Octane

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles, acceptable for assessment.

Objective of study:

distribution

toxicokinetics

Principles of method if other than guideline:

3 day toxicokinetic study in rats.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Møllegaard A/S, L1, Skensved, Denmark
- Age at study initiation: 40-50 days
- Weight at study initiation: 150 - 200 g
- Individual metabolism cages: no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4-6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±1 during exposure
- Humidity (%): 70 ± 20 during exposure
- Photoperiod (hrs dark / hrs light): 10/14

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: conical 0.7 m³ inhalation chambers with a glass front door and walls, accommodating 4 cages each containing 4 rats each.
TYPE OF INHALATION EXPOSURE: whole body

Dynamic exposure of anomals was performed in conically shaped 0.7 m3 steel chambers with glass front door and walls as described elsewhere (Walseth & Nilsen 1984). The concentration of hydrocarbons in the inhalation chambers was monitored automatically by on-line gas chromatography, Concentrations were measured in 15 min intervals. Altogehter 44 measurements at steady state each day.

Duration and frequency of treatment / exposure:

1, 2, and 3 days, 12 hours/day

Remarks:

Doses / Concentrations:
0.52 mg/L (corresponding to 100 ppm)

No. of animals per sex per dose / concentration:

4 per exposure duration

Control animals:

no

Positive control reference chemical:

not applicable

Details on study design:

The aimed concentration was 1000 ppm. All exposures were performed at daytime for 12 hr (8 a.m. - 8 p.m.). Measurements were done on days 1, 2, and 3 after 12 hr exposure. Animals were one by one removed, killed, and blood and organs obtained within 3 min after removal from exposure chamber.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, brain, liver, kidneys, perirenal fat
- Time and frequency of sampling: day 1, 2, and 3 within 3 min of removal from inhalation chamber

Preliminary studies:

Not performed

Details on absorption:

Not addressed.

Details on distribution in tissues:

n-Octane demonstrated the highest concentration in kidney and brain tissue with lowest levels on day 3. In perirenal fat, a different pattern was seen with concentrations increasing from day 1 to day 3.

Key result

Test no.:

#1

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Details on excretion:

Not addressed.

Metabolites identified:

not measured

Blood and tissue values in µmol/kg (with SD):

day	1	2	3
blood	3.9 ± 0.9	4.2 ± 0.0	3.6 ± 0.5
Brain	37.8 ± 8.1	37.2 ± 7.4	25.2 ± 2.1
liver	10.2 ± 1.0	10.6 ± 1.7	8.4 ± 2.8
kidney	64.9 ± 21.1	66.2 ± 4.3	41.9 ± 9.3
fat	362 ± 63	548 ± 46	697 ± 71

Conclusion:

n-Octane was found in higher concentrations in kidneys and in lower concentrations in blood and liver. The lowest tissue levels were determined on day 3. In perirenal fat, concentrations were the highest with concentrations increasing from day 1 to day 3.

Conclusions:

Interpretation of results (migrated information): other: see conclusions below
n-Octane was found in higher concentrations in kidneys and in lower concentrations in blood and liver. The lowest tissue levels were determined on day 3. In perirenal fat, concentrations were the highest with concentrations increasing from day 1 to day 3.

Executive summary:

n-Octane was found in higher concentrations in kidneys and in lower concentrations in blood and liver. The lowest tissue levels were determined on day 3. In perirenal fat, concentrations were the highest with concentrations increasing from day 1 to day 3.

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Objective of study:

excretion

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

- Only male rats were used. It would have been useful to see if the excretion patterns differed in female rats for which kidney toxicity may not be of concern; limited documentation.

Principles of method if other than guideline:

Accumulation and excretion study. Only males tested.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

14C

Species:

rat

Strain:

other: F344/N

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, P.O. Box 5890, Albuquerque, New Mexico 87185
- Age at study initiation: 9-15 weeks
- Weight at study initiation: 198 - 270 g, mean 231 ± 18 g
- Housing: in polycarbonate cages with hardwood chip bedding and filter tops
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: nose only

Exposure was by the nose-only mode, using a system modified from that described by Dahl et al. (1987). The modification consisted of removing the gas chromatograph from the system, as this was not needed for evaluation of these radiolabeled compounds.

Duration and frequency of treatment / exposure:

2 hour single exposure

Remarks:

Doses / Concentrations:
0.005, 1.659 mg/L (re-calculated from 1 and 350 ppm nominal)
0.01, 1.58 mg/L (re-calculated from 2.2 ± 0.5, 339 ± 55 ppm analytical)

No. of animals per sex per dose / concentration:

3 (low dose) and 4 (high dose)

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, exhaled air, whole carcasses (terminal)
- Time and frequency of sampling: 1, 2, 3, 6, 9, 18, 24, 30, 42, 54, 66 hours post-exposure (urine and feces at all times except 1 and 2 hours post-exposure, carcasses only at 66 hours post-exposure)

Statistics:

A Bonferroni correction was applied to each group of t-tests comparing high and low exposure groups.

Preliminary studies:

Not performed.

Details on absorption:

Uptake rates were 6.1 and 3.4 nmol/kg/min/ppm for low and high n-octane levels, respectively. The fraction of inhaled hydrocarbon that was metabolized [sum of excreta, exhaled CO2 and carbon-14 equivalents in the carcass] was higher at low inhaled concentration than at high inhaled concentration.

Details on distribution in tissues:

Not addressed.

Details on excretion:

Major route of elimination of 14C was carbon dioxide. For octane absorbed at low concentration, the amount of inhaled 14C in the carcass at 70 hours post-exposure was nearly 5% of total inhaled, a significantly higher level than that remaining after high concentration exposure (approx. 2%). The fraction of inhaled parent compound exhaled unchanged was 4.5 and 6.5% of high and low exposure levels, respectively. Half of octane 14C retained at the end of the 2hr exposure was eliminated within 5-10 hours post-exposure and stopped after 30hours when 75-85% of activity was eliminated. The rate of excretion of octane was markedly affected by the concentration of inhaled vapor. The ratio of 14CO2 to 14C in urine was 5:1 after inhalation at the low concentration but 1:1 after inhalation at the high concentration.
Absorbed [14C]-octane equivalents were eliminated as 14CO2 more readily at exposure of 1ppm for 2 hrs but were equally excreted via the kidneys and as CO2 after exposure at 350ppm. Kidney excretion was essentially complete after 10-15hrs, and overall elimination (75-85%) was complete by 30hrs.

Metabolites identified:

not measured

The excretion pattern of n-octane, fairly evenly distributed between 14CO2 and kidney by 15 hrs, and the rapid elimination differed from that of isooctane for which excretion was primarily through the kidney at a slower rate.

Conclusions:

Interpretation of results (migrated information): other: see conclusion below
The excretion pattern of n-octane, fairly evenly distributed between 14CO2 and kidney by 15 hrs, and the rapid elimination differed from that of isooctane for which excretion was primarily through the kidney at a slower rate.

Executive summary:

The excretion pattern of n-octane, fairly evenly distributed between 14CO2 and kidney by 15 hrs, and the rapid elimination differed from that of isooctane for which excretion was primarily through the kidney at a slower rate.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given.

Objective of study:

absorption

Principles of method if other than guideline:

The comparative rates of uptake of 19 hydrocarbon (including octane) vapours by rats were determined by a dual-column gas chromatography method.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

other: F344/N

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Lovelace ITRI colony
- Age at study initiation: 12 to 15 weeks
- Weight at study initiation: mean 298 g
- Housing: Before exposure, animals were housed in polycarbonate cages (2 animals/cage) with hardwood chip bedding and filter caps.
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): AM. Food (Lab Blox, Allied Mills, Chicago, IL, USA); ad libitum
- Water (e.g. ad libitum): water from bottles with sipper tubes; ad libitium


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22.2
- Humidity (%): 20 to 50
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: nose only

The exposure apparatus, exposure procedures, and method for handling data were described in detail by Dahl et al., 1987 (Amer Ind Hyg Assoc J 48:505-510)

The vapour was pumped at 400 mL/min from a Teflon supply bag through one sampling loop of a dual-column gas chromatograph, past the nose of a rat confined in a nose-only exposure tube, through the second sampling loop of the dual column gas chromatograph and, finally, into an exhaust bag.
The amount of hydrocarbon vapour absorbed was calculated from the output of the gas chromatograph and the flow rate past the rat´s nose. Rat exposures were preceded by a 10-15 min pre-exposure equilibration/calibration period without a rat in the system.

Duration and frequency of treatment / exposure:

80 min for 5 consecutive days (totally 450 min)

Remarks:

Doses / Concentrations:
on day 1: 1 ppm
on day 2: 10 ppm
on day 3: 100 ppm
on day 4: 1000 ppm
on day 5: 5000 ppm
See also "any other information on materials and methods".

No. of animals per sex per dose / concentration:

at 100 ppm: 10 male rats (not further specified)

Control animals:

not specified

Positive control reference chemical:

no data

Details on study design:

All animals were exposed for 80 min/day for 5 consecutive days with escalation of vapour concentration daily.

Details on dosing and sampling:

During the exposures (80 min/day), respiratory and gas chromatographic data were collected at 1 min intervals.

Statistics:

The calculation of vapour uptake from gas chromatography data see attached document.

Details on absorption:

Values of the uptake of inhaled octane vapours (of two independent experiments) were 7.1 ± 1.0 nmol/kg/min/ppm (N=10) and 6.1 ± 0.6 nmol/kg/min/ppm (N=10). The values are given for uptake during minutes 60 to 70 from start of exposure.

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Taking into account all data of the report, a number of trends relating uptake to chemicals properties were observed. Among these, highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; unsaturated compounds are better absorbed than saturated ones; and branched hydrocarbons are less well-absorbed than unbranched ones. These trends can be used to predict relative uptake rates within classes of hydrocarbons.

Executive summary:

Taking into account all data of the report, a number of trends relating uptake to chemicals properties were observed. Among these, highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; unsaturated compounds are better absorbed than saturated ones; and branched hydrocarbons are less well-absorbed than unbranched ones. These trends can be used to predict relative uptake rates within classes of hydrocarbons.

Reference 4

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles, acceptable for assessment.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Principles of method if other than guideline:

Guidance for conduct of the in vitro dermal kinetic experiments was posted in the United States FR, April 26, 2004 (Volume 69, Number 80), pages 22402-22441, "In vitro dermal absorption rate testing of certain chemicals of interest to the occupational safety and health administration".

GLP compliance:

not specified

Radiolabelling:

yes

Species:

other: in vitro human skin model

Strain:

other: in vitro human skin model

Sex:

not specified

Details on test animals or test system and environmental conditions:

not applicable

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

up to 60 min

Doses:

infinite dose: 1200 µL/cm2
10 min: 20 µL
60 min: 20 µL

No. of animals per group:

in vitro human skin model

Control animals:

no

Details on in vitro test system (if applicable):

see "any other information on materials and methods"

Signs and symptoms of toxicity:

not examined

Dermal irritation:

yes

The flux values for Normal-Heptane and the 10 and 60 min short-term absorption values (the quantity of chemical remaining in the skin plus that portion that had penetrated the skin was detected in the receptor fluid) were 63.2 µg/cm2/h, 113 µg/cm2/h (for the 10 min flux) and 22.1 µg/cm2/h (for the 60 min flux). Therefore, 10 min flux value for Normal-Heptane (based on both the amount in the skin and the receptor solution) was greater than the flux measured in a similar manner over 60 min.

Skin integrity measurements were taken before and after each experiment. All reporting laboratories (Normal-Heptane: Hask, DuPont Haskell Laboratory, USA) either used tritiated water permeability or electrical resistance (impedance) to confirm skin integrity; for consistency and to ease comparisons, all tritiated Kp values were converted to electrical impedance values expressed in kilo-ohms (k-ohms). A ratio of post- to pre-test impedance of "1" indicates that the skin barrier did not change over the course of the experiment. In the Kp experiments, skin exposed to Normal-Heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to Normal-Heptane. The barrier properties for the skin in the short-term experiments were given as the ratios of 0.90 for 10 min and 0.88 for 60 min.

Recovery of the applied dose, based on liquid scintillation count data when the radioactive chemical form was spiked into the non-radiolabeled chemical, was 95.5% (for the Kp experiment), 54.0% (for the 10 min experiment) and 110.0% (for the 60 min experiment).

At the end of the Kp experiment, the portion of Normal-Heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of Normal-Heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of Normal-Heptane following a 10 min exposure. The portion of Normal-Heptane in the donor solution (wash) was 6.84% at 10 min. The greater portion of the applied dose remaining in the skin at 10 min suggests that partitioning into the skin from the donor solution is the driver of penetration with this brief exposure. After the 60 min experiments, there was also a larger percentage of n-heptane in the receptor solution (0.12%) than in the skin (0.06%). The increased proportion of Normal-Heptane detected in the receptor solution illustrates and confirms the movement of the chemical from the skin into the receptor solution.

Conclusions:

Under the test conditions, Normal-Heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to n-heptane simultaneously reduced skin barrier function.

Executive summary:

Under the test conditions, Normal-Heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to Normal-Heptane simultaneously reduced skin barrier function.

Description of key information

Short description of key information on bioaccumulation potential result:
See toxicokinetics, metabolism and distribution.

Short description of key information on absorption rate:
Under dermal in vitro test conditions, normal-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to normal-heptane simultaneously reduced skin barrier function. Similar properties are expected for octane.

Due to the experimental setup, e. g. undepletable reservoir of test substance and therefore absence of any evaporation, the dermal penetration factors reported by Fasano and McDougal (2008) are very conservative. In contrast, when using a diffusion cell, which is a more realistic setup for volatile substances like hydrocarbon solvents, dermal penetration rates of 0.1 µg/cm2/h and 0.0005 µg/cm2/h were obtained for heptane and octane, respectively (Tsuruta et al., 1982).

Additional information

The inhaled uptake of octane vapors was explored by Dahl et al. (1988) in male rats exposed for 5 consecutive days, 80 min/day with escalation of vapor concentration daily (from 1 ppm up to 5000 ppm). During the exposures, respiratory and gas chromatographic data were collected at 1 min intervals. Uptake of inhaled octane vapors (of 2 independent experiments, each n = 10) was 7.1 ± 1.0 nmol/kg/min/ppm and 6.1 ± 0.6 nmol/kg/min/ppm. The values are given for uptake during minutes 60 to 70 from the start of exposure of the experiment.

In a subsequent study, differences in biological fate of inhaled nephrotoxic iso-octane and non-nephrotoxic octane were explored by Dahl (1989) in rats exposed to ¹⁴C-labeled vapor by nose-only inhalation at concentrations of 0, 1.0, and 350 ppm for a single 2 hour exposure. Radioactivity of exhalant, urine, and feces was measured for 70 hours post-exposure after which residual radioactivity in the carcasses was determined. Inhaled uptake of octane was greater than iso-octane uptake at both concentrations. The uptake rate at the low concentration for octane was twice that of the high concentration (6.1 and 3.4 nmol/kg/min/ppm, respectively).

 

The major route of elimination of ¹⁴C was carbon dioxide. For octane absorbed at low concentration, the amount of inhaled ¹⁴C in the carcass at 70 hours post-exposure was nearly 5% of total inhaled, a significantly higher level than that remaining after high concentration exposure (approx. 2%). The fraction of inhaled octane exhaled unchanged was 4.5 and 6.5% of high and low exposure levels, respectively. Half of octane ¹⁴C retained at the end of the 2 hour exposure was eliminated within 5-10 hours post-exposure and stopped after 30 hours when 75-85% of activity was eliminated. The rate of excretion of octane was markedly affected by the concentration of inhaled vapor. The ratio of ¹⁴CO2 to ¹⁴C in urine was 5:1 after inhalation at the low concentration but 1:1 after inhalation at the high concentration.

The excretion pattern of octane, fairly evenly distributed between ¹⁴CO2 and kidney by 15 hours, and the rapid elimination differed from that of iso-octane for which excretion was primarily through the kidney at a slower rate.

 

Toxicokinetic properties of octane were investigated in rats during inhalation of 100 ppm of the hydrocarbon for 3 days, 12 hours/day (Zahlsen et al., 1992). The concentration of octane was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. Octane was found in higher concentrations in kidneys and in lower concentrations in blood and liver. The lowest tissue levels were determined on day 3. In perirenal fat, concentrations were the highest with concentrations increasing from day 1 to day 3.

 

In general, octane is readily absorbed and distributed through the body. Furthermore it is readily metabolized and excreted in urine and expired as CO₂. Based on read-across from the structurally related compound normal-heptane within an analogue approach, there appears to be a very low rate of metabolism to potentially neurotoxic gamma diketones in rats.

Discussion on bioaccumulation potential result:

See toxicokinetics, metabolism and distribution.

Discussion on absorption rate:

There are no dermal absorption data available on octane. However, there are reliable data available for a structural analogue. Thus, read-across was conducted based on an analogue approach.

Fasano and McDougal (2008) described the procedures for determination of a permeability coefficient (Kp) and two short-term dermal absorption rates at 10 and 60 min. The flux values for normal-heptane and the 10 and 60 min short-term absorption values (the quantity of chemical remaining in the skin plus that portion that had penetrated the skin was detected in the receptor fluid) were 63.2 µg/cm2/h, 113 µg/cm2/h (for the 10 min flux) and 22.1 µg/cm2/h (for the 60 min flux). Therefore, the 10 min flux value for normal-heptane (based on both the amount in the skin and the receptor solution) was greater than the flux measured in a similar manner over 60 min.

 

Skin integrity measurements were taken before and after each experiment. A ratio of post- to pre-test impedance of "1" indicates that the skin barrier did not change over the course of the experiment. In the Kp experiments, skin exposed to normal-heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to normal-heptane. The barrier properties for the skin in the short-term experiments were given as the ratios of 0.90 for 10 min and 0.88 for 60 min. At the end of the Kp experiment, the portion of normal-heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of normal-heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of normal-heptane following a 10 min exposure. The portion of normal-heptane in the donor solution (wash) was 6.84% at 10 min. The greater portion of the applied dose remaining in the skin at 10 min suggests that partitioning into the skin from the donor solution is the driver of penetration with this brief exposure. After the 60 min experiments, there was also a larger percentage of normal-heptane in the receptor solution (0.12%) than in the skin (0.06%). The increased proportion of normal-heptane detected in the receptor solution illustrates and confirms the movement of the chemical from the skin into the receptor solution. Under the test conditions, normal-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to normal-heptane simultaneously reduced skin barrier function.