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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
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, non-guideline animal and human experimental study published in peer reviewed literature, minor restrictions in design but otherwise acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2008

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Species-specific propene oxide concentrations in blood resulting from propene exposure were measured in rats mice and human
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Propene, purity ≥99.95%, ex Messer Griesheim (Krefeld, Germany)
Propene oxide, purity 99.995%, ex Arco Chemie (Rotterdam, The Netherlands)
Radiolabelling:
no

Test animals

Species:
other: rat and human
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River WIGA, Sulzfeld, Germany
- Weight: 264.5 ± 32.5 g
- Housing: Up to at least 4 days before use, rats were housed (two per cage) in a macrolon type III cage placed in an individually ventilated cage top-flow system
- Diet: Standard pellet chow #1324 (Altromin, Lage, Germany) ad libitum.
- Water; Tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature: 22-24°C
- Humidity: 55-65%
- Air changes (per hr): not reported
- Photoperiod: 12 hrs dark /12 hrs light

HUMAN VOLUNTEERS
Four male, healthy, and non-smoking volunteers participated in the propene exposure study. Ages and bw were 55 years, 94 kg; 44 years, 58 kg; 33 years, 76 kg; 39 years, 79 kg.

Administration / exposure

Route of administration:
inhalation
Vehicle:
other: air
Details on exposure:
Closed chamber uptake system for rats. Exposure to humans via 2-way mask.

Duration and frequency of treatment / exposure:
Rats: Single exposure for at least 7h
Human: Multiple exposures of 3h at each concentration
Doses / concentrations
Remarks:
Doses / Concentrations:
Rats: 20-3000 ppm propene (34-5,200 mg/m3)
Human: approximately 10 and 23 ppm (17 and 40 mg/m3) propene
No. of animals per sex per dose:
Rats: 2
Human: 4
Control animals:
no
Details on dosing and sampling:
Rats: Propene concentrations were maintained constant (coefficient of variation less than 3% of the desired atmospheric concentration) by repeatedly re-injecting defined amounts of propene gas into the chamber atmosphere in order to replenish the losses resulting from propene uptake and metabolism by the exposed animals. Propene and propene oxide were measured in the chamber atmosphere; propene by gas chromatography with flame ionization detection (GC/FID), propene oxide by GC/FID or GC with mass-selective detection (GC/MSD). Blood concentrations of propene oxide were calculated based on the measured propene oxide concentrations in air using the blood-to-air partition coefficient of 60.

Humans: Propene was measured in inhaled and exhaled air by GC/FID. Propene oxide was quantified by GC/MSD from exhaled breath collected in gasbags. Blood concentrations of propene oxide were calculated based on the measured concentrations in air using the blood-to-air partition coefficient of 66.

Respiratory parameters of each volunteer were established immediately after each exposure by determining average breathing frequency, tidal volume and pulmonary ventilation, over a time span of 10 min, using a spirometer.
Statistics:
The rate of propene metabolism (µmol/h) was calculated for each volunteer using his pulmonary ventilation, the difference between the propene mean concentrations in inhaled and exhaled air, and the molar volume of an ideal gas (25 L) at 23°C and 740 Torr.
Rate of propene metabolism (µmol/h) = pulmonary ventilation (L/min) x 60 (min/h) x difference between mean inhaled and exhaled propene concentrations (ppb)/25 (L/mol). In order to calculate as a percentage the fraction of inhaled propene. which was metabolized at steady state, the difference of the mean inhaled and exhaled propene concentrations was multiplied by 100 and then divided by the mean concentration of propene in inhaled air.

Regression lines, means ± SD of measured data and comparison of means by the unpaired two tailed t-test were calculated using Prism 4 for Macintosh. Time weighed means and corresponding SD were calculated using Microsoft Excel 2004 for Macintosh.

Results and discussion

Preliminary studies:
The elimination rate of atmospheric propene oxide due to hydrolysis by soda lime was determined to be <5% of the total rate observed in the rat study.
Main ADME resultsopen allclose all
Type:
absorption
Results:
rats and humans exposed to similar concentrations of propene had similar steady state blood levels of propene, however propene oxide levels in blood were approximately 60x lower in humans than in rats
Type:
excretion
Results:
absorbed propene is eliminated by metabolism and exhalation of unchanged propene. Exposure of rats to propene concentrations of 1000 or 3000 ppm resulted in almost identical concentrations of exhaled propene oxide of 600 and 620 ppb, respectively

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Rats and humans exposed by inhalation to similar atmospheric concentrations of propene had similar steady state blood concentrations of propene. In rats the propene oxide concentration in blood was 53 nmol/L at an exposure concentration of 20.1 ppm propene whereas in humans, mean concentrations of propene oxide in blood were 0.44 and 0.92 nmol/L at mean exposure concentrations of 9.82 and 23.4 ppm propene, respectively. Propene oxide concentrations in blood were approximately 60x lower in humans than in rats exposed to similar concentrations of propene.
Details on excretion:
Absorbed propene is eliminated by metabolism and exhalation of unchanged propene. Following exposure of rats to propene concentrations of 1000 and 3000 ppm (1720 and 5160 mg/m3), concentrations of exhaled propene oxide in the atmosphere quickly reached maximum values of 830 and 900 ppb (2.0 and 2.1 mg/m3), respectively, followed by decreases after about 7h of exposure to almost identical plateau concentrations of 600 and 620 ppb (1.5 mg/m3), respectively.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Propene oxide

Any other information on results incl. tables

Table 1: Concentrations of propene in the inhaled and exhaled air of volunteers. The fraction of inhaled propene metabolised, metaboliic rates(propene) and concentrations of exhaled propene oxide, reflecting blood concentrations of propene oxide.

(Table based on Filser et al, 2008 Toxicological Sciences 102(2), 219-231, Table 3)

Volunteer identity

Concentrations measured experimentally

Information subsequently derived by calaculation

 

conc. propene in inhaled air mean±S.D. (n)(ppm)

conc. propene in exhaled air mean±S.D. (n)(ppm)

conc. propene oxide in exhaled air mean±S.D. (n)(ppb)

Proportion of inhaled propene metabolised (%)

Rate of metabolism of propene mean (µmol/h)

conc. propene oxide in blood mean (nmol/L)

A

10.5±0.97 (23) 23.5±0.69 (18)

9.76±0.4 (6) 21.8±0.89* (6)

0.13±0.01 (6) 0.20±0.03 (6)

7.0

7.2

8.57

19.7

0.51

0.80

B

9.51±0.33 (25) 23.7±1.4 (17)

8.38±0.17* (6) 21.4±1.4* (6)

0.083±0.03 (6) 0.20±0.03 (6)

11.9

9.7

18.7

38.1

0.33

0.80

C

9.83±0.61 (19) 22.8±1.3 (23)

9.09±0.70* (6) 21.3±1.3* (6)

0.15±0.03 (6) 0.30±0.06 (6)

7.5

6.6

10.8

22.0

0.59

1.19

D

9.40±0.68 (19) 23.8±1.9 (16)

8.54±1.2 (4) 21.7±0.95* (6)

0.086±0.02 (6) 0.23±0.03 (6)

9.1

8.8

13.7

33.4

0.35

0.90

Note.

* Statistically significant difference between propene concentrations in inhaled and exhaled air (two sided t-test, p<0.05).

a Mean and standard deviation calculated from the area under the concentration–time curve obtained in single exposure experiments (concentrations at time point zero not considered for exhaled propene and propene oxide).

b Values calculated from the means listed in ‘‘Measured data’’.

Number of data points given by ‘‘n’’.

Table 2: Average exposure concentrations of propene and metabolised fractions of inhaled propene, rates of metabolism of propene, and concentrations of propene oxide in blood, calculated for an average volunteer

(Table based on Filser et al, 2008 Toxicological Sciences 102(2), 219-231, Table 4)

Propene concentration in inhaled air

(ppm)

Fraction of inhaled propene metabolised b (%)

Rate of propene metabolism

(µmol/h)

Propene oxide in blood

(nmol/L)

9.82±0.80

8.90±2.2

12.9±4.4

0.44±0.13

23.4±1.40

8.08±1.4

28.3±8.9

0.92±0.19

a Calculated as weighted mean±SD of the propene concentrations in the air inhaled by the individual volunteers.

b Calculated as mean±SD of the individual values, valid for an average male volunteer (mean±SD; n=4) of 76.8±14.8 kg.

Table 3: Closed chamber exposure concentrations of propene, concentrations of the proximate metabolite (propene oxide) in the chamber and blood of exposed animals.

(Table based on Filser et al, 2008 Toxicological Sciences 102(2), 219-231, Table 2)

Air concentration of propene within the chamber (ppm)

Air concentration of propene oxide within the chamber at plateau (ppb)

Concentration of propene oxide in blood (nmol/L)

20.1± 0.4

21.1± 1.8

53

63± 2

44± 4

105

101± 2

92± 12

220

251± 6

230± 23

546

378± 4

320± 13

774

495± 13

490± 24

1160

1010± 14

610± 35

1650

3000± 36

650± 56

1750

Applicant's summary and conclusion