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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Objective of study:
absorption
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Combined evaluation of gas uptake inhalation measurements, plethysmography and a blood sampling system (for analysis of each parent chemical and its alcohol or acid metabolites) developed to determine the respiratory bioavailability of a series of alcohols and acetate esters in rats.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): n-pentanol
- Analytical purity: 99%
- Lot/batch No.: PO 0123620 (from Aldrich)
- Other: the test substance was evaluated in parallel with pentyl acetate, ethyl acetate, propyl acetate, n-propanol, isopropyl acetate, n-butanol, isobutyl acetate, isobutanol, isobutyl isobutyrate, amyl acetate mixture, and amyl alcohol mixture
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: male SD rats with indwelling jugular cannulas from Hilltop Lab Animals, Inc. (Scottsdale, PA)
- Age at study initiation: no data
- Weight at study initiation: 270 - 350 g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): PMI 5002 Cetified Rodent Diet (Animal D
- Water (e.g. ad libitum): deionised water (reverse osmosis)
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: head only

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: closed, 8-l gas uptake exposure chambe. The tubular shaped plethysmograph chamber was modified to be positioned inside the gas uptake chamber so that respiratory parameters (tidal volume, respiratory rate, and minute volume) could be measured concurrent with the gas uptake studies. The gas uptake exposure chamber was retrofitted to accommodate the plethysomgraph and intravenous jugular cannula without changing the existing chamber lid by fabricating a 1" thick Plexiglas ring positioned between the desiccator-style chamber and the chamber lid. Both the pneumotachograph tube and cannula were passed through ports attached to this ring.
- Method of holding animals in test chamber: A restrained whole-body plethysmograph from Buxco Electronics, Inc. (Sharon, CT) was used for non-invasive ventitatory measurements on conscious animals. The animals were restrained in a constant-pressure plethysmograph with an attached pneumotachograph. A neck seal separated the head of the animal from the body chamber and ventilatory parameters were computed from flow measurements through the pneumotrachograph from the body chamber. Total length of time taht any given animal was restrained in the gas uptake chamber never exceeded 2.5 hours, in accordance with the Batelle ACC committee instructions
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating particulates/aerosols: each test material was added through a heated injection port
- Composition of vehicle (if applicable): no data
- Concentration of test material in vehicle (if applicable): not applicable; the concentration in the chamber was monitored using gas chromatography at 7-9 min intervals (depending on the chemical) for up to 2 hours
- Method of particle size determination: no data
- Treatment of exhaust air: no data

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: no data
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): no data
Duration and frequency of treatment / exposure:
once for 2 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
2000 ppm in normal air (corresponding to approx. 7.32 mg/L)
No. of animals per sex per dose:
6
Control animals:
other: same animals (pre-exposure values) and historical
Positive control:
None specified; the test substance was evaluated together with 12 additional compounds and mixtures
Details on study design:
- Dose selection rationale: these studies were designed to determine the respiratory bioavailability of chemicals. They were not intended to determine metabolie rate constants. Therefore, animals were exposed to a single concentration/chemical. For chemicals for which this group has previous gas uptake data (ethyl acetate, butanol, propanol, propyl acetate, isobutanol) gas uptake parameters were linear for 200 and 2000 ppm exposures. Therefore, 2000 ppm exposures were utilized to maximize analytical quantification. For chemieals with which previous data is not available, 2000 ppm was also used.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood
- Time and frequency of sampling: blood samples of about 0.1 ml each were drawn from the jugular cannula using a heparinised syringe prior to exposures and at 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 min after injection of test material into the chamber.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: see above
- From how many animals: samples not pooled
- Method type(s) for identification: GC-FID; blood was placed in pre-weighed 4-ml screw cap vials containing 2 µg phenylmethylsulfonyl fluoride to stop any further hydrolysis. The vials were quickly sealed, weighed, and placed on dry ice. Samples were frozen at -80°C until analysis. The samples were analysed by gas chromatography using Stabilwax DA capillary column/FID as column/detector, pentyl acetate, pentyl alcohol and valeric acid as internal standards, 3.4, 4.5 and 9.2 min as retention time, and ethyl acetate as extracting solvent.
Statistics:
None

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
During the first 20 minutes of exposure, pentanol concentrations in the rat blood increased up to a mean of 103.1 µM, then they decreased again. 90 minutes after start of exposure, a mean blood concentration of 50.3 µM was determined.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
After inhalative exposure the test substance present in the blood is converted to its acid metabolite (valeric acid). The metabolite valeric acid was detected at all times only in trace amounts (3.1 - 5.2 µM), probably due to the fact that the acid represents an intermediate degradation product.

Any other information on results incl. tables

Test substance loss

The non-specific loss (in the absence of animals) of test substance from the chamber was biphasic, showing an initial more rapid loss, and generally tended to be slightly greater for the acetates than for the alcohols.

The specific chamber loss rates were fairly high (up to 67% over the first hour). The additional loss of chemical from the chamber in the presence of a live rat was always substantially greater than non-specific chamber loss (Table 1).

 

Respiratory parameters

Minute volume and tidal volume decreased immediately after the introduction of chemical, resulting in a relatively stable respiratory rate.

 

Table 1: Test substance uptake (average of all live rats)

Average time (hours)

Test substance chamber concentration (ppm)

Mean

Standard deviation

Mean

Standard deviation

0.15

0.00

1906.74

511.08

0.29

0.01

1523.76

443.10

0.43

0.02

1262.54

381.93

0.57

0.02

1074.15

348.83

0.72

0.02

937.25

312.99

0.85

0.03

822.59

275.08

0.99

0.03

727.17

259.01

1.13

0.04

654.71

233.27

1.28

0.03

595.79

216.49

1.42

0.04

535.70

196.10

1.56

0.05

489.54

182.83

1.70

0.04

445.30

172.79

1.85

0.05

404.72

149.51

1.97

0.04

383.42

193.41

 

Table 2: Average blood n-pentanol and valeric acid concentrations from vapour uptake exposures to n-pentanol (at indicated average time period)

Average time (min)

Test substance blood concentration (µM)

 

n-pentanol

valeric acid

 

mean

standard deviation

mean

standard deviation

0

0

0

0

0

5

103.1

35.1

3.48

1.14

10

141.7

75.0

4.33

1.96

15

148.9

76.4

4.52

2.10

20

143.6

63.4

5.18

1.91

25

125.9

59.2

4.95

1.76

30

137.3

98.3

4.54

2.24

40

92.0

53.0

4.01

1.26

50

66.7

43.4

3.35

1.61

60

81.7

23.9

3.12

1.67

90

50.3

19.5

3.51

2.14

Applicant's summary and conclusion