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Description of key information

Short description of key information on bioaccumulation potential result: 
One key toxicokinetics study was identified for 2-methylbutane. In this study (non-guideline), F344 rats were exposed to a variety of hydrocarbon vapours, including pentane, via inhalation for 80 minutes for 5 consecutive days.
One read-across study (OECD 417) was identified on the inhalation kinetics of cyclopentane in the rat. A bioaccumulation factor of 2.5 was calculated for lower concentrations and increased to about 9.1 at 1000 ppm with a maximum value of 11.5, which is the thermodynamic partition coefficient of whole body to air.
Two read-across studies were identified on the toxicokinetics of n-pentane. In one study (OECD 417), rats were exposed to rabiolabeled n-pentane via inhalation. Tissue and organ results from experiment 1 showed that the liver, small intestine, and kidneys contained the highest radioactivity per gram of tissue (wet weight). Muscle and liver accounted for the largest proportion of the estimated total of radioactivity expressed as a percentage of the total radioactivity injected into the chamber. In the other study (non-guideline), F344 rats were exposed to a variety of hydrocarbon vapours, including pentane, via inhalation for 80 minutes for 5 consecutive days. When pentane was inhaled at 100 ppm, the uptake ranges were 3.6±0.2 and 4.2±0.4 nmol/kg/min/ppm (the mean of two experiments).
Short description of key information on absorption rate:
See Below

Key value for chemical safety assessment

Additional information

One toxicokinetic study was available on 2-methylbutane (Dahl et al., 1988).  F344 rats were exposed to a variety of hydrocarbon vapours, including 2-methylbutane, via inhalation for 80 minutes for 5 consecutive days. Doses were as follows: 1 ppm on day 1; 10 ppm on day 2; 100 ppm on day 3; 1000 on day 4; and 5000 ppm on day 5. The study report only presents data for the 10 ppm dose. When pentane was inhaled at 10 ppm, the uptake ranges were 1.6±0.2 and 1.5±0.2 nmol/kg/min/ppm (the mean of two experiments). Additionally, the uptake rate of pentane was greater than that of 2-methylbutane. The study authors concluded that (1) highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; (2) unsaturated compounds are better absorbed than saturated ones; and (3) branched hydrocarbons are less well-absorbed than unbranched ones. This study received a Klimisch score of 2 and was classified as reliable with restrictions because although the study did not follow an OECD guideline and it was not stated whether the study was GLP compliant, the study appears to be scientifically sound and there is an adequate level of detail.

One read-across study on the inhalation kinetics of cyclopentane in the rat was identified (Filser, 1997). This study was conducted in two parts. The first study was conducted to quantify the toxicokinetic parameters of inhaled cyclopentane, while the second part of the study was conducted to develop a physiological toxicokinetic model that would enable the study of toxicokinetic process occurring in the rat when exposed to cyclopentane vapours. In the first study, two male rats were exposed to cyclopentane at concentrations of 10, 30, 100, 300, 1000, 3000, or 10,000 parts per million (ppm) via inhalation in a closed exposure system. Metabolism of cyclopentane was found to be saturable with two different metabolic processes distinguished. One metabolic process had low affinity and high capacity while the other had high affinity and low capacity. The authors’ assumption that cyclopentane metabolism was oxidative, was supported by the findings that biotransformation of cyclopentane was almost completely inhibited for the whole 6 hour exposure duration when the rats were administered dithiocarb, a P-450 inhibitor. The study authors reported that the rate of metabolism was dose related with a proportional increase in metabolism up to 100 ppm concentration following which metabolism became saturated at about 1000 ppm. The bioaccumulation factor was 2.5 at the lower concentrations and increased to about 9.1 at 1000 ppm with a maximum value of 11.5, which is the thermodynamic partition coefficient of whole body to air. The steady state in the rat was estimated by multiplying the bioaccumulation factor with the exposure concentration. The steady state curve was shaped like a hockey stick, which reached a value of 0.36 µmol/mL of tissue at 1000 ppm. The alveolar retention of cyclopentane declined from 35% (observed with concentrations <20 ppm) to 5.4% at 1000 ppm and was related to an exposure dependent increase in the exhalation of unmetabolized cyclopentane. At concentrations <20 ppm 20% of the cyclopentane was exhaled unmetabolized compared to 88% at 1000 ppm and 99% at 10,000 ppm. In the second part of the study, the authors used the results presented above to develop a physiological toxicokinetic model. This model permitted a better understanding of the toxicokinetic processes occurring in rats exposed to cyclopentane vapors. It enabled the prediction of not only the average cyclopentane concentration in the whole body, but also concentrations in select organs and tissues (lung, arterial and venous blood, live, muscle, fat and richly perfused tissues). According to the model demand, distribution coefficients of 2.6, 2.7, 2.3, and 63 were determined for the blood: air, muscle: air, liver: air, and fat: air, respectively. The model was validated by comparing simulated concentration-time curves of the test chemical in the atmosphere of closed exposure systems and of predicted cyclopentane concentrations in blood of exposed animals. Steady-state concentrations of 0.0015, 0.0037, and 0.053 µmol/mL were determined in the mixed venous blood entering the right ventricle in rats exposed to 53, 111, or 1100 ppm, respectively. Based on the physiological toxicokinetic model performance the authors concluded that the model predictions were in agreement with the experimental data. This study was classified as reliable without restrictions because it is indicated in the study protocol that the study was conducted according to GLP or equivalent and the study appears to be well conducted and provides important information on the inhalation kinetics of cyclopentane.

 

Two read-across studies were identified on the toxicokinetics of n-pentane. In a metabolism study to see whether pentane was metabolized in the intact rat, [1,5-14C]n-pentane was administered to male Sprague-Dawley rats via inhalation in two experiments (Daugherty et al., 1988). Both experiments used an average of 3.44 microcuries of [1,5 -14C]n-pentane plus 1.0 milliliter of 10.1 μmol/mL unlabeled n-pentane gas. In the first experiment, 6 mice were exposed and in the second experiment 4 mice were exposed. Differing amounts of calcium sulfate desiccant were used for each experiment; experiment I used 271 grams calcium sulfate desiccant, and experiment II used 130 grams calcium sulfate desiccant. In a preliminary study that was conducted without animals, n-pentane was detected in the chamber atmosphere after rapidly evacuating the chamber system and resealing the system whenever calcium sulfate was present. This result suggests that the desiccant traps n-pentane but releases back into the chamber as chamber n-pentane concentration decreases. For experiment 1, radioactivity in whole blood and various tissues was measured after animals were sacrificed once the experiment ended. Urine samples were collected in experiment II, and both experiments collected expired air by measuring the chamber atmosphere and carbon dioxide trap. Approximately 78.9% of total radioactivity administered as radiolabeled [14C] n-pentane was recovered when combining the results of the two experiments. According to the study authors, a proportion of the total 14C activity unaccounted for may be due to the trapping of n-pentane in the desiccant. Tissue and organ results from experiment I showed that the liver, small intestine, and kidneys contained the highest radioactivity per gram of tissue (wet weight). Muscle and liver accounted for the largest proportion of the estimated total of radioactivity expressed as a percentage of the total radioactivity injected into the chamber. Based on these results, the study authors concluded that pentane was metabolized in the intact rat. This study received a Klimisch score of 2 and was classified as reliable with restrictions because while there is no statement regarding whether this study was conducted according to GLP or equivalent, the full study protocol was provided, including test materials and methods.

 

In a second study on the toxicokinetics of n-pentane, F344 rats were exposed to a variety of hydrocarbon vapours, including pentane, via inhalation for 80 minutes for 5 consecutive days. Doses were as follows: 1 ppm on day 1; 10 ppm on day 2; 100 ppm on day 3; 1000 ppm on day 4; and 5000 ppm on day 5 (Dahl et al., 1988). The study report only presents data for the 100 ppm dose. When pentane was inhaled at 100 ppm, the uptake ranges were 3.6±0.2 and 4.2±0.4 nmol/kg/min/ppm (the mean of two experiments). Additionally, the uptake rate of pentane was greater than that of 2-methylbutane. The study authors concluded that (1) highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; (2) unsaturated compounds are better absorbed than saturated ones; and (3) branched hydrocarbons are less well-absorbed than unbranched ones. This study received a Klimisch score of 2 and was classified as reliable with restrictions because although the study did not follow an OECD guideline and it was not stated whether the study was GLP compliant, the study appears to be scientifically sound and there is an adequate level of detail.

Discussion on absorption rate:

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

 

 

 

Table2. 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.