Hydrocarbons, C6-C7, n-alkanes, isoalkanes, cyclics, <5% n-hexane

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.

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

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)

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:

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.

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	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 (migrated information): 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.

Reference 2

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:

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

Objective of study:

metabolism

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.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

other: F344/N

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 9-15 weeks

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

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 / concentration:

4

Control animals:

no

Positive control reference chemical:

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 (migrated information): low bioaccumulation potential based on study results
Low bioaccumulation potential based on study results.

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: Study well documented, 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

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)

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 4

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:

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

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 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)

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:

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 (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 5

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles.

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Principles of method if other than guideline:

Penetration rates of 10 hydrophobic solvents through the excised abdominal rat skin were quantitatively determined

GLP compliance:

no

Type of coverage:

other: chamber

Vehicle:

unchanged (no vehicle)

Duration of exposure:

4, 5, 6, 10, 13, 16, 20 hours

Doses:

N/A

No. of animals per group:

N/A

Control animals:

no

Remarks:

N/A

Details on study design:

see below

Details on in vitro test system (if applicable):

Materials
The solvents were examined for purity by a gas chromatograph with a flame ionization detector. The purity of the solvents was more than 98%.

Excised skin
The rats (SD-JCL), weighing 400 to 600 g, were anesthetized by a subcutaneous injection of 0.60 to 0.90 ml of sodium pentobarbital solution. The skin of the abdominal wegion was clipped with an electric clipper and then completely de- pilated with, a depilatory cream. After three days of depilating the hair of the abdominal skin, the rat was sacrificed with carbon monoxide gas, and the abdominal skin freed of subcutaneous tissue was stripped with scissors. The skin obtained was spread on aluminium foil and stored at 20°C. Before use, the skin was allowed to adjust itself gradually to room temperature.

Operation of the in vitro experiment by the diffusion cell
The area of the skin attached to the diffusion cell was 2.55 cm2. The lower chamber was filled with 0.9% NaCI solution. After 1 ml of test solvent was added to the upper chamber with a glass stopper, the diffusion cell was reciprocally shaken at 25 deg C. After a certain number of hours of shaking, the 0.9% NaCl solution in the lower chamber was throughly removed, and amount of the test solvent that had penetrated into the 0.9% NaC1 solution was determined.


Analysis of the solvents by gas chromatography
A Shimadzu GC-4BM gas chromatograph with a gas sampling valve of a 2-mL gas sampler attached to it was used in this study. The carrier gas was nitrogen. The chromatograph column was a 0.5-rn glass tube (ID. 3 mm, O.D. 5 umm) packed with Porapak OS, 60-80 mesh. The column temperature was 190 deg C for n-heptane.

Data
A plot of the log of the solvent concentration in the gas phase versus the number of equilibrations produces a straight line. The rate of penetration was determined by measuring the accumulation of the test solvent in the 0.9% NaCl solution beneath the skin.

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Dose:

N/A

Remarks on result:

other: overall absorption rate

Remarks:

0.0241 nmol/min/cm2 of skin

Conclusions:

The percutaneous absorption rate for n-heptane was determined to be 0.0241 nmol/min/cm2.

Executive summary:

The percutaneous absorption rate for n-heptane was determined to be 0.0241 nmol/min/cm2.

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, 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, n-alkanes, iso-alkanes, cyclics. 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).

Additional information

There are no toxicokinetic data available on hydrocarbons, C6-C7, n-alkanes, isoalkanes, cyclics, <5% n-hexane. However, there are reliable data available for other structural analogues. Thus, read-across was conducted based on a analogue-approach.

The inhaled uptake of 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 heptane, only data from one exposure at 100 ppm were available. Uptake of inhaled 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 to¹⁴C-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 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 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 heptane was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. 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 heptane were determined in human blood and tissues by Perbellini et al. (1985). The solubility of 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 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 a category approach, C₇-C₉alkanes are readily absorbed and distributed through the body. n-Alkanes are readily metabolized and excreted in urine and expired as CO₂. Isoalkanes are less readily metabolized to a range of metabolites that are excreted in the urine. Tissue/blood ratios are greater than unity, especially for isoalkanes, 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 isoalkanes.

Discussion on bioaccumulation potential result:

See toxicokinetics, metabolism and distribution.

Discussion on absorption rate:

Under dermal in vitro test conditions, n-heptane was able to penetrate the skin. During prolonged, occluded 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, n-alkanes, iso-alkanes, cyclics.

 

Due to the experimental setup, e. g. undepletable reservoir of test substance, absence of any evaporation, and an absorption sink, the dermal penetration factors reported by Fasano and McDougal (2008) are unreliable for substances with vapour pressures >= 8mm Hg. 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).

 

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.