Propene

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

other: combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

supporting 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

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

Principles of method if other than guideline:

Method: other: NTP - 2 year Inhalation Study

GLP compliance:

not specified

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

Details on test material:

purity 98.6-99.7%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

- 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 (during exposure 78 ± 2°F)
- 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

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: air

Details on 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.

Details on mating procedure:

not applicable

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:

Exposure period: 103 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

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

Doses / concentrations 2

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.

Examinations

Parental animals: Observations and examinations:

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: Once per week for 14 weeks, once per month for 76 weeks and then biweekly thereafter.

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

Postmortem examinations (parental animals):

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), 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: P0 (first parental generation)

Effect levels (P0)

Key result

Dose descriptor:

NOAEC

Effect level:

10 000 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: (17,200 mg/m3) prostate/testes and ovaries/uterus

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

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.

 

Histopathological lesions in the reproductive system 

		exposure concentration (ppm)
		males			females
		0	5000	10000	0	5000	10000
Prepuce	inflammation suppurative	1
	abscess	1
	hyperplasia epithelial	1
Preputial gland	carcinoma		1	2
	inflammation suppurative	1	1
Prostate	inflammation	3	1
	inflammation suppurative	13	9	2
	hyperplasia	2	1	1
	hyperplasia focal	4	5	2
Testis	interstitial cell tumour	37	36	33
	mineralisation	21	14	21
	hyperplasia interstitial cells	6	9	6
	hyperplasia mesothelial			1
	atrophy	38	38	38
Epididymis	granuloma spermatic		1	2
Mammary gland	adenoma					1
	adenocarcinoma	1				1
	fibroadenoma		1		9	11	6
	galactocele	2			3	3	7
	hyperplasia				28	30	25
	hyperplasia	18	26	27
Seminal vesicle	inflammation suppurative	6	15	12
Vagina	endometrial stromal sarcoma					1
Clitoral gland	carcinoma					2
Uterus	leiomyosarcoma						1
	endometrial stromal polyp				3	4	4
	endometrial stromal sarcoma				2		2
	dilation						1
	inflammation suppurative					1	3
Uterus / Endometrium	hyperplasia cystic				6	3	4
	hyperplasia					6	4
	cysts				4	5	3
Cervix	inflammation suppurative	2
Ovary	cysts				4	5	3
	inflammation acute/chronic				1
	atrophy				12	7	9

 

Applicant's summary and conclusion

Conclusions:

Reproductive organs from rats exposed to propene at concentrations of up to 10000 ppm for 2 years were evaluated histopathologically and there were no changes considered to be related to propene exposure.