2,3-epoxypropyl phenyl ether

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study which meets basic scientific principles.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1986

Report date:

1986

Reference 2

Reference Type:

publication

Title:

Morphologic expression of glandular differentiation in the epidermoid nasal carcinomas induced by phenylglycidyl ether inhalation.

Author:

Lee KP, Schneider PW, Trochimowicz HJ

Year:

1983

Bibliographic source:

Am J Pathol 111(2): 140-8

Reference 3

Reference Type:

publication

Title:

Unnamed

Year:

1982

Report date:

1982

Reference 4

Reference Type:

publication

Title:

Unnamed

Year:

1979

Report date:

1979

Reference 5

Reference Type:

publication

Title:

Unnamed

Year:

1984

Report date:

1984

Reference 6

Reference Type:

publication

Title:

Unnamed

Year:

1979

Report date:

1979

Reference 7

Reference Type:

publication

Title:

Unnamed

Year:

1979

Reference 8

Reference Type:

publication

Title:

Unnamed

Reference 9

Reference Type:

publication

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

only 2 concentrations tested, animals were not treated during holidays

GLP compliance:

yes

Remarks:

no certificate

Test material

Test material information

Constituent 1

Reference substance name:

2,3-epoxypropyl phenyl ether

EC Number:

204-557-2

EC Name:

2,3-epoxypropyl phenyl ether

Cas Number:

122-60-1

Molecular formula:

C9H10O2

IUPAC Name:

2-(phenoxymethyl)oxirane

Details on test material:

- Name of test material (as cited in study report): Oxirane, (phenoxymethyl)-
- Physical state: colorless liquid
- Analytical purity: 99%
No further information.

Test animals

Species:

rat

Strain:

other: Chr:CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 4 weeks
- Weight at study initiation: 131 g (males), no data were given for female rats
- Housing: 3 animals/stainless steel, wire-mesh cages
- Diet (ad libitum): Purina Laboratory Chow Checker #5001
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4.6 m3 stainless steel and glass chambers, quadrangular in shape with pyramidal tops and bottoms were used for the first 23 months, then 3.5 m3 chambers similarly constructed; all chambers were operated in one-pass, flow-through mode with an air flow rate of approximately 1200 l/min.
- Method of holding animals in test chamber: whole body exposure
- Source and rate of air: approximately 1200 l/min
- Method of conditioning air: Chamber atmospheres were generated by heating liquid PGE in glass washing bottles mounted in silicone oil baths maintained at approximately 125%. Nitrogen gas was metered through the heated sample and the PGE-laden vapours delivered through heated Teflon tubing to the chamber air flow.
- Treatment of exhaust air: exhaust air from chambers were passed through a 1.0 normal NaOH solution for removal of the test substance

TEST ATMOSPHERE
- Brief description of analytical method used: Approximately 10 liter samples of chamber atmospheres were drawn through impingers which contained 0.1 normal NaOH in a 50:50 ethanol:water mixture. The trapped PGE was compared against standards, prepared by adding PGE to the-NaOH solution, with a Bausch and Lomb Nodel 710 spectrophotometer at 270 nm. Chamber atmospheres were measured at approximately 60-minute intervals during each 6-hour exposure with daily time-weighted average concentrations calculated from these data.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

6 hours/day, 5 days/week, excluding holidays

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 1, 12 ppm
Basis:
nominal conc.
corresponding to ca. 0.006 and 0.07 mg/l (calculated by Derelanko M, 2008)

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1.04 +/- 0.11, 11.8 +/- 0.78 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

100

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: The exposure concentrations for this study were based on results of an acute study (6 male rats exposed to 29 ppm of the test substance for 4 hours/day, 5 days/week for 2 weeks followed by a 2 week recovery period) and a subchronic study (32 male and 32 female rats were exposed to 1, 5 or 12 ppm of the test substance for 6 hours/day, 5 days/week for 90 days followed by a 90-day postexposure recovery period).

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on working days, once on holidays and weekends

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during each weighing

BODY WEIGHT: Yes
- Time schedule for examinations: twice monthly for the first 6 month, then once monthly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 12, 18 and 24 month after initiation of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data.
- Parameters checked: The hematological parameters measured at each interval consisted of erythrocyte and leukocyte counts; relative (percent of total leukocytes) numbers of neutrophils, lymphocytes, eosinophils, monocytes, and basophils; hemoglobin and hematocrit. Mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration indices were calculated from the erythrocytic data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 12, 18 and 24 month after initiation of the study
- Animals fasted: No data
- How many animals: No data
- Parameters checked: Clinical chemistry examinations consisted of measures of bilirubin, urea nitrogen, and total protein concentrations, and serum activities of alkaline phosphatase, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, gamma-glutamyl transpeptidase, and lactate dehydrogenase.

URINALYSIS: Yes
- Time schedule for collection of urine: 12, 18 and 24 month after initiation of the study
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: A 16-hour urine specimen was collected from each rat designated for clinical evaluation before the taking of blood samples. Urine samples were measured for volume, osmolality, and pH and analyzed for the presence of blood, sugar (glucose), urobilinogen, bilirubin, protein, and acetone. Urine color and appearance were recorded and the sediment from pooled group samples was examined microscopically.

Sacrifice and pathology:

GROSS PATHOLOGY and HISTOPATHOLOGY: Yes
The brain, heart, lungs, liver, spleen, kidneys, stomach, adrenal glands, pituitary, thymus, and testes were weighed and relative organ weights (organ weight to final body weight ratio expressed as percent body weight) were calculated. These organs were also weighed from all rats sacrificed in extremis although relative organ weights were not calculated. Along with these organs, the trachea, salivary glands, esophagus, duodenum, jejunum, ileum, colon, cecum, pancreas, bladder, thyroid, parathyroids, epididymides, prostate, seminal vesicles, ovaries, uterus, mammary gland, eyes, exorbital lacrimal gland, ears (external auditory canal with Zyinbal's gland), lymph nodes (tracheobronchial, cervical, and mesenteric), skeletal muscle (thigh), femur, femoral bone marrow, skin, spinal cord, sciatic nerve, nasal tissue (three coronal sections from the anterior and two coronal sections from the posterior nasal cavity), adipose tissue, and all gross lesions were examined microscopically from male and female rats in all exposure groups. These tissues were also examined from all rats that were sacrificed in extremis or found dead (tissue integrity permitting). The lungs, trachea, thyroid, parathyroids, pituitary, adrenal glands, testes, and kidneys were fixed in Bouin's solution while all other tissues were fixed in 10% formalin. The tissue sections were stained with hemotoxylin and eosin, alcian blue, or trichrome stains or by the periodic acid-Shiff (PAS) method.

Other examinations:

The epichlorohydrin content present in the test substance was determined.
As part of the analyses of purity, the American Public Health Association (APHA) color of the test substance was determined.

Statistics:

Body weights, organ weights (absolute and relative), and clinical laboratory data were analyzed by a one-way analysis of variance. When the test for difference among the test group means (F-test) was significant, pairwise comparisons were made between test and control groups. For body weights, body weight gains, and clinical laboratory data these comparisons were made with the least significant difference (LSD) test. For organ weights, the comparisons were made with both LSD and Dunnett's tests. Bartlett's test for homogeneity of variances and a test for linear trend were conducted on the organ weight data. The incidences of clinical observations and mortality were analyzed by Fisher's Exact test. Survival probabilities were estimated by the Kaplan-Meier procedure and differences in survival among groups were judged by the dose-response test of Tarone. Significance for the comparisons of means was judged at the p < 0.05 level.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

survival of male rats exposed to 12 ppm was significantly lower (6 %) than that of male control-group rats and exhibited an exposure-related decrease

Mortality:

mortality observed, treatment-related

Description (incidence):

survival of male rats exposed to 12 ppm was significantly lower (6 %) than that of male control-group rats and exhibited an exposure-related decrease

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

9% greater body weight gain in male rats exposed to 12 ppm compared to control male rats; since food intake was not monitored, biological significance is unclear

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:

effects observed, treatment-related

Description (incidence and severity):

total leukocyte counts tended to be slightly higher among 12 ppm exposed male rats than among control male rats throughout the study

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

dose-related nasal tumors were developed in the rats exposed to the test substance at 12 ppm

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

undifferentiated glandular cells of the nose appear to differentiate to neoplastic squamous cells

Details on results:

GROSS PATHOLOGY
A significantly greater incidence of nasal tumors, most of which were epidermoid carcinomas, was observed in rats exposed to 12 ppm of the test substance. These tumors, which developed in the anterior nasal cavity and frequently invaded the dorso-lateral bones, protruded outward from the nasal cavity causing extensive osteolysis. While one such tumor was detected in a control male rat, none occurred in rats exposed to 1.0 ppm. In addition, rhinitis and squamous metaplasia or dysplasia of the respiratory epithelium and subepithelial gland and in the anterior or nasal cavity occurred with significantly greater frequency in the 12 ppm rats after 24 months on study (see Table 1).

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

ca. 0.07 mg/L air (nominal)

Based on:

test mat.

Remarks:

corresponding to 12 ppm

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

2

Dose descriptor:

NOAEL

Effect level:

ca. 0.006 mg/L air (nominal)

Based on:

test mat.

Remarks:

corresponding to 1 ppm

Sex:

male/female

Basis for effect level:

other: no effects

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Any other information on results incl. tables

Table 1: Incidence of pathologic changes in the air passage and nasal tumors of rats (males and females) exposed to the test substance

	Exposure level (ppm)
	0	1	12
Rhinitis	39/176 (22%)	40/171 (23.3%)	136/174 (78.1%)
Squamous metaplasia, nasal epithelium	6/176 (3.4%)	8/171 (4.7%)	125/174 (72.0%)
Nasal tumor	1/176 (0.6%)	--	13/174 (7.5%)
Tracheitis	13/176 (7.3%)	13/171 (7.6%)	16/174 (9.2%)
Epithelial desquamation/regeneration, trachea	--	--	3/174 (1.7%)
Bronchitis, bronchopneumonia	2/176 (1.1%)	3/171 (1.8%)	7/174 (4.0%)

Epichlorohydrin was present in the test substance at levels of 25 ppm (in supply containers) and 2.5 ppm (in material that had been used to generate test atmospheres). However, the concentration of epichlorohydrin in the test atmospheres was considered to be very low. Whether the low levels of epichlorohydrin present in the test atmospheres contributed to the development of the nasal tumors observed in this study is, however, uncertain.

The APHA values obtained for PGE ranged from 5-500 for the study. APHA color values of 0-50 are considered "water white" in color whereas values of 500 or greater are considered to be "dark red". Thus, an increase in the APHA value for a liquid over time could be suggestive of the formation of a decomposition product.