Gases (petroleum), catalytic-cracked gas oil depropanizer bottoms, C4-rich acid-free

Repeated dose toxicity: inhalation

Administrative data

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

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1985

Reference 2

Reference Type:

publication

Title:

Two-year inhalation toxicity study of propylene in F344/N rats and B6C3F1 mice.

Author:

Quest J, Tomaszewski J, Haseman J, Boorman G, Douglas J and Clarke W

Year:

1984

Bibliographic source:

Toxicol Appl Pharmacol 76, 288-295.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propene

EC Number:

204-062-1

EC Name:

Propene

Cas Number:

115-07-1

Molecular formula:

C3H6

IUPAC Name:

prop-1-ene

Constituent 2

Reference substance name:

propylene

IUPAC Name:

propylene

Constituent 3

Reference substance name:

1-propene

IUPAC Name:

1-propene

Details on test material:

Purity 98.8-99.7%

Test animals

Species:

mouse

Strain:

B6C3F1

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 28-29 g; mean bw per group for females 22-23 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); ad libitum 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 59 ± 8 %)
- Air changes: 20/hour
- Photoperiod: 12 hrs dark /12 hrs light

IN-LIFE DATES: From: 29 October 1979 To: 30 October 1981

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 5000, 10000 ppm
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 4999±285, 9957±533 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 in the 2-year study. Concentrations higher than 10000 ppm propene could not be selected because of the risk of explosion.

Examinations

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 examination 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), gall bladder, 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.

Results and discussion

Results of examinations

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: After week 59, mean body weights of high concentration male mice were approximately 5% lower than those of the controls. Throughout the study, mean body weights of low concentration and control male mice and of exposed and control female mice were comparable.

HISTOPATHOLOGY - NON-NEOPLASTIC: Chronic focal inflammation of the kidneys occurred at increased incidences in male and female mice exposed at both concentrations and appeared to be related to propene exposure. The biological relationship of the renal effect to propene exposure is unknown.

HISTOPATHOLOGY - NEOPLASTIC: Haemangiosarcomas were found in one low dose male mouse (liver), two high dose male mice (spleen), and three high dose female mice (subcutis. spleen, and uterus). Haemangiomas were found in one low dose and in one high dose female mouse (liver). Vascular tumours were not found in control mice of either sex. The low incidences of vascular tumours and their occurrence in a variety of organs suggest
that they are not related to administration of propene.

The occurrence of uterine endometrial stromal polyps in female mice showed a positive trend (P≥0.05; 0/47; 0/47; 3/48); the incidence in the 10,000 ppm group was not significantly greater than that in the concurrent control group, but the incidence was higher than the mean historical control
rate (22/2411, 0.9%) and was within the range (0%-6%) observed in studies throughout the Carcinogenesis Program. The occurrence of endometrial stromal polyps in three high concentration female mice was not considered to be clearly related to exposure to propene.

The incidence of male mice with alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a negative trend (P<0.05; 16/50; 4/49; 7/50), and the reduced incidences in both exposed groups were less than (P<0.05) that in the control group. The control incidence of these tumours in an inhalation study conducted concurrently at the same laboratory was similar (15/50), suggesting a possible exposure-related decrease. The biologic significance of this decrease in male mice is difficult to assess; the incidences seen in these control and exposed animals are within the range of incidences (2%-34%; mean, 16.7%) observed in control male mice in other studies throughout the Carcinogenesis Program.

Effect levels

Dose descriptor:

LOAEC

Effect level:

5 000 ppm

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Chronic focal inflammation of the kidneys was reported at an increased incidence in low concentration and high concentration mice of each sex. Refer to subsequent expert evaluation. Hard G (2001). Expert Report on Renal Histopathological Changes in Mouse and Rat Inhalation Studies with Propene.

Executive summary:

Toxicology and carcinogenesis studies of propene (greater than 99% pure) were conducted by exposing groups of 50 B6C3F1 mice 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 mice of each sex received air only on the same schedule and served as chamber controls. The highest concentration of propene that was considered safe was 10000 ppm because of the risk of explosion that can occur at higher concentrations

The survival of exposed and control mice was comparable. After week 59 of the study, mean body weights of 10000 ppm male mice were usually slightly lower (5%) than those of the controls, whereas those in other exposed groups of male and female mice were generally comparable with those of the controls. No compound-related adverse clinical signs were observed.

A NOAEC was not reported. Chronic focal inflammation of the kidneys was reported with an increased incidence in low concentration and high concentration mice of each sex however subsequent expert re-evaluation was reported by Hard, G (2001) and concluded that kidney effects were not treatment-related.