2,3-epoxypropyl phenyl ether

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

repeated dose toxicity: inhalation

Remarks:

other: Acute, subacute and sub chronic exposure studies were performed

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Although this study was not conducted in accordance with current international guidelines or GLP, in accordance with REACH Annex XI, Section 1.1.2, the study was conducted under the same scientific principles of the repeated dose toxicity: inhalation test and adequate documentation of the study is provided. The study is therefore considered adequate for fulfilling this endpoint and for risk assessment purposes.

Data source

Reference

Reference Type:

publication

Title:

The inhalation toxicity of phenylglycidyl ether. I. 90-day inhalation study

Author:

James B Terrill

Year:

1977

Bibliographic source:

Terrill, J.B. and Lee, K.P. (1977) The inhalation toxicity of phenylglycidyl ether. I. 90-day inhalation study. Toxicology and Applied Pharmacology, 42:263-269.

Materials and methods

Principles of method if other than guideline:

This study was conducted in 1977, before OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study) was adopted in 1981. Although this study was not conducted in accordance with OECD 413, the methods and analyses used can be considered as being equivalent to OECD 413 as described herein.

GLP compliance:

no

Limit test:

no

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:

PGE purity was 99.6 % with trace amounts of phenol and diglycidyl ether as determined by gas chromatography.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Sprague-Dawley (ChR-CD, Charles River Breeding Labs) rats were given 1 week of acclimatisation prior to testing. At the start of the test, body weights were 250-260 g for males and 180-200 g for females. Food and water were given ad libitum, except during exposure.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

The test atmosphere was generated by syringe-driving unheated liquid into a tube furnace. The furnace tube (2 in. i.d. x 24 in. length, stainless steel) was constructed in such a way that the wall temperature of the delivery tube and the pure nitrogen stream (10 L/min) were the same temperature, 310 degrees celsius. The nitrogen-PGE atmosphere was delivered directly to the exposure chamber.
2-week inhalation studies were carried out in a 20 litre glass chamber. Chamber temperature was maintained below 32 degrees celsius by cooling with ice packs and by dilution of concentrated PGE vapours with a room temperature oxygen/air mixture.
Subchronic exposures were run in 5 cubic metre chambers. Satisfactory chamber temperature (< 32 degrees celsius) and oxygen levels were maintained by the 2000 L/min inlet air velocity.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber atmospheres were monitored for PGE and phenol by UV analysis of impinger samples. Typically a 1 L/min sample was drawn through 15 ml of 0.1 N NaOH in 50:50 ethanol:water for 10 minutes. At 5 ppm (v/v), this solution has an absorbance of 0.4 (1 cm cell) at lambda max of 270nm. Phenol has a lambda max at 288 nm and can be detected at 5 % or greater of the PGE concentration (minimum sensitivity: 1 ppm of PGE, phenol >/= 0.05 ppm; 5 ppm, phenol >/= 0.25 ppm; 12 ppm, phenol >/= 0.6 ppm) using the analytical procedure.
Samples were taken hourly and the final concentrations were calculated on a time-weighted-average (TWA) basis (+/- σ).
Phenol, the major degradation product of heated PGE, was not detected at the limit of analytical sensitivity (5 % of the PGE concentration).

Duration of treatment / exposure:

2 week study: 4 hours per day
90 day study: 6 hours per day

Frequency of treatment:

2 week study: 5 days per week (10 exposures)
90 day study: 5 days per week (63 exposures)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
29 ppm (v/v) - 2 week study
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1.3 ± 0.5 ppm (v/v) - 90 day study
Basis:
analytical conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
5.0 ± 1.3 ppm (v/v) - 90 day study
Basis:
analytical conc.

Doses / concentrations 4

Remarks:

Doses / Concentrations:
11.8 ± 2.8 ppm - 90 day study
Basis:
analytical conc.

No. of animals per sex per dose:

2-week study: 6 male rats per dose level.
90 day study: 32 rats per sex per dose level.

Control animals:

yes

Details on study design:

The highest dose level in the 90-day study was chosen on the basis of: first, a calculated saturated vapour concentration of 13 ppm, using the value of 0.01 mm Hg at 25 degrees celsius; and second, treatment-related effects in the preceding 2-week study at 29 ppm.

Examinations

Observations and examinations performed and frequency:

2 week study:
All rats were weighed and physically examined daily.

90 day study:
Physical inspection of all animals was conducted daily and body weights were measured twice a week. On days 30, 60 and 90 of exposure and at 30, 60, and 90 days post exposure, blood and urine samples (from 10 rats per sex per dose level) were taken for examination and analyses.
Hematologic and clinical chemical indices were determined from blood collections by the following procedures: serum glutamic pyruvic transaminase (SGPT), bilirubin, alkaline phosphatase, glucose and RBC, WBC, PCV, and Hb - conventional methods.
Urine collections from rats were analysed by lab-Stir and other conventional methods for osmolality, volume, colour, appearance of sediment, sugar, protein, blood, and urobilinogen.

Sacrifice and pathology:

2 week study:
At the end of the test half of the rats from each group were sacrificed for histopathologic evaluation. After a 2 week postexposure period, the remaining rats were sacrificed and examined histopathologically.

90 day study:
Rats were sacrificed at 30, 60 and 90 days of exposure and at 28-days postexposure for histopathologic evaluation.
All major tissues and organs were examined both grossly and microscopically. The brain, heart, lungs, liver, kidneys, spleen, pituitary gland, thyroid, adrenals, and testes (ovaries for females) were weighed, and the ratio of organ to body weight was calculated. The lung and trachea were inflated with 10 % formalin. Sections of heart*, aorta, spleen*, bone marrow, lymph node, lung*, thorax*, liver*, stomach*, duodenum, jejunum, ilium, cecum, colon, rectum, pancreas*, kidney*, urinary bladder, salivary gland, thyroid*, adrenal gland*, pituitary gland*, thymus*, testis*, epididymis, prostate (or ovary, uterus, mammary gland) brain*, spinal chord, eye, sciatic nerve, muscle* and skin* were fixed in Bouin's solution and stained with hematoxylin eosin for subsequent microscopic examination.
* - These sections were also examined in the 2 week study.

Statistics:

Results of blood and urine examinations were analysed by split-unit analysis of variance and least significant difference test. Significance was assessed at the 0.05 probability level.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Alopecia

Mortality:

mortality observed, treatment-related

Description (incidence):

Alopecia

Body weight and weight changes:

no effects observed

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:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

2 week study:
Depression in weight gain, atrophic changes in the kidney, liver, spleen, thymus and testes, depletion of hepatic glycogen, and chronic catarrhal tracheitis were observed.

90 day study:
Weight gains for treated and control rats were similar, all rats appeared to be unaffected by treatment during and after exposure, except for significant hair loss which occurred in both sexes at the 5 and 12 ppm treatment levels after about 45 days of exposure. At the end of the 90-day exposure period, 10 % of the males and 25 % of the females at the two highest dose levels exhibited areas of alopecia. The alopecia appeared bilateral and frequently developed on the dorsal anterior portion of the body, especially the head, neck, and shoulder region. Occasionally, hair loss was found posterior to the abdominal area and on the hind legs. The alopecia was frequently symmetrically distributed and sharply demarcated from the adjacent normal hair coat. On the other hand, weight gain and qualitative indices such as behaviour and sociability for all treated rats was not altered as compared to the control group. Whether or not the hair loss was reversible could not be assessed, for all the affected rats were sacrificed after the 90th exposure for histopathological examination.
Results of blood and urine examinations showed an occasional significant difference (p < 0.05) between treated and control animals. However, review of all test data indicated these variations were random and not due to treatment.
Histopathologically, all tissues and organs from all test animals showed no significant changes when compared to controls at any sacrifice interval, except for the skin/hair system of those rats in the 5 and 12 ppm treated groups which exhibited alopecia. In the bald areas, some hair follicles were damaged, while others were in growing phases. Also, these areas showed very slight acanthosis, parakeratosis, and inflammatory cellular infiltration of the dermis and hair follicles. The hair shaft was disintegrated due to cellular infiltration and necrosis of the hair follicles. Frequently, the upper portions of the hair shaft were destroyed or embedded in excessive keratin material forming epidermal pearls. Normal hair growth appeared disturbed by destruction of the hair follicles, inflammatory cell infiltration, and hyperkeratosis.

Effect levels

Dose descriptor:

NOAEC

Effect level:

>= 11.8 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The only effects observed in this study were local effects: respiratory irritation (29 ppm in 2 week exposure study) and patchy, bilateral hair loss, possibly as a result of dermal irritation (5 and 12 ppm in 90 day study).

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The estimated inhalatory NOAEC for rats exposed to vapours of PGE is 11.8 ppm.
However, local effects (respiratory irritation and alopecia) were observed at 1.3 and 5 ppm; these observations should also be considered in the derivation of DNELs for skin and respiratory irritation.