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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
871 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86.
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEC
Value:
10 400 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
5 226 mg/m³
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting value of 10400 mg/m3 was modified to account for duration adjustment and differences in breathing volume in rats and humans with light worker activity.

Modified concentration = 10400 mg/m3 x (6h/8h) x (6.7 m3/10m3)

AF for dose response relationship:
1
Justification:
Point of departure is based on a NOAEC.
AF for differences in duration of exposure:
2
Justification:
Factor of 2 is appropriate when extrapolating from a subchronic to a chronic duration of exposure [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not appropriate when extrapolating inhalation to inhalation exposure [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for intraspecies differences:
3
Justification:
Worker population [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
77 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86.
Overall assessment factor (AF):
24
Dose descriptor starting point:
other: BMDL with a 2-fold increase in concurrent control mean used as the BMR
Value:
1 857 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 857 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Worst-case systemic concentration from oral route. Although human skin is considered to be less permeable than rat skin, a species-specific absorption factor was not used in the rat to human dermal DNEL calculations. 100% absorption through dermal application was assumed.

AF for dose response relationship:
1
Justification:
Point of departure is based on a BMDL.
AF for differences in duration of exposure:
2
Justification:
AF of 2 is appropriate when extrapolating from subchronic to chronic duration [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling (rat to humans) is appropriate when extrapolating from dermal exposures [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for intraspecies differences:
3
Justification:
Worker population [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The long-term DNEL for workers through the inhalation route (systemic effects) was based on a study of rats exposed to a C9-C14 aliphatic (<2% aromatics) hydrocarbon solvent, 6 hours/day, 5 days/week for 13 weeks (Carrillo et al, 2013). The highest concentration tested (10,400 mg/m3) was close to a maximally attainable vapor concentration. There were no effects at this concentration that were relevant to humans. The resultant DNELs are protective of acute CNS effects as indicated below.

In studies in rodents, 8 hours of exposure to n-decane (Lammers et al., 2010) produced limited evidence of acute CNS effects at 5000 mg/m3 with 1500 mg/m3 as a no effect level. Similar results were obtained with a C9-C11 isoparaffinic solvent (Lammers et al., 2001a). A C10 cycloparaffinic solvent also produced limited evidence of CNS effects at 5000 mg/m3, but the no effect level was established at 2500 mg/m3 (Lammers et al. 2001b).

In other studies, n-alkanes containing more than 9 carbons were reported as without effect in 8 hour studies of acute CNS effects in rats at levels up to the maximally attainable vapor concentrations (Nilsen et al., 1988). Similarly, it was reported that isoparaffinic solvents containing 9 or more carbons could not form stable vapor concentrations at levels which could produce acute CNS effects in mice in 30 minutes (Bowen and Balster). 

For dermal DNEL calculations, NOAEL was based on a 90 -day subchronic oral toxicity study in rats with C9 -C14 aliphatics, <2% aromatics. Point of departure was determined to be 1857 mg/kg/day, a BMDL value based on increased serum ALT levels in the rat.

Dermal and inhalation are the relevant routes of exposure. Aspiration is a potential hazard, but a DNEL calculation is not appropriate for an aspiration hazard.

Workers are expected to have infrequent and short-term exposures; however, for calculation of the DNEL for REACH purposes it is assumed that workers have maximal repeated exposure for 8 hr/day for 5 day/wk.

In summary the animal and human data indicate that the worker long term inhalation DNEL is also protective for short term effects including acute CNS effects.

References:

Carrillo, J. C., David Adenuga, M., McKee, R. H., Roth, R. N., Steup, D., & Simpson, B. J. (2013). The sub-chronic toxicity in rats of isoparaffinic solvents. Regul Toxicol Pharmacol, 67(3), 446-455.

Lammers, J. et al. (2010). Neurobehavioral effects of acute exposure to normal (n-) paraffins. International Journal of Toxicology (submitted for publication)

Lammers, J. et al. (2001a). The effects of short term inhalatory exposure to Isane IP 155 on behavior in the rat. TNO Report V99.1111 (unpublished data).

Lammers, J. et al. (2001b). The effects of short-term inhalatory exposure to Nappar 10 on behavior in the rat. TNO Report V99.1112. (unpublished data).

Nilsen, O. et al. (1988). Toxicity of n-C9 to n-C13 alkanes in the rat on short term inhalation. Pharmacology and Toxicology 62:259-266.

Bowen, S. and Balster, R. (1998). The effects of inhaled isoparaffins on locomotor activity and operant performance in mice. Pharmacology, Biochemistry and Behavior 61:271-280.

McKee, R., et al. (2010). Neurobehavioral effects of acute exposure to aromatic hydrocarbons. International Journal of Toxicology in press.

Korsak, K. et al. (1998). Toxic effects of acute inhalation exposure to 1-methylnaphthalene and 2-methylnaphthalene in experimental animals. International Journal of Occupational Medicine and Environmental Health 11:335-342.

Carpenter, C. et al. (1975). Petroleum hydrocarbon toxicity studies VII. Animal and human response to vapors of “70 solvent.” Toxicology and Applied Pharmacology 34:395-412.

Adenuga D, Carrillo J-C, McKee RH (2014) The sub-chronic oral toxicity of dearomatized hydrocarbon solvents in Sprague–Dawley rats.Regulatory Toxicology and Pharmacology70:659-672

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
185 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86.
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
Value:
10 400 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
1 857 mg/m³
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting value of 10400 mg/m3 was modified to account for duration adjustment.

Modified concentration = 10400 mg/m3 x (6h/24h) x (5days/7days)

AF for dose response relationship:
1
Justification:
Point of departure is based on a NOAEC.
AF for differences in duration of exposure:
2
Justification:
AF of 2 is appropriate when extrapolating from subchronic to chronic duration [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not appropriate when extrapolating dermal to dermal exposure [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for intraspecies differences:
5
Justification:
General Population [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
46 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86.
Overall assessment factor (AF):
40
Dose descriptor starting point:
other: BMDL with a 2-fold increase in concurrent control mean used as the BMR
Value:
1 857 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 857 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Worst-case systemic concentration from oral route. Although human skin is considered to be less permeable than rat skin, a species-specific absorption factor was not used in the rat to human dermal DNEL calculations. 100% absorption through dermal application was assumed.

AF for dose response relationship:
1
Justification:
Point of departure is based on a BMDL.
AF for differences in duration of exposure:
2
Justification:
AF of 2 is appropriate when extrapolating from subchronic to chronic duration [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling (rat to humans) is appropriate when extrapolating from dermal exposures [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for intraspecies differences:
5
Justification:
General Population [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
46 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86.
Overall assessment factor (AF):
40
Dose descriptor starting point:
other: BMDL with a 2-fold increase in concurrent control mean used as the BMR
Value:
1 857 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 857 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation with oral exposure. No further modification of the starting point needed.

AF for dose response relationship:
1
Justification:
Point of departure is based on a BMDL.
AF for differences in duration of exposure:
2
Justification:
AF of 2 is appropriate when extrapolating from subchronic to chronic duration [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling (rat to humans) is appropriate when extrapolating from dermal exposures [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
AF for intraspecies differences:
5
Justification:
General Population [ECETOC. (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86].
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The long-term DNEL for general population through the inhalation route (systemic effects) was based on a study of rats exposed to a C9 -C14 aliphatic (<2% aromatics) hydrocarbon solvent, 6 hours/day, 5 days/week for 13 weeks (Carrillo et al, 2013). The highest concentration tested (10400 mg/m3) was close to a maximally attainable vapor concentration. There were no effects at this concentration that were relevant to humans. The resultant DNELs are protective of acute CNS effects as indicated below.

In studies in rodents, 8 hours of exposure to n-decane (Lammers et al., 2010) produced limited evidence of acute CNS effects at 5000 mg/m3 with 1500 mg/m3 as a no effect level. Similar results were obtained with a C9-C11 isoparaffinic solvent (Lammers et al., 2001a). A C10 cycloparaffinic solvent also produced limited evidence of CNS effects at 5000 mg/m3, but the no effect level was established at 2500 mg/m3 (Lammers et al. 2001b).

In other studies, n-alkanes containing more than 9 carbons were reported as without effect in 8 hour studies of acute CNS effects in rats at levels up to the maximally attainable vapor concentrations (Nilsen et al., 1988). Similarly, it was reported that isoparaffinic solvents containing 9 or more carbons could not form stable vapor concentrations at levels which could produce acute CNS effects in mice in 30 minutes (Bowen and Balster). 

For oral/dermal DNEL calculations, NOAEL was based on a 90 -day subchronic oral toxicity study in rats with C9 -C14 aliphatics, <2% aromatics.Point of departure was determined to be 1857 mg/kg/day, a BMDL value based on increased serum ALT levels in the rat.

Dermal and inhalation are the relevant routes of exposure. An oral DNEL was calculated for use in an indirect exposure assessment; the oral route is not expected to be a significant exposure route. Aspiration is a potential hazard, but a DNEL calculation is not appropriate for an aspiration hazard.

Consumers in the general population are expected to have infrequent and short-term exposures. However, for calculation of DNELs for REACH, it is assumed that consumers have a maximal repeated dose for 24 hr/day for 7 day/wk.

References:

Carrillo, J. C., David Adenuga, M., McKee, R. H., Roth, R. N., Steup, D., & Simpson, B. J. (2013). The sub-chronic toxicity in rats of isoparaffinic solvents. Regul Toxicol Pharmacol, 67(3), 446-455.

Lammers, J. et al. (2010). Neurobehavioral effects of acute exposure to normal (n-) paraffins. International Journal of Toxicology (submitted for publication)

Lammers, J. et al. (2001a). The effects of short term inhalatory exposure to Isane IP 155 on behavior in the rat. TNO Report V99.1111 (unpublished data).

Lammers, J. et al. (2001b). The effects of short-term inhalatory exposure to Nappar 10 on behavior in the rat. TNO Report V99.1112. (unpublished data).

Nilsen, O. et al. (1988). Toxicity of n-C9 to n-C13 alkanes in the rat on short term inhalation. Pharmacology and Toxicology 62:259-266.

Bowen, S. and Balster, R. (1998). The effects of inhaled isoparaffins on locomotor activity and operant performance in mice. Pharmacology, Biochemistry and Behavior 61:271-280.

McKee, R., et al. (2010). Neurobehavioral effects of acute exposure to aromatic hydrocarbons. International Journal of Toxicology in press.

Korsak, K. et al. (1998). Toxic effects of acute inhalation exposure to 1-methylnaphthalene and 2-methylnaphthalene in experimental animals. International Journal of Occupational Medicine and Environmental Health 11:335-342.

Carpenter, C. et al. (1975). Petroleum hydrocarbon toxicity studies VII. Animal and human response to vapors of “70 solvent.” Toxicology and Applied Pharmacology 34:395-412.

Adenuga D, Carrillo J-C, McKee RH (2014) The sub-chronic oral toxicity of dearomatized hydrocarbon solvents in Sprague–Dawley rats. Regulatory Toxicology and Pharmacology70:659-672