous metaplasia of the nasal cavity was observed in female rats exposed at 5000 and 10000 ppm (control, 0/49; low, 15/50; high, 6/50) and in male rats exposed at 5000 ppm (2/50; 19/50; 7/50). Epithelial hyperplasia of the nasal cavity was increased in female rats exposed at the 10000 ppm concentration (0/49; 4/50; 9/50); the incidences in male rats were 2/50, 2/50, and 5/50. Inflammation of the nasal cavity, characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and by granulocytes into the lumen, occurred at increased incidences in low concentration and high concentration male rats and in high concentration female rats. In the nasal cavity, propene induced squamous metaplasia of the respiratory epithelium in male and female rats and epithelial hyperplasia in female rats.

The nasal findings reported in this study were further investigated by re-evaluation of the archived tissue specimens (Harkema, 2002).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
8 600 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
Adequate for assessment

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeat dose toxicity data are available for the main components of this category and Liquefied Petroleum Gas; also data are available on C1-C4 alkane mixtures.

 

Other Petroleum Gases are flammable at room temperature and therefore exposure via the dermal or oral routes is unlikely and the requirement to test is waived in accordance with REACH Annex XI.

 

Non-human studies

Methane CAS Number 74-82-8

No quantitative repeat dose toxicity data are available specifically for methane.

 

Ethane CAS Number 74-84-0

No systemic toxicity (i.e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity) were observed in a 6-week study to modern guidelines and GLP in which ethane was administered to rats by inhalation. The experimentally defined NOAEC is 16,000 ppm (19678 mg/m3), the highest exposure level tested and 50% of the lower explosive limit (HLS 2010).

 

Propane CAS Number 74-98-6

No neurological, haematological, or clinical chemistry effects were observed in a 6-week study to modern guidelines and GLP in which propane was administered to male and female rats by inhalation. There was no effect of treatment on survival and there were no exposure-related systemic effects or effects on body weight, except the 12000 ppm exposed male animals showed an exposure-related 25% decrease in weight gain during the first week of exposures and this difference persisted for the remainder of the 4 weeks of exposure. The lowest observed adverse effect concentration (LOAEC) in this study is 12,000 ppm (equivalent to 21641 mg/m3), the highest exposure level tested and 50% of the lower explosive limit, based on the reduced bodyweight gain in males. The NOAEC is 4,000 ppm or 7214 mg/m3(HLS 2009).

 

 

Isobutane CAS Number 75-28-5

No systemic toxicity (i.e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity) were observed in a 6-week study to modern guidelines and GLP in which isobutane was administered to rats by inhalation. The experimentally defined NOAEC is 9,000 ppm (21394 mg/m3), the highest exposure level tested and 50% of the lower explosive limit (HLS 2010).

A 90 day inhalation study on a 50:50 wt% mixture of isobutane:isopentane exposed male and female rats to nominal 1000 and 4500 ppm daily for 13 weeks, with an interim kill after 28 days. There were no deaths and transient clinical signs were considered treatment but were not dose related. There were no treatment related gross lesions or kidney/liver weight changes. The rats were not significantly affected by the exposures and there was no evidence of hydrocarbon-induced nephropathy in either sex at study termination. At the 28 -day interim kill mild, transient treatment-related kidney effects were observed in the male rats, statistically significant at 1000 ppm only, however there was no evidence of a dose response and the effect disappeared by 90 days. The NOAEC for this study was 4458 ppm, the highest dose tested (Aranyi 1986).

 

Butane CAS Number 106-97-8

No systemic toxicity (i.e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity) were observed in a 6-week study to modern guidelines and GLP in which butane was administered to rats by inhalation. The experimentally defined NOAEC is 9,000 ppm (21394 mg/m3), the highest exposure level tested and 50% of the lower explosive limit (HLS 2008).

A 90 day inhalation study on a 50:50 wt% mixture of n-butane:n-pentane exposed male and female rats to nominal 1000 and 4500 ppm daily for 13 weeks, with an interim kill after 28 days. There were no deaths and transient clinical signs were considered treatment but was not dose related. Statistically significant decreases in body weights of both sexes were observed by test weeks 3 and 4, with the males, but not the females, recovering towards the end of the exposure period. There were no treatment related gross lesions or kidney/liver weight changes. Rats were not significantly affected by the exposures and there was no evidence of hydrocarbon-induced nephropathy in either sex at study termination. At the 28-day interim kill mild, transient treatment-related but not exposure-related kidney effects were observed in the male rats, this effect disappeared by 90 days. The NOAEC for this study is 4489 ppm, the highest dose tested (Aranyi 1986).

 

In a mixture study, male rats were exposed by inhalation to concentrations up to 11.8 mg/L (11800 mg/m3 or 4437 ppm) of a mixture containing 25% (by weight) each of isobutane, n-butane, n-pentane, and isopentane for 6 hours per day, 5 days per week, for 3 weeks. There were no signs of systemic toxicity, no effects on bodyweight, organ weights, haematology or serum chemistry and no treatment-related gross or microscopic lesions. The NOAEC for systemic effects and kidney effects is 11.8 mg/L (11800 mg/m3 or 4437 ppm), the highest dose tested (Halder, 1986).

 

 

Propene CAS Number 115-07-1

Key information for the assessment of the repeat-dose toxicity of propene has been reported in several near-guideline sub-chronic and chronic studies via the inhalation route (NTP, 1985). Propene has been thoroughly tested for repeated exposure toxicity up to very high exposure concentrations (10,000 ppm (17,200mg/m3), half of its lower explosive limit value) in sub-chronic and chronic studies. Overall, only minimal local irritation effects to the nasal cavity were observed and only following chronic lifetime exposure to high doses in rats and mice. The mild classification of the lesion and lack of dose-response relationship is consistent with results of shorter term studies, where nasal effects have not been reported in any studies, including 28 day and 90 day NTP studies on propene.The LOAEC for mild rhinitis, only reported following lifetime exposure, is 5000 ppm (8600 mg/m³) in rats and mice. Although there was no clear dose-response relationship or NOAEL for this effect, the weight of evidence clearly indicates that any irritant properties of propene must be extremely weak.

 

 

Liquefied Petroleum Gases

The major constituents are identified as propane and propene (93.5%).

 

The repeated-dose inhalation toxicity of petroleum gas products in laboratory animals was investigated in a 90 day study to modern guidelines and GLP. Groups of rats were exposed to target concentrations of 0; 1,000; 5,000; or 10,000 ppm liquefied petroleum gas (LPG) for 13 weeks (HLS, 2008). The highest exposure concentration was approximated 50% of the lower explosive limit. There was no treatment-related effect on survival, terminal body weight, food consumption, functional observational battery, motor activity parameters, haematological parameters, clinical chemistry values, macroscopic or microscopic evaluations, or on organ weights at any exposure concentration. A no observed adverse effect concentration (NOAEC) of 10,000 ppm is reported for the repeated-dose toxicity of the LPG tested.

 

 

Human studies

Little quantitative data on Other Petroleum Gases were identified.

In a controlled exposure study, Stewart et al (1977, 1978) exposed adult volunteers to isobutane at 500 ppm (1189 mg/m3) 1, 2 or 8 hours/day, five days/week for 2 weeks. During the investigation, all volunteers were kept under comprehensive medical surveillance which included cardiac and pulmonary responses. Repetitive exposures to isobutane were without any measurable untoward physiological effect.

 

Summary

Simple short chain alkanes (i.e methane, ethane, propane, butane, isobutane) can be considered in a similar manner, inhalation exposure is the most relevant route, and current GLP-compliant guideline study data are available for ethane, propane, butane and isobutane which demonstrate low repeat dose toxicity (up to six weeks in duration). These data are supported by studies up to 90 days in duration on C4-C5 mixtures and a 90 day study on liquefied petroleum gas (LPG, main constituent propane and propene), which gave a no observed adverse effect level (NOAEC) of 10,000 ppm, the maximum dose level tested. A consideration of the data available for the alkene, propene, similarly supports a conclusion of low sub-chronic toxicity.

 

The mammalian toxicity effects of this category will be not driven by the content of benzene as the latter is present at levels of <1%.However, Petroleum Gas streams may contain carbon monoxide, levels of which could trigger classification.

 

Carbon Monoxide CAS number 630-08-0

(Classification: CLP - STOT-RE Category 1, H372)

The World Health Organisation published an extensive review of carbon monoxide in 1999 (WHO, 1999, updated 2004). In the human body, the gas reacts readily with haemoglobin to form carboxyhaemoglobin (COHb). Its toxic effects on humans are due to hypoxia, which becomes evident in organs and tissues with high oxygen consumption such as the brain, the heart, exercising skeletal muscle (and the developing foetus).Chronic exposure to low concentrations of carbon monoxide may lead to cardiovascular effects, tiredness, lethargy, headaches, nausea, dizziness, personality changes, memory problems, as well as impairment of visual, auditory or cognitive function.

 

Reference

World Health Organisation, 1999

Environmental Health Criteria 213 (Carbon Monoxide, second edition)

1999, updated 2004

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
These streams are gases at room temperature, hence repeated dose toxicity testing via the oral route is not technically feasible.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Information available for the short chain alkanes ethane, propane, propene, butane and isobutene, supported by results obtained when testing C4-C5 mixtures and liquefied petroleum gas (main constituent propane and propene), are consistent with a NOAEC of up to 10,000 ppm.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Mild rhinitis (nasal inflammation) and associated epithelial alteration suggesting chronic, low-grade irritation in these rodents was observed following chronic exposure to 5000 (8600 mg/m3) and 10000 ppm (17200 mg/m3) propene.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
These streams are gases at room temperature, hence repeated dose toxicity testing via the dermal route is not technically feasible.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
These streams are flammable gases at room temperature, hence repeated dose toxicity testing via the dermal route is not technically feasible.

Justification for classification or non-classification

Members of the Other Petroleum Gases category are flammable gases at room temperature and therefore dermal and oral exposure is unlikely.

There is sufficient repeat-dose information on the component alkanes and alkene to indicate they have low sub-acute, sub-chronic and chronic inhalation toxicity and therefore do not warrant classification.

Levels of benzene and carbon monoxide in excess of 1% will trigger classification under CLP.