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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-08-21 to 1992-08-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restriction because it is an acceptable, well-documented study report that followed basic scientific principles.
Objective of study:
toxicokinetics
Qualifier:
no guideline available
Principles of method if other than guideline:
The absorption, metabolism, distribution and excretion of radio labeled n-hexane and radio labeled methylcyclopentane were studied in male and female F344 rats following iv bolus, nose-only inhalation or dermal administration of each of the compounds, formulated in commercial hexane.
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
other: iv bolus, nose-only inhalation or dermal administration
Vehicle:
unchanged (no vehicle)
Remarks:
Doses / Concentrations:
900 and 9000 ppm
Details on study design:
Studies were conducted following IV bolus at 10 mg/kg, single inhalation exposures at 900 and 9000 ppm for 6 h, 900 ppm exposures for six hours/day for eight days, and dermal application for 6 h at 1.1 and 11 mg/cm2. Pharmacokinetic modeling of the disappearance of total radioactivity from the blood was performed for the studies employing radio labeled n-hexane. Metabolites eliminated in the urine and breath were profiled chromatographically.
Details on absorption:
Pharmacokinetics: Disappearance of total radioactivity from the blood was best described by a one compartment model with apparent first order output. No dose related changes were noted in the half-life for the elimination of radioactivity from the blood. The average estimated half-life for the disappearance of radioactivity from the blood of male and female rats across all studies was 9.6 h. Insufficient early sampling following iv bolus resulted in a poor statistical fit of the model to the data. Consequently, an artifactually long half-life of 23.8 h was estimated by the pharmacokinetic model for female animals. This estimate does not accurately reflect the data, since the time-course of radioactivity in the blood of females as compared to males is very similar. Across all of the studies, there were no discernible differences in the rates of disappearance of radioactivity from the blood between male and female animals.

Dose-Dependent Absorption of Commercial Hexane During Inhalation: Based upon literature reports for the weight-normalized respiratory minute volume of rats we can broadly estimate that commercial hexane was relatively poorly absorbed during inhalation exposure. Approximately 12- 14% of the mass of commercial hexane passing through the lungs of rats was actually absorbed during inhalation of 900 ppm. However, during inhalation of 9000 ppm only 6-7% of the mass of commercial hexane available was absorbed.
Details on excretion:
Excretion and Tissue Distribution of n-Hexane: n-Hexane and its radio labeled metabolites were rapidly and efficiently cleared from the body following all routes of administration. Average totals of approximately 47 to 80% of the dose of radio labeled n-hexane were exhaled in all studies. As a result, exhalation was the primary route for the elimination of n-hexane following iv bolus, inhalation or dermal administration. Within 72 h following iv bolus or 9000 ppm inhalation and 24 h following either 1.1 or 11 mg/cm2 dermal administration the majority of the exhaled radioactivity (approximately 40-65% of the dose) was exhaled as unchanged parent n-hexane. The balance of radiolabel exhaled in the breath was radio labeled as CO2. Within 168 h following a single exposure or 72 h following the last of eight consecutive daily 6 h exposures to 900 ppm commercial hexane, radioactivity was exhaled primarily (approximately 35-47% of the dose) as radio labeled CO2 with the balance of the exhaled radiolabel being trapped as unchanged parent compound.

Following IV bolus or inhalation of 9000 ppm commercial hexane, rats eliminated average totals of approximately 12 to 17% of the dose in the urine, whereas following either single or repeated inhalation of 900 ppm, rats excreted 25 to 39% of the dose In the urine. Following dermal application of commercial hexane approximately 1-3% of the applied dose was excreted in the urine.

None of the organs examined retained appreciable amounts of radiolabel following sacrifice. Among the organs studied, kidney, liver and thymus retained the highest concentration of radioactivity following excretion of the majority of the dose. Following IV bolus or inhalation, 2.7 to 8.1% of the dose was recovered from the residual carcass, the bulk of which was found in the skin, skeletal muscle, and adipose tissue. Following dermal exposure, residual carcasses retained less than 0.5% of the applied dose 24 h following application. In general, no differences were noted between males and females.


Excretion and Tissue Distribution of Methylcyclopentane: Methylcyclopentane and its radio labeled metabolites were rapidly and efficiently cleared from the body following all routes of administration. Exhalation was the predominant means for elimination following IV bolus, inhalation of 9000 ppm commercial hexane, and dermal exposure, with 51 to 79% of the dose being exhaled within 96 h of the administration of the radio labeled dose. Following inhalation of 900 ppm for 6 h either once or daily for eight consecutive days, rats exhaled 21 to 35% of the dose. Following all routes of administration, methylcyclopentane and its radio labeled metabolites were exhaled almost exclusively as unchanged methylcyclopentane. Rats exhaled 3% or less of the dose as radio labeled CO2, regardless of the route or dose.

Following iv bolus administration rats eliminated 13 to 19% of the of the administered dose in the urine; whereas after inhalation of 9000 ppm commercial hexane for 6 h rats excreted an average of approximately 34% of the recovered dose in the urine. Following single or multiple exposures to 900 ppm commercial hexane, the urine was the main pathway for elimination of dose, averaging of 56 and 65% of the dose in the urine, respectively. Following dermal application of 1.1 or 11 mg/cm2 of commercial hexane rats excreted averages of 3.0 and 4.8% of the applied dose in the urine, respectively.

None of the organs examined retained appreciable amounts of radiolabel following excretion of the majority of the dose. Among the organs studied kidney, liver and in several cases the ovaries of female animals retained the highest concentrations of radioactivity after the majority of the dose had been excreted. Only after IV bolus administration, the spleen retained very high concentrations of radioactivity relative to the blood. This observation was not repeated and may have been due to some unique interaction with the erythrocytes that occurred as a result of the route of administration. Following inhalation of commercial hexane containing radio labeled methylcyclopentane, approximately 1 to 3% of the dose remained in the residual carcass. Following IV bolus and dermal administration, less than 1% of the dose remained in the residual carcass. Following all routes of administration of radio labeled methylcyclopentane, the bulk of the terminal body burden of radioactivity was generally found to remain in the skin, skeletal muscle and adipose tissue.
Metabolites identified:
no
Details on metabolites:
Metabolism of n-Hexane: The radio labeled urinary metabolites of n-hexane were studied chromatographically following IV bolus and inhalation of commercial hexane. There were no discernible qualitative differences in the metabolites excreted by males versus females.
Conclusions:
Interpretation of results: no bioaccumulation potential based on study results

Based on the study results, there is little potential for n-hexane or methylcyclopentane to bioaccumulate.
Executive summary:

n-hexane was metabolized and excreted within 168 h of iv bolus administration, inhalation exposure or dermal application. Exhaled breath and urine were the two primary routes for the excretion and its metabolites. n-hexane was widely distributed to the body tissues but were not concentrated significantly by any of those tissues. It was extensively metabolized and a number of radio labeled metabolites were excreted in the urine. n-hexane and its radio labeled metabolites disappeared from the blood of rats with a half-life of approximately 9-10 h. No significant differences between males and females were noted in the rates and routes of metabolism and excretion of the test compounds. Repeated inhalation exposure had no apparent effect on the rates or routes of excretion of either of the test compounds or their metabolites.

Description of key information

Animal Information:

One identified key toxicokinetics study was read-across commercial hexane (52 % n-hexane) (API, 1990; Klimisch score = 1). In an animal toxicokinetics metabolism and distribution study commercial n-hexane was metabolized and excreted within 168 hours of iv bolus administration, inhalation exposure or dermal application. Exhaled breath and urine were the two primary routes for the excretion of n-hexane and its metabolites. n-hexane was widely distributed to the body tissues but were not concentrated significantly by any of those tissues. It was extensively metabolized and a number of radio labeled metabolites were excreted in the urine. n-hexane and its radio labeled metabolites disappeared from the blood of rats with a half-life of approximately 9-10 hours. No significant differences between males and females were noted in the rates and routes of metabolism and excretion of the test compounds. Repeated inhalation exposure had no apparent effect on the rates or routes of excretion of either of the test compounds or their metabolites.

Human Information:

In a study in which metabolites in urine were measured in workers exposed to n-hexane (Perbellini et al., 1981), mean concentrations of n-hexane metabolites in urine were: 2,5-hexanedione, 5.4 mg/L; 2,5-dimethylfuran, 3.7 mg/L; gamma-valerolactone, 3.3 mg/L; and 2-hexanol, 0.19 mg/L. (2,5-Dimethylfuran and gammavalerolactone are believed to be artifacts of sample preparation and analysis rather than true metabolites of n-hexane (ATSDR, 1999)). The first reaction that takes place is hydroxylation of n-hexane at the 2 position to form 2-hexanol. Further reactions result in 2,5-hexanedione, presumably through transient intermediates, including 2-hexanone, 2,5-hexanediol, and 5-hydroxy-2-hexanone. Correlations between concentrations of n-hexane in air and urinary metabolites were best for total n-hexane metabolites (r=0.7858), followed by 2-hexanol (r=0.6851) and 2,5-hexanedione (r=0.6725).

Key value for chemical safety assessment

Additional information