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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.
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose:
read-across: supporting information
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 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:
4 per exposure duration
Control animals:
no
Positive control:
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:
Normal-Heptane demonstrated moderate concentrations in kidneys. In perirenal fat, concentration are highest, however decreasing with lasting exposure. This is in contrast to other n-alkanes, which showed increasing concentrations.
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

2.4 ± 0.8

2.9 ± 0.9

2.1 ± 0.2

Brain

5.2 ± 0.8

6.9 ± 0.6

6.2 ± 1.0

liver

1.6 ± 0.6

2.3 ± 0.1

1.5 ± 0.1

kidney

15.7 ± 4.2

15.2 ± 2.6

17.1 ± 3.0

fat

140 ± 14

127 ± 28

121 ± 10

Conclusion:

n-Heptane was found in moderate concentrations in the kidneys and only in marginal concentrations in blood, brain and liver. In perirenal fat, concentrations were the highest, however, decreasing with lasting exposure.

Conclusions:
Interpretation of results: other: see conclusions below

Normal-Heptane was found in moderate concentrations in the kidneys and only in marginal concentrations in blood, brain and liver. In perirenal fat, concentrations were the highest, however, decreasing with lasting exposure.
Executive summary:

Normal-Heptane was found in moderate concentrations in the kidneys and only in marginal concentrations in blood, brain and liver. In perirenal fat, concentrations were the highest, however, decreasing with lasting exposure.

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 well documented, meets generally accepted scientific principles, acceptable for assessment.
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose:
read-across: supporting information
Objective of study:
excretion
Qualifier:
equivalent or similar to
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 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:
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: 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.

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.
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose:
read-across: supporting information
Objective of study:
metabolism
Qualifier:
equivalent or similar to
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.
GLP compliance:
not specified
Radiolabelling:
yes
Species:
rat
Strain:
other: F344/N
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9-15 weeks
Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: nose only

Duration and frequency of treatment / exposure:
one single dose for 2 hours
Remarks:
Doses / Concentrations:
nominal: 1.0 and 350 ppm (corresponding to 0.00473 and 1.7 mg/L)
analytical: 0.79 ± 0.22 and 385 ± 56 ppm
No. of animals per sex per dose:
4
Control animals:
no
Positive control:
no data
Details on study design:
no data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum or other tissues, cage washes, bile
- Time and frequency of sampling: Urine and feces were collected at all times except 1 or 2 hours post-exposure.



METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, tissues, cage washes, bile
- Time and frequency of sampling:
- From how many animals: (samples pooled or not)
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC)
- Limits of detection and quantification:
- Other:


TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):
Statistics:
A Bonferroni correction was applied to each group of t-tests comparing high and low exposure groups.
Metabolites identified:
not specified

Uptake rates were 3.4 and 2.2 nmol/kg/min/ppm for low and high iso-octane levels, respectively. The fraction of inhaled hydrocarbon that was metabolised [sum of excreta, exhaled CO2 and carbon-14 equivalents in the carcass] was higher at low inhaled concentrations than at high inhaled concentrations. Major route of elimination was urine, for low exposure concentration 14C in urine exceeded 11% of total inhaled isooctane. The amount of inhaled 14C in the carcass at 70 hours post-exposure was less than 2% of total inhaled for both low and high concentrations. The fraction of inhaled parent compound exhaled unchanged was approx. 2%. Half of isooctane 14C retained at the end of the 2 hour exposure was eliminated within 15 hours post-exposure but elimination continued primarily by the urinary route throughout 70 hours of observation. The almost exclusive elimination of metabolites of inhaled isooctane via the kidney with little production of 14CO2 suggests that kidneys may be exposed to a higher concentration of high molecular weight metabolites of isooctane.

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results

Low bioaccumulation potential based on study results.
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.
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose:
read-across: supporting information
Objective of study:
absorption
Principles of method if other than guideline:
The comparative rates of uptake of 19 hydrocarbon (including heptane) 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 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:
at 100 ppm: 10 male rats (not further specified)
Control animals:
not specified
Positive control:
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:
Only data from one exposure at 100 ppm were available. Uptake of inhaled heptane vapour was 4.5 ± 0.3 nmol/kg/min/ppm (N=10). The value is given for uptake during minutes 60 to 70 from start of exposure.
Conclusions:
Interpretation of results: 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.

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:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose:
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 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:

This data is being read across from the source study that tested heptane based on analogue read across.

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 toxicokinetic, metabolism and distriubtion.

Short description of key information on absorption rate:
Under dermal in vitro test conditions, n-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. Similar properties are expected for hydrocarbons, C7-C9, iso-alkanes.


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 subsances 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, 1982).

Key value for chemical safety assessment

Additional information

There are no toxicokinetic data available on hydrocarbons, C7-C9, iso-alkanes. However, there are reliable data available for structural analogues. Thus, read-across was conducted based on a analogue approach.

 

The inhaled uptake of n-heptane 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. For n-heptane, only data from one exposure at 100 ppm were available. Uptake of inhaled n-heptane vapor was 4.5 ± 0.3 nmol/kg/min/ppm (n = 10). The value is given for uptake during minutes 60 to 70 from the start of exposure of the experiment. 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.

 

In a subsequent study, differences in biological fate of inhaled nephrotoxic iso-octane and non-nephrotoxic n-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. Thenephrotoxicityof iso-octane is due to male rat specific alpha 2u-globulin nephropathy and is not relevant to humans as they do not have this protein. 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 n-octane was greater than iso-octane uptake at both concentrations. The uptake rate at the low concentration for n-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 n-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 n-octane exhaled unchanged was 4.5 and 6.5% of high and low exposure levels, respectively. Half of n-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 n-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 n-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 n-heptane 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 n-heptane was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. n-Heptane was found in moderate concentrations in the kidneys and only in marginal concentrations in blood, brain and liver. In perirenal fat, concentrations were the highest, however, decreasing with lasting exposure. This is in contrast to other n-alkanes, which showed increasing concentrations.

 

Partition coefficients of n-heptane were determined in human blood and tissues by Perbellini et al. (1985). The solubility of n-heptane was tested in blood, saline, olive oil and in the most important human tissues (lung, kidney, liver, brain, muscle, heart, and fat). The solubility of n-heptane in saline was low and very high in olive oil, displaying a partition coefficient of 452 (20.0 SD). The partition coefficients were therefore high in fat and fatty tissues compared to the other examined tissues.

 

Based on read-across from structurally related compounds within an analogue approach, C7-C9alkanes are readily absorbed and distributed through the body. n-Alkanes are readily metabolized and excreted in urine and expired as CO2. iso-Alkanes are less readily metabolized to a range of metabolites that are excreted in the urine. Tissue/blood ratios are greater than unity, especially for iso-alkanes, but on prolonged administration, metabolizing enzymes appear to be induced and ratios decrease. For n-alkanes, there appears to be a very low rate of metabolism to potentially neurotoxic gamma diketones, and no such metabolism for the iso-alkanes.

 

Discussion on bioaccumulation potential result:

See toxicokinetic, metabolism and distriubtion.

Discussion on absorption rate:

There are no dermal absorption data available onhydrocarbons, C7-C9, iso-alkanes. However, there are reliable data available for a structural analogue. Thus, read-across was conducted based on a 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 n-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 n-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 n-heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to n-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 n-heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of n-heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of n-heptane following a 10 min exposure. The portion of n-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 n-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, n-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.

OVERVIEW OF PERCUTANEOUS ABSORPTION OF HYDROCARBON SOLVENTS

There are no studies of repeated dose toxicity of hydrocarbon solvents using the dermal route of administration. Accordingly, where it is necessary to calculate dermal DNELs, systemic data from studies utilizing other routes of administration, normally inhalation but also oral data, can be used in some situations.  In accordance with ECHA guidance, read across from oral or inhalation data to dermal should account for differences in absorption where these exist (R8, example B.6). In fact, hydrocarbon solvents are poorly absorbed in most situations, in part because some are volatile and do not remain in contact with the skin for long periods of time and also because, due to their hydrophobic natures, do not partition well into aqueous environments and are poorly absorbed into the blood. 

If these differences in relative absorption are introduced into the DNEL calculations to calculate external doses, the DNELs based on systemic effects are highly inflated. This seems potentially misleading as it implies that substances have different intrinsic hazards when encountered by different routes whereas in fact the differences are due ultimately to differences in absorbed dose. Accordingly, it is our opinion that it would be more transparent if the differences in absorption were taken into account in the exposure equations rather than in DNEL derivation. 

 

Shown below is a compilation of percutaneous absorption information for a number of hydrocarbon solvent constituents covering carbon numbers ranging from C5 to C14 as well as examples of both aliphatic and aromatic constituents. The low molecular weight aliphatic hydrocarbons (n-pentane, 2-methylpentane, n-hexane, n-heptane, and n-octane) were tested by Tsuruta (1982) using rat skin in an in vitro model system. As shown (Table 1), the highest percutaneous absorption value was 2 ug/cm2/hr for pentane. Lower values (< ~ 1 ug/cm2/hr) were reported for aliphatic hydrocarbons ranging from hexane to octane. Several authors have assessed the percutaneous absorption of higher molecular weight aliphatic constituents including Baynes et al. (2000), Singh and Singh (2003), Muhammad et al. (2005), and Kim et al., (2006). The first three of these authors used porcine skin models and reported that, except for one anomalous result with tridecane, the percutaneous absorption values for aliphatic constituents ranging from nonane to tetradecane were well below 1 ug/cm2/hr. Rat and human skin are considered to be more permeable than human skin (Kim et al., 2006), so these numbers can be considered conservative. 

 

Kim et al. (2006) reported results of percutaneous absorption studies with human skin under in vivo conditions. In this case, the assessment method was based on tape stripping. The authors reported percutaneous absorption values ranging from 1 – 2 ug/kg/day for decane, undecane and dodecane. These values are higher than those reported by other authors, most likely because this technique measures absorption into the skin but not through the skin as was done in the studies listed above. Accordingly, it seems likely that these numbers are conservative as well.

 

With respect to aromatic hydrocarbons, most of the reported percutaneous absorption values [Baynes et al. (2000); Singh and Singh (2003); Mohammad et al. (2005); and Kim et al. (2006)] are less than 2 ug/cm2/day. The only exceptions are the values for naphthalene from Mohammad et al. (2005) which range from 4.2-6.6 ug/cm2/hr. 

 

After considering all of the above, it seems reasonable to assume apparent that across the entire range of hydrocarbon solvent constituents, percutaneous absorption values are less than 2 ug/cm2/day. Accordingly, when systemic dermal DNELs are calculated using route to route extrapolations, the values will not be corrected for differences in absorption. Rather, 2 ug/cm2/hr will be used as a common percutaneous absorption rate for all hydrocarbon solvents for which dermal exposure estimates are provided. 

           

Table 1: Summarized information on percutaneous absorption of hydrocarbon solvent constituents (C5-C16). 

 

Constituent

Molecular Weight

nmol/min/cm2

nmol/hr/cm2

ug/cm2/hr

Reference

Aliphatic Constituents

Pentane

72

0.52

31.2

2.2

Tsuruta et al. 1982

 

 

 

 

 

 

2-methyl pentane

86

0.02

1.2

0.1

Tsuruta et al., 1982

 

 

 

 

 

 

n-hexane

86

0.02

0.6

0.5

Tsuruta et al., 1982

 

 

 

 

 

 

n-heptane

100

0.02

1.2

0.1

Tsuruta et al., 1982

 

 

 

 

 

 

n-octane

114

0.08 x 10-3

0.005

0.0005

Tsuruta et al., 1982

 

 

 

 

 

 

Nonane

128

 

 

0.03

Muhammad et al., 2005

Nonane

 

 

 

0.38

McDougal et al., 1999

 

 

 

 

 

 

Decane

142

 

 

2

Kim et al., 2006

Decane

 

 

 

1.65

McDougal et al., 1999

 

 

 

 

 

 

Undecane

156

 

 

0.06-0.07

Muhammad et al., 2005

Undecane

 

 

 

1.0

Kim et al., 2006

Undecane

 

 

 

1.22

McDougal et al., 1999

 

 

 

 

 

 

Dodecane

170

 

 

0.02-0.04

Muhammad et al., 2005

Dodecane

 

 

 

2

Kim et al., 2006

Dodecane

 

 

 

0.3

Singh and Singh, 2003

Dodecane

 

 

 

0.51

McDougal et al., 1999

Dodecane

 

 

 

0.1

Baynes et al. 2000

 

 

 

 

 

 

Tridecane

184

 

 

0.00-0.02

Muhammad et al., 2005

Tridecane

 

 

 

2.5

Singh and Singh, 2003

Tridecane

 

 

 

0.33

McDougal et al., 1999

Tetradecane

198

 

 

0.3

Singh and Singh, 2003

Hexadecane

 

 

7.02 x 10E-3

0.00004

Singh and Singh, 2002

 

 

 

 

 

 

Aromatic Constituents

Trimethyl benzene

120

 

 

0.49 - 1.01

Muhammad et al., 2005

Trimethyl benzene

 

 

 

1.25

McDougal et al., 1999

 

 

 

 

 

 

Naphthalene

128

 

 

6.6 - 4.2

Muhammad et al., 2005

Naphthalene

 

 

 

0.5

Kim et al., 2006

Naphthalene

 

 

 

1.4

Singh and Singh 2002

Naphthalene

 

 

 

1.8

Baynes et al. (2000)

Naphthalene

 

 

 

1.0

McDougal et al., 1999

 

 

 

 

 

 

1 methyl naphthalene

142

 

 

0.5

Kim et al., 2006

Methyl naphthalene

 

 

 

1.55

McDougal et al., 1999

 

 

 

 

 

 

2-methyl naphthalene

 

 

 

0.5

Kim et al., 2006

2-methyl naphthalene

 

 

 

1.1

Singh and Singh, 2002

 

 

 

 

 

 

 

 

 

 

 

 

Dimethyl naphthalene

156

 

 

0.62 – 0.67

Muhammad et al., 2005

Dimethyl naphthalene

 

 

 

0.59

McDougal et al. 1999

 

 

 Table 2. Estimated percentages of various hydrocarbon solvent constituents absorbed

 

Based on the information provided below, an overall estimate of 1% for all hydrocarbon solvents seems reasonable. 

 

Category

Representative Substance

Estimate of Percent absorption

Proposal for category

Reference for percent value

 

 

 

 

 

1

Trimethyl benzene

0.2%

0.2%

Based on data in Muhammad et al. (2005)

2

Naphthalene

1.2%

1.2%

Riviere et al. 1999

3

Dodecane (75%)

0.63%

0.5%

Riviere et al., 1999

 

TMB (25%)

0.2%

 

Muhammad et al., 2005

 

 

 

 

 

4

Hexadecane (70%)

0.18%

0.5%

Riviere et al., 1999

 

Naphthalene (30%)

1.2%

 

Riviere et al., 1999

 

 

 

 

 

5

Pentane

 

 

 

 

 

 

 

6

Hexane

 

 

 

 

 

 

 

7

Heptane

0.14%

0.14%

Singh et al. 2003

 

 

 

 

 

8

Dodecane

0.63%

0.63%

Riviere et al. 1999

 

 

 

 

 

9

Hexadecane

0.18%

0.18%

Riviere et al., 1999

 

 

 

 

 

 

Kim, D., Andersen, M., and Nylander-French (2006). Dermal absorption and penetration of jet fuel components in humans. Toxicology Letters 165:11-21.

 

Muhammad, F., N. Monteiro-Riviere, R. Baynes, and J. Riviere (2005). Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents. Journal of Toxicology and Environmental Health Part A. 68:719-737.

 

Singh Somnath, Zhao Kaidi, Singh Jagdish. (2002). In vitro permeability and binding of hydrocarbons in pig ear and human abdominal skin. Drug and chemical toxicology, (2002 Feb) Vol. 25, No. 1, pp. 83-92.

 

Singh, S. and Singh, J. (2003). Percutaneous absorption, biophysical and macroscopic barrier properties of porcine skin exposed to major components of JP-8 jet fuel. Environmental Toxicology and Pharmacology 14:77-85.

 

Singh, S., Zhao, K., Singh, J. (2003). In vivo percutaneous absorption, skin barrier perturbation and irritation from JP-8 jet fuel components. Drug Chem. Toxicol 26:135-146.

 

McDougal, J., Pollard, D., Weisman, W., Garrett, C., and Miller, T. (2000). Assessment of skin absorption and penetration of JP-8 jet fuel and its components. Toxicological Sciences 25:247-255.

 

Muhammad, F., N. Monteiro-Riviere, R. Baynes, and J. Riviere (2005). Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents. Journal of Toxicology and Environmental Health Part A. 68:719-737.

 

Riviere, J., Brooks, J., Monteiro-Riviere, N., Budsaba, K., and Smith, C. (1999). Dermal absorption and distribution of topically dosed jet fuels jet A, JP-8 andJP-8(100). Toxicology and Applied Pharmacology 160:60-75.

 

Tsuruta, H. et al. (1982). Percutaneous absorption of organic solvents III. On the penetration rates of hydrophobic solvents through the excised rat skin. Industrial Health 20:335-345.