Alcohols, C12-14

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Objective of study:

absorption

distribution

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: Groups of 3 hairless mice were used. The 1-C14 labelled test substances were applied to the dorsal skin using a plaster for a 24 hour period. Immediately following application of the test material each animal was placed in a container to measure expiratory excretion. At the end of the exposure period the treated area of skin was excised and dissolved using tissue solubiliser. The carcass was homogenised in a blender wwith sodium hydroxide. An aliquot of the homogenate was then dried and combusted for determination of radioactivity.
The effect of different solvents and concentration of the solvent was also investigated. The role of skin irritation in absorption of test substance was also examined.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

mouse

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Groups of 3 hairless mice were used. The 1-C14 labelled test substances were applied to the dorsal skin using a plaster for a 24 hour period. Immediately following application of the test material each animal was placed in a container to measure expiratory excretion. At the end of the exposure period the treated area of skin was excised and dissolved using tissue solubiliser. The carcass was homogenised in a blender wwith sodium hydroxide. An aliquot of the homogenate was then dried and combusted for determination of radioactivity.

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

24 hour period.

No. of animals per sex per dose / concentration:

Groups of 3 hairless mice were used

Control animals:

yes

Distribution results were reported for lauryl alcohol (98% pure). 95% of the dose adminstered was recovered from the application site at 24 hours after dosing. 0.13% remained in the body while 0.10% was excreted in the urine and faeces. 2.61% was excreted in expired air as CO2. The ratio of the amount of compound excreted via expired air to the amount absorbed is the expiratory excretion rat. It was 91% for lauryl alcohol. The respiratory excretion rates for all the other alcohols investigated were >65% although all the actual data is not reported.

Absorption decreased with increasing carbon chain length. The absorption rate was investigated in different solvents (squalene, castor oil, triethyl citrate (TEC). The percutaneous absorption rate of undiluted n-octanol was 50%, this was increased in squalene but decreased in castor oil or TEC. This was also reported with the other alcohols tested and the tendency was more pronounced at higher concentrations.

The degree of skin irritation was proportionally related to the degree of percutaneous absorption.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
Following skin application of lauryl alcohol about 2.84 % of the administered dose was absorbed. Of this absorbed dose >90% was excreted in expired air (CO2). A similar trend was observed with the other alcohols tested. Absorption decreased with increasing carbon chain length and was affected by solvent and concentration.

Executive summary:

At least 65% of the absorbed dose is excreted as CO2 in the expired air. Absorption decreased with increasing carbon chain length and was affected by solvent and concentration.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

distribution

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

These studies were carried out to determine the extent to which various monohydric aliphatic alcohols, including C6-C18 alcohols included in this category, form glucuronic acid conjugates in the rabbit.
Groups of 3 Chinchilla rabbits, about 3 kg in weight, were administered various alcohols in water by gavage at a dose level of 25 m.moles/rabbit. The excretion of glucuronic acids was determined daily in the urine for a week prior to administration of the test compound to establish a base line. Following dosing the urine was collected for 24 hours and the glucuronides extracted.

GLP compliance:

no

Radiolabelling:

not specified

Species:

rabbit

Strain:

Chinchilla

Sex:

male/female

Details on test animals or test system and environmental conditions:

Groups of 3 Chinchilla rabbits, about 3 kg in weight, were administered various alcohols in water by gavage at a dose level of 25 m.moles/rabbit. The excretion of glucuronic acids was determined daily in the urine for a week prior to administration of the test compound to establish a base line. Following dosing the urine was collected for 24 hours and the glucuronides extracted.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

daily

Remarks:

Doses / Concentrations:
25 m.moles/rabbit.

No. of animals per sex per dose / concentration:

Groups of 3 Chinchilla rabbits, about 3 kg in weight,

Control animals:

yes

Test no.:

#1

Toxicokinetic parameters:

half-life 1st:

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd:

Test no.:

#3

Toxicokinetic parameters:

half-life 3rd:

Metabolites identified:

yes

Details on metabolites:

The extra glucuronide excreted as % of dose (average of 3 rabbits, 2 rabbits for *) was as follows:
n-hexanol 10.3%; n-heptanol 5.3%; n-octanol 9.5%; n-nonanol 4.1%; n-decanol* 3.5%; n-octadecanol* 7.6%.
It was reported that absorpton of n-decanol and n-octadecanol was incomplete and irregular and the alcohol could be isolated in quantity from the faeces.

The extra glucuronide excreted as % of dose (average of 3 rabbits, 2 rabbits for *) was as follows:

n-hexanol 10.3%; n-heptanol 5.3%; n-octanol 9.5%; n-nonanol 4.1%; n-decanol* 3.5%; n-octadecanol* 7.6%.

It was reported that absorpton of n-decanol and n-octadecanol was incomplete and irregular and the alcohol could be isolated in quantity from the faeces.

No further information on other biotransformation pathways of these alcohols was provided.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
All the primary alcohols investigated form glucuronic acid conjugates which are excreted in the urine. However this was generally <10% of the dose.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

Male Sprague-Dawley rats, average weight 200 g which has been maintained on a laboratory diet (Altromin, Altromin GmbH, Lage, Federal Republic of Germany) were used as experimental animals. Solutions of cis-9-octadecenol.,8 5 MBq in 0.1 ml ethanol, were injected into the tail veins of groups of 5-9 rats. The rats were killed by cervical dislocation at intervals of 1 h, 24 h, 48 h and 96 h after application of the substrate. Each tissue was homogenized in a mixture of chloroform/methanol (1 : 2, v/v), and the lipids were isolated according to an established procedure. Radioactivity in aliquots of the lipid extracts was measured. For further analysis the lipid extracts from each type of tissue were pooled for every group.

Route of administration:

intravenous

Vehicle:

other: ethanol

Duration and frequency of treatment / exposure:

only once

Remarks:

Doses / Concentrations:
olutions of cis-9-octadecenol.,8 5 MBq in 0.1 ml

No. of animals per sex per dose / concentration:

29

Control animals:

yes

Positive control reference chemical:

see attached file

Details on study design:

see attached file

Details on dosing and sampling:

see attached file

Statistics:

see attached file

Preliminary studies:

The test material was rapidly utilised for the biosynthesis of lipids in most tissues of the rat (heart, lungs, liver,
intestine, kidney, brain and plasma).

Details on absorption:

see attached file

Details on distribution in tissues:

see attached file

Details on excretion:

see attached file

Toxicokinetic parameters:

half-life 1st: 1-24 h

Toxicokinetic parameters:

half-life 2nd: 1-24 h

Toxicokinetic parameters:

half-life 3rd: 1-24 h

Metabolites identified:

yes

Details on metabolites:

The results indicate that the test material was rapidly utilised for the biosynthesis of lipids in most tissues of the rat (heart, lungs, liver, intestine, kidney, brain and plasma). Most of the radioactive label was incorporated into the acyl moieties of both phospholipids and neutral lipids.
The pattern of incorporation of radioactivity into the alkyl, alk-1-enyl and acyl moieties of the lipids suggested that oxidation and esterification of the resulting fatty acid to a wide variety of lipids are the predominant reactions. Acylation is observed mostly in the liver while alkylation to alkoxylipids occurred predominately in the heart. The presence of a large proportion of the dose (52%) in the lungs 1 hour after dosing and an increase in the proportion of  radioactivity in acyl moieties at 24 hours suggests  preferential deposition in the lungs followed by incorporation into lipids.

The results indicate that the test material was rapidly utilised for the biosynthesis of lipids in most tissues of the rat (heart, lungs, liver, intestine, kidney, brain and plasma). Most of the radioactive label was incorporated into the acyl moieties of both phospholipids and neutral lipids.

The pattern of incorporation of radioactivity into the alkyl, alk-1-enyl and acyl moieties of the lipids suggested that oxidation and esterification of the resulting fatty acid to a wide variety of lipids are the predominant reactions. Acylation is observed mostly in the liver while alkylation to alkoxylipids occurred predominately in the heart. The presence of a large proportion of the dose (52%) in the lungs 1 hour after dosing and an increase in the proportion of  radioactivity in acyl moieties at 24 hours suggests  preferential deposition in the lungs followed by incorporation into lipids.

 

Radioactivity decreased most rapidly in the liver, kidneys and intestines.

 

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
The test material was rapidly utilised for the biosynthesis of lipids in most tissues of the rat (heart, lungs, liver, intestine, kidney, brain and plasma).
This study was cited in the Cosmetic Ingredients Review, 1985.

Executive summary:

The distribution of radioactivity from intravenously administered cis-9-octadecenol to various tissues of the rat was studied as a function of time. The pattern of incorporation of radioactivity into alkyl, alk-I-enyl and acyl moieties of the lipids in heart, lungs, liver, intestine, kidney, brain and plasma revealed that oxidation of the long-chain alcohol and esterification of the resulting fatty acid to a wide variety of lipids are by far the most predominant reactions. Acylation of the long-chain alcohol is observed especially in liver, which appears to be the major site of biosynthesis of wax esters. Alkylation of the long-chain alcohol to alkoxylipids occurs in most tissues, most predominantly in the heart.

 

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

distribution

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: Groups of 3 hairless mice were used. The 1-C14 labelled test substances were applied to the dorsal skin using a plaster for a 24 hour period. Immediately following application of the test material each animal was placed in a container to measure expiratory excretion. At the end of the exposure period the treated area of skin was excised and dissolved using tissue solubiliser. The carcass was homogenised in a blender wwith sodium hydroxide. An aliquot of the homogenate was then dried and combusted for determination of radioactivity.
The effect of different solvents and concentration of the solvent was also investigated. The role of skin irritation in absorption of test substance was also examined.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

mouse

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Groups of 3 hairless mice were used. The 1-C14 labelled test substances were applied to the dorsal skin using a plaster for a 24 hour period. Immediately following application of the test material each animal was placed in a container to measure expiratory excretion. At the end of the exposure period the treated area of skin was excised and dissolved using tissue solubiliser. The carcass was homogenised in a blender wwith sodium hydroxide. An aliquot of the homogenate was then dried and combusted for determination of radioactivity.

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

24 hour period.

No. of animals per sex per dose / concentration:

Groups of 3 hairless mice were used

Control animals:

yes

Distribution results were reported for lauryl alcohol (98% pure). 95% of the dose adminstered was recovered from the application site at 24 hours after dosing. 0.13% remained in the body while 0.10% was excreted in the urine and faeces. 2.61% was excreted in expired air as CO2. The ratio of the amount of compound excreted via expired air to the amount absorbed is the expiratory excretion rat. It was 91% for lauryl alcohol. The respiratory excretion rates for all the other alcohols investigated were >65% although all the actual data is not reported.

Absorption decreased with increasing carbon chain length. The absorption rate was investigated in different solvents (squalene, castor oil, triethyl citrate (TEC). The percutaneous absorption rate of undiluted n-octanol was 50%, this was increased in squalene but decreased in castor oil or TEC. This was also reported with the other alcohols tested and the tendency was more pronounced at higher concentrations.

The degree of skin irritation was proportionally related to the degree of percutaneous absorption.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
Following skin application of lauryl alcohol about 2.84 % of the administered dose was absorbed. Of this absorbed dose >90% was excreted in expired air (CO2). A similar trend was observed with the other alcohols tested. Absorption decreased with increasing carbon chain length and was affected by solvent and concentration.

Executive summary:

At least 65% of the absorbed dose is excreted as CO2 in the expired air. Absorption decreased with increasing carbon chain length and was affected by solvent and concentration.

Reference 5

Endpoint:

dermal absorption in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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

Justification for type of information:

QSAR prediction:US EPA accepted QSAR method for chemicals properties assessment.

Qualifier:

no guideline required

Principles of method if other than guideline:

Using the DERMWIN v2.01 QSAR model

GLP compliance:

no

Remarks:

not applicable to QSAR models

Radiolabelling:

no

Species:

other: QSAR model,

Strain:

other: QSAR model,

Sex:

not specified

Type of coverage:

other: QSAR model

Vehicle:

other: QSAR model

Duration of exposure:

not applicable to QSAR models

Doses:

not applicable to QSAR models

No. of animals per group:

not applicable to QSAR models

Control animals:

no

Details on study design:

not applicable to QSAR models

Details on in vitro test system (if applicable):

not applicable to QSAR models

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

A QSAR model predicts that the permeability of Alcohols, C12-14 to human skin is quite low. The permeability coefficient was determined to be 0.00571 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=0.362 cm/hr.

A QSAR model predicts that the permeability of Alcohols, C12-14 to human skin is quite low. The permeability coefficient was determined to be 0.00571 mg/cm2, which is around 1% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)=0.362 cm/hr.

Conclusions:

A QSAR model predicts that the permeability of Alcohols, C12-14 to human skin is quite low. The permeability coefficient was determined to be 0.00571 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=0.362 cm/hr.

Executive summary:

A QSAR model predicts that the permeability of Alcohols, C12-14 to human skin is quite low. The permeability coefficient was determined to be 0.00571 mg/cm2, which is around 1% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)=0.362 cm/hr.

Description of key information

Alcohols, C12-14  has not bioaccumulation potential. In summary, Alcohols, C12-14 (CAS# 80206-82-2) is from the category of Long Chain Alcohols (C6-22 primary aliphatic alcohols).Long chained alcohols are generally highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products. 
From the available data and the data on the closely related substances it is concluded that it is unlikely that Alcohols, C12-14 causes genetic effects or has an effect on male or female fertility and has not bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

1

Additional information

Alcohols, C12-14 is from the categoryof Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22. 

 The substance (C12-14 Alcohols CAS № 80206-82-2) comprises 100% linear; >90% C12 and C14 (C12>14), <10% C16

All of the alcohols would be expected to be stable in respect of abiotic degradation in water. Photo-oxidation in aqueous systems will not be significant.

Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. This substance has no hydrolysable structural features and would be expected to be stable in respect of hydrolysis. Alcohols have no hydrolysable groups and are therefore not susceptible to hydrolysis. Oxidation would not be expected under normal environmental conditions.

Bioaccumulation is considered to be low for Alcohols, C12-14 which is from the category of Long Chain aliphatic Alcohols, which are rapidly metabolised in higher organisms.

The estimated Log BCF of Alcohols, C12-14 is 1.677 (BCF = 47.59 L/kg wet-wt).This substance has a limited potential to bioaccumulate (based on log Kow used by BCF estimates: 5.13, and predicted bioconcentration factors, log BCF = 1.677 (EPIWIN/BCF Program).

A 96 hours, hexadecan-1-ol bioconcentration factors (BCFs) for the Brachydanio rerio (new name: Danio rerio) species ranged from 500 to 1000 (Unilever,1996).

These experimental and estimated BCF values suggest that Alcohols, C12-14 has a low potential for bioaccumulation.

Chain lengths C11 and above have log Kow >4.5 and so could be considered to be potentially bioaccumulative.

Two evidences result in the conclusion that Alcohols, C12-14 is not expected to be B/vB:

1. Due to rapid degradation combined with evidence of rapid metabolism in mammalian and fish studies, it is unlikely that bioaccumulation of Alcohols, C12-14 would be demonstrated in studies.

2. The conduct of guideline-standard studies of bioaccumulation in fish would be confounded by the technical difficulties of maintaining the test alcohol in solution according to results of other long-term studies with invertebrates. In these studies, severe difficulties were encountered in conducting the study as biodegradation of the substance in the test system was almost complete within the 24 h test media renewal period.

Therefore, Alcohols, C12-14 is not considered to be bioaccumulative.

Toxicokinetics, metabolism and distribution

The substance Alcohols, C12-14 (CAS# 80206-82-2) is from the category of Long Chain Alcohols (C6-22 primary aliphatic alcohols).Aliphatic alcohols are expected to be absorbed by all common routes of exposure. Based on comparative in vitro skin permeation data and dermal absorption studies in hairless mice, aliphatic alcohols show an inverse relationship between absorption potential and chain length with the shorter chain alcohols having a significant absorption potential (Iwataet al., 1987).

The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrialb-oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids. In the case of unsaturated carboxylic acids, cleavage of C2-units continues until a double bond is reached. Since double bonds in unsaturated fatty acids are in the cis-configuration, whereas the unsaturated acyl-CoA intermediates in theb-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter,b-oxidation continues as with saturated carboxylic acids (WHO, 1999).

The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids Mukherjeeet al. 1980). A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate (Kamilet al., 1953).

Similar to the dermal absorption potential, it is expected that orally administered aliphatic alcohols also show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols.

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.

In summary, Alcohols, C12-14 (CAS# 80206-82-2) is from the category of Long Chain Alcohols (C6-22 primary aliphatic alcohols).Long chained alcohols are generally highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products.

From the available data and the data on the closely related substances it is concluded that it is unlikely that Alcohols, C12-14 causes genetic effects or has an effect on male or female fertility and has not bioaccumulation potential.