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Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Scientific opinion
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Justification for type of information:
Data from secondary source
Type:
absorption
Results:
The substance is expected to be rapidly absorbed in the gastrointestinal tract
Type:
distribution
Results:
The substance is expected to be rapidly distributed throughout the body.
Type:
metabolism
Results:
The substance is expected to be extensively metabolized in mammals.
Type:
excretion
Results:
The substance is expected to be eliminated via urine and feces.

In general, aliphatic secondary alcohols are expected to be rapidly absorbed in the gastrointestinal tract (WHO, 2000).

The expected metabolic reactions in laboratory animals of these substances have been extensively reviewed by the EFSA CEF Panel (EFSA 2009a; EFSA CEF Panel 2012d).

The potential metabolic reactions involved in the biotransformation of secondary alcohols are (i) conjugation of secondary alcohols with glucuronic acid followed by excretion in the urine or bile; (ii) oxidation of secondary alcohols to the corresponding ketone (minor pathway in vivo); (iii) reduction of ketones to the corresponding secondary alcohol with subsequent excretion as conjugate of glucuronic acid; (iv) omega oxidation of short-chain ketones (carbon atoms < 5) or oxidation of the terminal methyl group and subsequent oxidation to yield an alpha-ketocarboxylic acid; (v) oxidation of double bonds; (vi) hydrolysis of esters via carboxylesterases (Heymann, 1980) followed by excretion of the secondary alcohol as glucuronide-conjugate and metabolism of the linear carboxylic acid by beta-oxidation in the fatty acid pathway and citric acid cycle.

Secondary alcohols are thus rapidly converted to innocuous substances and there is no evidence that they or their metabolites would accumulate in tissues.

References :

- WHO (World Health Organization), 2002. Evaluation of certain food additives. Fifty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives. Geneva, 4–13 June 2002. WHO Technical Report Series, No 913. WHO, Geneva, Switzerland.

- EFSA (European Food Safety Authority), 2009a. Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC) on Flavouring Group Evaluation 7, Revision 2 (FGE.07Rev2): Saturated and unsaturated aliphatic secondary alcohols, ketones and esters of secondary alcohols and saturated linear or branched-chain carboxylic acids from chemical group 5. The EFSA Journal 2009, 1020, 1–70. doi:10.2903/j.efsa.2011.1020

- EFSA CEF Panel (Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids), 2012d. Scientific Opinion on Flavouring Group Evaluation 7, Revision 4 (FGE.07Rev4): Saturated and unsaturated aliphatic secondary alcohols, ketones and esters of secondary alcohols and saturated linear or branched-chain carboxylic acids from chemical group 5. EFSA Journal 2012, 10(10): 2899, 78 pp. doi:10.2903/j.efsa.2012.2899

- Heymann E, 1980. Carboxylesterases and amidases. In: Enzymatic basis of detoxication, second edn. Ed Jakoby WB. Academic Press, New York, NY, USA, 291–323.

Conclusions:
Available data from secondary alcohols suggest rapid absorption of the chemical in the gastrointestinal tract, followed by extensive metabolism involving oxidation to ketones thus reduction of ketones with subsequent excretion as conjugate of glucuronic acid or oxidation of the terminal methyl group and subsequent oxidation to yield an alpha-ketocarboxylic acid; and metabolism of the linear carboxylic acid by beta-oxidation in the fatty acid pathway and citric acid cycle. Excretion is reported to occur in the urine or bile. Thus, there is no evidence that they or their metabolites would accumulate in tissues.
Executive summary:

Available data from secondary alcohols suggest rapid absorption of the chemical in the gastrointestinal tract, followed by extensive metabolism involving oxidation to ketones thus reduction of ketones with subsequent excretion as conjugate of glucuronic acid or oxidation of the terminal methyl group and subsequent oxidation to yield an alpha-ketocarboxylic acid; and metabolism of the linear carboxylic acid by beta-oxidation in the fatty acid pathway and citric acid cycle. Excretion is reported to occur in the urine or bile. Thus, there is no evidence that they or their metabolites would accumulate in tissues.

Endpoint:
dermal absorption, other
Remarks:
QSAR
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
Guideline:
other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment
Principles of method if other than guideline:
IH SkinPerm (v2.04) is a mathematical tool for estimating dermal absorption. The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum (SC) and the amount evaporating from the skin to the air.
Species:
other: human
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on study design:
DATA INPUT
Molecular weight: 130g/mol
Temperature: 25 °C
Vapour Pressure: 40 Pa
Water solubility: 986 mg/L
Log Kow: 2.86
Density: 819.6 mg/cm3
Melting point: -31.6°C

SCENARIO PARAMETERS
- Instantaneous deposition
Deposition dose*: 1000 mg
Affected skin area**: 1000 cm²
Maximum skin adherence***: 2 mg/cm²
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. End time observation: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

- Deposition over time
Affected skin area**: 1000 cm²
Maximum skin adherence***: 1 mg/cm²
Dermal deposition rate: 2 mg/cm²/hr
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

*Default value defined according to the internal validation study
**Estimated skin surface of two hands of an adult.
***The skin adherence field is greyed out and a default of -1 is indicated if the substance is a liquid at 25°C. Smart logic is built into IH SkinPerm; the program recognizes whether a substance is a solid or liquid at standard temperature (25°C) based on the physicochemical properties. For substances
that are solids at 25°C a maximum adherence value up to 2 mg/cm² is allowed based on studies of soil-on-skin adherence. If the deposition rate results in an increase above the input figure (0.2-2 mg/cm²), it is assumed that the surplus disappears just by removal from the skin.
*** 3 cm if clothing involved, 1 cm if bare skin involved

Time point:
8 h
Dose:
1000 mg
Parameter:
percentage
Absorption:
19.6 %
Remarks on result:
other: Instantaneous deposition
Time point:
8 h
Dose:
2 mg/cm²/h
Parameter:
percentage
Absorption:
4.6 %
Remarks on result:
other: Deposition over time for 8 hr
Conclusions:
The dermal absorption of octan-2-ol is estimated to be moderate (~20%).
Executive summary:

The dermal absorption of octan-2-ol leads to the following results, obtained using the SkinPerm v2.04 model according to the input data:

 

Instantaneous deposition

 

Deposition over time

End time observation 8 hr

Total deposition (mg) or deposition rate (mg/cm²/hr)

1000

1

Fraction absorbed (%)

19.6

 4.06

Amount absorbed (mg)

 196

650

Lag time stratum corneum (min)

5.93

Max. derm. abs. (mg/cm²/h)

0.0407

Description of key information

Toxicokinetic

In general, aliphatic secondary alcohols are expected to be rapidly absorbed in the gastrointestinal tract. The absorption, distribution, metabolism and elimination (ADME) of substances such as isopropanol have been well characterized in mammals and show that the substance is readily absorbed in animals and humans through the lungs, skin and the gastrointestinal tract.

The potential metabolic reactions involved in the biotransformation of secondary alcohols are (i) conjugation of secondary alcohols with glucuronic acid followed by excretion in the urine or bile; (ii) oxidation of secondary alcohols to the corresponding ketone (minor pathway in vivo); (iii) reduction of ketones to the corresponding secondary alcohol with subsequent excretion as conjugate of glucuronic acid; (iv) omega oxidation of short-chain ketones (carbon atoms < 5) or oxidation of the terminal methyl group and subsequent oxidation to yield an alpha-ketocarboxylic acid; (v) oxidation of double bonds; (vi) hydrolysis of esters via carboxylesterases followed by excretion of the secondary alcohol as glucuronide-conjugate and metabolism of the linear carboxylic acid by beta-oxidation in the fatty acid pathway and citric acid cycle.

Secondary alcohols are thus rapidly converted to innocuous substances and there is no evidence that they or their metabolites would accumulate in tissues.

The absorption/excretion, toxicokinetics, metabolism and distribution data of octan-2-ol were evaluated also from the available toxicological data and the physicochemical properties as suggested by the REACH Guidance Chapter R.7c:

Molecular weight: 130 g/mol

Vapour Pressure: 64.7 Pa (25 °c)

Water solubility: 986 mg/L

Log Kow: 2.86

Density: 819 mg/cm3

Melting point: -31.6°C

Oral absorption

According to the REACH Guidance, the physicochemical characteristics of octan-2-ol (log Pow 2.86) and the molecular mass (130. g/mol) are in a range suggestive of absorption as such from the oral route subsequent to ingestion. Indeed, generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. As octan-2-ol is a moderate water-soluble substance, it should dissolve partially into the gastrointestinal fluids. However, as its molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Therefore, as suggested by the QSAR models, a default value of 100% oral absorption will be used for risk assessment.

Inhalation

According to the REACH Guidance, the physicochemical characteristics of octan-2-ol (log Pow 2.86) and the molecular mass (130. g/mol) are in a range suggestive of absorption as such from the respiratory subsequent to inhalation exposure.

Therefore, according to the REACH Guidance, a default value of 100% inhalation absorption will be used for risk assessment.

Dermal absorption

According to the REACH Guidance, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Between 100 -1000 mg/l absorption is anticipated to be moderate to high. Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

The rate of absorption was estimated using the IH SkinPerm model (v2.04). For an instantaneous deposition of 1000 mg over 1000 cm² of skin or a deposition over time of 2 mg/cm²/h, the absorption rates were 19.6% and 4.06%, respectively.

Therefore, according to the REACH Guidance, a default value of 50% skin absorption will be used for risk assessment.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information


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