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Carcinogenicity

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Description of key information

No specific carcinogenicity data are available on any of the streams identified for this category or the C1-C4 alkanes. However there are substantial data on one of the main components, propene. There is no evidence of carcinogenicity of propene following evaluation in rats and mice. Benzene and 1,3–butadiene have been identified as potential specific components present in some streams and these have been shown to be carcinogenic in animals and man. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
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
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
Remarks:
predates implementation of GLP
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
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.
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 AND COMPOUND INTAKE: 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), 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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
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:
NOAEC
Effect level:
10 000 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: (17,200 mg/m3), no evidence of carcinogenicity at 5000 or 10000 ppm
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Refer to expert report of Harkema (2002) for further evaluation of this endpoint.

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:
Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats.

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.

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.  

Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats and, therefore, the NOAEC for carcinogenicity for male and female F344/N rats is 10000 ppm.

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.

Subsequent re-evaluation of the archived tissue specimens of the nasal cavity from this study was conducted by Harkema (2002) and the results are discussed in this report.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
17 200 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
Adequate for assessment

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Members and main components of this category, including streams that contain <0.1% benzene and 1,3-butadiene, are considered not to be carcinogenic and no labelling is required CLP. However streams that contain ≥0.1% benzene or 1,3-butadiene are likely to be carcinogenic to animals and humans. Some streams are already listed in Annex VI of CLP and are classified Carc 1B:H350 (May cause cancer) (see Section 3). It is proposed that all remaining streams that contain ≥0.1% benzene or 1,3-butadiene are classified Cat1A: H350 (May cause cancer).

Additional information

There are no specific carcinogenicity data are available on any of the streams identified and also no carcinogenicity studies for any of the C1-C4 alkanes in the Other Petroleum Gases category. However, a consideration of their simple chemical structures, which have no reactive groups and carry no alerts for likely genotoxic carcinogenic activity from established Structure Activity Relationship analysis (Tennant RW and Ashby J (1991). Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 39 chemicals by the US National Toxicology Program.  Mutat Res 257 (3) 209-227), together with the conclusion that C1-C4 alkanes are not genotoxic, provide a strong case for concluding that none will show any significant carcinogenic activity. 

There are data for main component propene:

Propene CAS No: 115-07-1

There was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F1 mice exposed to propene by inhalation at concentrations of 5000 or 10000 ppm (8,600 or 17,200 mg/m3), for 103 weeks (NTP, 1985), or in the supporting study in male and female Swiss mice at concentrations up to 5000 ppm (8,600 mg/m3), following exposure for 78 weeks, or in male and female Sprague-Dawley rats at concentrations up to 5000 ppm (8,600 mg/m3), following exposure for 104 weeks (Ciliberti et al, 1988).

 

Summary:

No specific carcinogenicity data are available on any of the streams identified for this category or the C1-C4 alkanes. However there are data on one of the main components, propene, to indicate that members of this category have low potential for carcinogenicity. Propene, like the C1-C4 alkanes, is also considered to be non-genotoxic both in vitro and in vivo, and furthermore, has carcinogenicity data in animals that provides evidence of non-carcinogenicity.

Taking all these data into account, together with the general lack of toxicity across other endpoints, it is considered that there is no justification for conducting further animal carcinogenicity studies. The above reasoning leads to the conclusion that Other Petroleum Gases category can be considered to have low concern for human carcinogenicity.

However, benzene and 1,3–butadiene have been identified as potential specific components present in some streams and these have been shown to be carcinogenic in animals and man:

Benzene

(Classification: CLP - Category 1A, H350): Long term experimental carcinogenicity bioassays have shown that benzene is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia). Human epidemiological studies indicate a causal relationship between benzene exposure and acute non-lymphatic leukaemia (Crump, 1994; Glass et al, 2003, 2004, 2006; Rinsky et al, 2002; Schnatter, 2004).

1,3-Butadiene

(Classification: CLP - Category 1A, H350): In experimental animals, there is a marked species difference in carcinogenicity (EU RAR 2002). In the mouse, 1,3-butadiene is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours (NTP 1993). In the rat, fewer tumour types, mostly benign, develop at exposure concentrations of 100 to1000-times higher (Owen et al 1987). In humans a positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia) (Sathiakumar et al 2005, Graff et al 2005, Delzell et al 2006, Cheng et al 2007, Sielken et al 2006, 2007 & 2008).

 

Category streams are considered to be carcinogens if they contain ≥0.1% benzene or 1,3-butadiene.

Additional Reference:

EU RAR (2002). European Union Risk Assessment Report for 1,3-butadiene. Vol. 20. European Chemicals Bureau (http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019. pdf)


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

Justification for selection of carcinogenicity via inhalation route endpoint:
There was no evidence of carcinogenicity in male and female rats or mice exposed to propene by inhalation at concentrations of 8,600 or 17,200 mg/m3 for 103 weeks, or in a supporting studies in mice (up to 8,600 mg/m3, 78 weeks) or rats (up to 8,600 mg/m3, 104 weeks). However streams containing >0.1 % butadiene or benzene should be considered potentially carcinogenic.

Justification for selection of carcinogenicity via dermal route endpoint:
These streams are gases at room temperature, hence carcinogenicity toxicity testing via the oral route is not technically feasible.