Methyloxirane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP non-guideline study performed according to scientific standards, published in peer reviewed literature, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

Uptake of Inspired Propylene Oxide in the Upper Respiratory Tract of the F344 Rat

Author:

John B. Morris, Marcy I. Banton, and Lynn H. Pottenger

Year:

2004

Bibliographic source:

Toxicological sciences 81, 216–224

Materials and methods

Objective of study:

other: uptake in the upper respiratory tract

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

The precise methodology for exposure and measurement of URT uptake efficiency has been described in detail (Morris, 1999, a method for measuring upper respiratory tract vapor uptake and its applicability to quantitative inhalation risk assessment).

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyloxirane

EC Number:

200-879-2

EC Name:

Methyloxirane

Cas Number:

75-56-9

Molecular formula:

C3H6O

IUPAC Name:

2-methyloxirane

Details on test material:

Propylene oxide (reagent grade, 98%) was obtained from Fisher Scientific (Pittsburgh,PA).

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Male F344 rats (Charles River, Wilmington, MA, VAF/Plus Crl:CDBR, 125–150 g at time of purchase) were used in all experiments. Animals were housed over hard wood bedding in animal rooms maintained at 22–25 degreesC with a 12 h light-dark cycle.
Food (Lab Diet, PMI Nutrition International, Brentwood, MO) and tap water were provided ad libitum. Animals were acclimated one week
prior to use and were used within four weeks of arrival. Body weights averaged 200 g at the time of uptake measurement.

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

Rats were exposed in a 0.5-l PVC nose-only exposure chamber. Chamber air flow rates were maintained at 5–10 l/min (depending on
the exposure concentration) with clean, heated, and humidified air. Chamber air temperature averaged approximately 40°C, water content approximately 33 mg/l, corresponding to greater than 75% relative humidity at 37°C. The chamber walls and air supply lines were heated to prevent condensation.
Propylene oxide atmospheres were generated by feeding the liquid via a syringe pump into a glass T tube maintained at approximately 60°C through
which 0.8 l/min of air was passed. The vapor-rich air was then passed through a mixing chamber and into the nose-only exposure chamber. Propylene oxide (reagent grade, 98%) was obtained from Fisher Scientific (Pittsburgh, PA). The exposure chamber and vapor generation apparatus were housed in a fume hood.

Duration and frequency of treatment / exposure:

Groups of six rats each were exposed to 300 ppm propylene oxide for 15, 30, 45, or 60 min at a flow rate of 200 ml/
min or 50 ml/min.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 50, 100 or 300 ppm (or 500 ppm)

No. of animals per sex per dose / concentration:

6

Control animals:

yes, concurrent no treatment

Details on study design:

Respiratory mucosal NPSH content was measured in rats exposed to 300 ppm propylene oxide for 15, 30, 45, or 60 min at a flow rate of 200 ml/min.

Respiratory mucosal NPSH content was also measured in rats exposed for 60 min (at a flow rate of 200 ml/min) to 0, 50, 100, 300, or 500 ppm propylene oxide.

Propylene oxide uptake efficiency during isolated URT exposure was measured in rats exposed to 0, 25, 50, 100 or 300 ppm at flow rate of 50 or 200 ml/min.

Details on dosing and sampling:

Groups of six rats each were exposed to 300 ppm propylene oxide for 15, 30, 45, or 60 min at a flow rate of 200 ml/min or 50 ml/min.
Measured propylene oxide concentration averaged 313 (+-17) ppm (mean +- SD). For controls, groups of three rats each were exposed to clean air for 15, 30, 45, or 60 min.

Statistics:

Data are reported as mean 6 SEM unless otherwise indicated. Each group contained 6–8 animals, unless otherwise stated. NPSH
data were log transformed due to heteroscedasticity. Data were compared by ANOVA followed by Newman-Keuls test. A p < 0.05 was required for
significance.

Results and discussion

Main ADME results

Main ADME results 1

Type:

other:

Results:

Uptake averaged approximately 25% efficient at the 50 ml/min flow rate compared to approximately 11% efficient at the 200 ml/min flow rate, regardless of the exposure concentration.

Main ADME results 2

Type:

other:

Results:

After 1 h exposure at concentrations of 50, 100, 300, or 500 ppm nasal NPSH levels averaged approximately 75, 45, 35, and 15% of control levels

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Uptake averaged approximately 25% efficient at the 50 ml/min flow rate compared to approximately 11% efficient at the 200 ml/min flow
rate, regardless of the exposure concentration.
The total delivered dose rate for propylene oxide can be calculated as the product of the inspired concentration, inspiratory flow rate,
and uptake efficiency. Such calculation results in the following oxide at flow rates of 50 and 200 ml/min, respectively: 10, 20, 50,
and 130 nmol/min (50 ml/min flow rate) and 25, 45, 90, and 290 nmol/min (flow rate of 200 ml/min).

Metabolite characterisation studies

Metabolites identified:

no