Oligomerisation products of beta-pinene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Report on the toxicokinetics of alpha-pinene in human volunteers exposed by inhalation, published in a peer-reviewed scientific journal

Data source

Reference

Reference Type:

publication

Title:

Uptake, distribution and elimination of alpha-pinene in man after exposure by inhalation

Author:

Falk, A.A. et al

Year:

1990

Bibliographic source:

Scand. J. Work Environ. Health 16: 372-8

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Human volunteers exposed by inhalation to alpha-pinene during two hours of light exercise, on four occasions. Pulmonary uptake, blood clearance and bioelimination monitored, together with lung function.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

alpha-pinene

IUPAC Name:

alpha-pinene

Details on test material:

Alpha-pinene (Aldrich), purity 98%. (+)- and (-) isomers used separately

Radiolabelling:

no

Test animals

Species:

human

Sex:

male

Details on test animals or test system and environmental conditions:

8 healthy men aged 24-39 years

Administration / exposure

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

Details on exposure:

Volunteers exposed by inhalation, on four occasions: three (+)-alpha –pinene exposures (10, 225, and 450 mg/cu.m) plus one (-)- alpha –pinene exposure (450 mg/cu.m)). Exposure chamber 12 cu.m with 10 airchanges/h and slight negative pressure.

Duration and frequency of treatment / exposure:

2 x 4h exposures

Doses / concentrations

Remarks:

Doses / Concentrations:
10, 225, and 450 mg/cu.m (+ isomer), 450 mg/cu.m (- isomer). Monitored continuously during exposure period by IR spectrophotometer.

No. of animals per sex per dose / concentration:

2 volunteers/treatment on each of four occasions of exposure

Control animals:

no

Details on study design:

Volunteers exposed during 2h light exercise (on bicycle ergometer). Exhaled air sampled: 4 x 4 min collection periods. Volunteer heart rates monitored and fingertip blood samples taken at intervals during exposure for GC-FID analysis. Urine collected prior to exposure, 30 mins after and then on 3 further occasions up to 21h post-exposure. Volunteers self-rated for irritation and CNS effects. Lung function tested before exposure and 20-30 mins post-exposure.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Relative pulmonary uptake averaged 59% at 225 and 450 mg/cu.m, with absolute uptake increasing linearly with increasing (+)-alpha –pinene concentration.
No difference in uptake was seen between the two alpha-pinene isomers investigated.

Details on distribution in tissues:

A long half-life in poorly perfused tissues indicated a high affinity to adipose tissues.

Details on excretion:

Blood clearance post exposure was triphasic: over 21h post-exposure the clearance rate was high at 1.1 l/h/kg. Elimination of pinene by respiration after the exposure period amounted to 7.5-7.7% of uptake, and urinary elimination of unchanged pinene was minimal (<0.001% of uptake during 30 minutes post-exposure, then undetectable). After exposure was terminated, less than 0.001% of the total uptake was eliminated unchanged in the urine and about 8% in exhaled air.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 4.8 mins (triphasic, phase 1: (+) isomer)

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

half-life 2nd: 38 mins (triphasic, phase2: (+) isomer)

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

half-life 3rd: 695 mins (triphasic, phase 2: (+) isomer

Toxicokinetic parameters 4

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 5.6 mins (triphasic, phase 1: (-) isomer)

Toxicokinetic parameters 5

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: 40 mins (triphasic, phase 2: (-) isomer)

Toxicokinetic parameters 6

Test no.:

#3

Toxicokinetic parameters:

half-life 3rd: 555 mins (triphasic, phase 3: (-) isomer)

Any other information on results incl. tables

No differences in uptake, distribution or elimination were seen between the two alpha-pinene isomers investigated. Time for near-complete body clearance estimated at >2 days.

No acute changes in lung function were seen during or immediately after exposure.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Alpha-pinene, a direct analogue of the monomer unit within pinene oligomers, was well absorbed following inhalational exposure. Rapid clearance was obsrved, indicating that it is readily metabolised.