Undecan-1-ol

Endpoint summary

Description of key information

They key study by Jacobs & Martens (1992) (reliability 2) reports the undiluted undecanol to be irritating to skin following a 4 hour occlusive exposure to rabbit skin. The study on undecan-1-ol for eye irritation (Younger Labs 1972; rel 2) found undecanol to be a mildly irritating. The related substance, undecacn-1-ol, linear and branched, was found to be irritant (Biolab 1985; rel 2), therefore undecan-1-ol is concluded to be irritant to the eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

reporting of results limited

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

No data available.

Type of coverage:

not specified

Preparation of test site:

shaved

Vehicle:

other: undiluted (also as 25 and 50% solution in PEG 400)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL

- Concentration (if solution): Test material was applied as three different doses; undiluted and 25% and 50% in polyethylene glycol MW 400.


VEHICLE : glycol MW 400

Duration of treatment / exposure:

4 hour(s)

Observation period:

72 hours (Examination points at 1, 24, 48 and 72 hours)

Number of animals:

6

Details on study design:

TEST SITE

- coverage: 6cm2


REMOVAL OF TEST SUBSTANCE

-not reported

SCORING SYSTEM: Draize scoring criteria.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24/48/72h

Score:

> 2

Max. score:

3

Remarks on result:

other: Compound preparation: neat. Irritating to skin.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24/48/72h

Score:

> 2

Max. score:

2.8

Remarks on result:

other: Compound preparation: 50% undecanol in polyethylene glycol MW 400. Irritating to skin.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24/48/72h

Score:

> 1

Max. score:

2

Remarks on result:

other: Compound preparation: 25% undecanol in polyethylene glycol MW 400. Not irritating.

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24/48/72h

Score:

0.8

Max. score:

0.8

Remarks on result:

other: Compound preparation: neat.

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24/48/72h

Score:

> 0.5

Max. score:

0.8

Remarks on result:

other: Compound preparation: 50% undecanol in polyethylene glycol MW 400.

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24/48/72h

Score:

0

Max. score:

0

Remarks on result:

other: Compound preparation: 25% undecanol in polyethylene glycol MW 400.

Irritant / corrosive response data:

Individual animal scores were not reported.

Other effects:

REVERSIBILITY: Irritation scores were only reported up to 72 hours after exposure and over this time course the irritant effects were not reversible. 
Group mean erythema scores increased over this observation period for all test concentrations. For undiluted material erythema scores were as 
follows 24 hour 1.5; 48 hours 2.4; 72 hour 3, oedema remained constant at 0.8. Erythema scores with the 50% solution increased from 2.2 to 2.8 
while the oedema score reduced from 0.8 to 0.2. The 25% solution showed an increase in erythema score from 1.2 to 2.0 there was no oedema. 

Interpretation of results:

Category 3 (mild irritant) based on GHS criteria

Conclusions:

Following a 4 hour occlusive exposure to rabbit skin undiluted undecanol was found to be irritant according to both EU and GHS (category 2) criteria. 25 and 50% dilutions in PEG400 were also tested, the 50% dilution was irritant under EU criteria while both the 25% and 50% dilutions would be considered mild irritants (category 3) under GHS.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1972

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

The eye reactions were scored according to Draize.

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Vehicle:

unchanged (no vehicle)

Controls:

other: other eye

Amount / concentration applied:

Amount applied: 0.1 ml

Duration of treatment / exposure:

single instillation

Observation period (in vivo):

7 days (Scored at 1, 24, 48, 72, 120 and 168 hours).

Number of animals or in vitro replicates:

3M, 3F

Details on study design:

Eyes rinsed with warm isotonic solution after the 24 hour reading.

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

24 h

Score:

13.3

Max. score:

110

Reversibility:

fully reversible within: 120 hours

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

48 h

Score:

7.3

Max. score:

110

Reversibility:

fully reversible within: 120 hours

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

72 h

Score:

0.6

Max. score:

110

Reversibility:

fully reversible within: 120 hours

Remarks on result:

other: individual animal scores for conjunctivae, iris, chemosis and cornea were not reported.

Irritant / corrosive response data:

AVERAGE SCORE (24+48+72 hour) 10.7/110 combined cornea, iris and conjunctivae.

The individual scores were not reported only the calculated Draize scores.


DESCRIPTION OF LESIONS: There was immediate slight discomfort with slight redness and copious discharge at 10 minutes which developed to 

slight to moderate redness with copious discharge at 1 hour. At 24 hours there was barely perceptible corneal dullness, the reaction of the iris to 

light was sluggish in 2 rabbits (maximum score 1), conjunctival involvement (slight to moderate redness with whitish discharge) was observed in 

all eyes at this time period.

REVERSIBILITY: After 24 hours there was a gradual improvement through to 120 hours when the iris and cornea appeared normal. All eyes 

appeared  completely normal by 7 days.

Interpretation of results:

Category 2B (mildly irritating to eyes) based on GHS criteria

Conclusions:

Undecyl alcohol is described as slightly irritating to the eye in this test. Under GHS criteria the results suggest classification as mild. Under EU criteria undecyl would not be considered irritant.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Observation period could have been extended to fully observe reversal of effects.

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

Cited as Directive 84/449/EEC, B.5

Principles of method if other than guideline:

Observation period was only 7 days.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

- Source: Padre Antonio Breeding Centre, Mariano Comense, Italy
- Weight at study initiation: 2-3 kg

Vehicle:

unchanged (no vehicle)

Remarks:

undiluted

Controls:

other: untreated eye

Amount / concentration applied:

TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): undiluted

Duration of treatment / exposure:

unspecified

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE

- Washing (if done): no data
- Time after start of exposure: no data

SCORING SYSTEM: according to guideline

TOOL USED TO ASSESS SCORE: direct observation and UV lamp

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

1.11

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritant / corrosive response data:

- Conjunctivae (Redness): individual scores all 2 (group mean score 2)
- Conjunctivae (Chemosis): individual scores 4 rabbits 1, 2 rabbits 1.3  (group mean score 1.11)

REVERSIBILITY: Conjunctival redness and chemosis persisted to 7 days.  Individual scores for redness were 4 rabbits grade 1, 2 rabbits 0 
(group  mean score 0.66) and for chemosis wer 3 rabbits grade 1, 3 at 0 (group  mean score 0.5)

Other effects:

None reported.

Interpretation of results:

Category 2A (irritating to eyes) based on GHS criteria

Conclusions:

Using EU criteria Lial 111 is a category 2 irritant based on 24+48+72 hour scores for conjunctival redness of 2 in all rabbits and persistence to 7 days. The evidence of conjunctival irritation at 7 days was noticeably less than at 72 hours.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The skin irritation key study was chosen as it was the most recent. Two reliability 2 supporting studies which used undiluted test substance were available also. The first of these, Biolab SGS (1985) reports skin irritation scores that fall just below that which would classify as irritant according to the EU guideline. Younger Labs (1977) is in accordance with the key study, reporting undecanol to be irritating to rabbit skin. However, a study by Jacobs et al. (1978; rel 2) carried out in man and rabbit finds the test substance irritating in rabbit but not in man, which is taken into account in the justification for classification or non-classification. Human evidence on decan-1-ol suggests decan-1-ol not to be irritating by skin contact. A comparative 24 hour semi-occluded human skin patch study by Kaestner (1977) reported only slight, readily reversible irritation in humans. It should be noted that results from Kaestner’s comparative study suggests the percutaneous irritative effects of decan-1-ol to be more pronounced in rabbits than man.

The key study for eye irritation (Younger Labs 1977; rel 2) found undecan-1-ol only slightly irritating to the eye. However, in the light of the category trend and similar alcohols of related chain length it is likely that undecan-1-ol is irritating to the eye. Therefore, data from a related substance undecan-1-ol, linear and branched, was used as weight of evidence in order to derive an objective classification outcome. The study on the analogous undecan-1-ol, linear and branched, found the test material an eye irritant based on 24+48+72 hour scores for conjunctival redness of 2 in all rabbits and persistence to 7 days (Biolab 1985; rel 2).

Discussion of trends in the Category of C6-24 linear and essentially-linear aliphatic alcohols:

Animal studies in the lower members of both the linear alcohols and the UVCBs (C6-11) have a skin irritancy potential ranging from mild to irritant, whereas alcohols in the range of C12 and C16 are graded as mild, essentially non-irritant. Alcohols with a carbon chain length C18 and above demonstrated no skin irritation potential.

However, comparative studies in different species demonstrate the increased sensitivity of rabbit as a test species to aliphatic alcohols compared to man (Kaestner, 1977; Motoyoshi et al., 1979). Read across from this study has been used consistently across the LCAAs category for linear and UVCB substances, and no classification is proposed for skin irritation based on category trend of lack of irritant effects in humans despite positive data from animal studies.

Longer-chain linear alcohols in pure form, which are in a solid state at standard temperature, are produced in powder form as well as liquids or pastes in some cases. Powders can cause a transient eye irritation and trigger eye classification. This was recognised by the Directive 67/548/EEC classification criteria to the extent that if an irritation response is observed with a powder but not with a paste or liquid, the classification was discounted as a physical effect. However, under the CLP Regulation (Regulation (EC) No 1272/2008) criteria, this difference has been eliminated and irritation as a result of testing with powders triggers a positive classification.

The nature of UVCBs means that they can only be manufactured as liquid or amorphous forms; so UVCB alcohols are commercially supplied as pastes only. This phenomenon is the reason for some differences between eye irritation classifications for UVCB alcohols compared to the linear constituents in pure form.

Studies with Alcohols, C7-9 have provided evidence that this substance is classified as Eye irritant Category 2, despite the physical form of the substance. This is thought to be consistent with the category trend that shorter chain lengths are more toxic, and hence more irritant, than longer chain lengths. There is substantial experimental evidence that Alcohols, C9-11 and Alcohols, C9-11-branched and linear are not eye irritants. Therefore, even though this substance has the potential of being classified, the studies conducted with this substance underline that this is not the case. The UVCB LCAAs with chain lengths above C12-13 do not require classification for eye irritation.

In the case of the single-constituent linear LCAAs of the chain length between C6-C14, category 2 classification as eye irritant is proposed, whereas linear alcohols of chain length between C15-C24 are deemed not irritating. C14 is an exception due to a positive test result determined with a powder test sample; tetradecan-1-ol is therefore classified Category 2 eye irritant under CLP.

Data supporting respiratory irritation of the linear and essentially linear LCAAs is not sufficient to trigger classification via this route.

Respiratory irritation and the basis of DNEL for inhalatory local effects

The registrant has referred to the AGW values for several linear and essentially-linear aliphatic alcohols, established by the German regulatory authority. These have been extrapolated from a concentration of octan-1-ol at which respiratory irritation levels had been found to be low/acceptable. The threshold value is 20 ppm, which appears to derive from the 2-ethylhexanol test results from Van Thriel et al. (2003). No additional assessment factors have been applied. Respiratory irritation effects from three separate published papers were cited in reference to this, which the registrant has evaluated and drawn the following overview conclusions:

1. The extrapolation has been made based on molecular weight correction i.e. making the assumption that the equivalent effect would be caused by the equivalent ppm concentration. The value for undecan-1-ol (not derived in the AGW paper) is 140.9 mg/m3

2. The studies are concerned with local effects, not systemic effects.

3. The effects investigated were self-reported symptoms/changes, and physiological responses that do not necessarily indicate harm or damage.

4. In view of the non-standard test design, subjective assessment of results, and lack of evidence to connect the reported effects with evidence of harmfulness, these results cannot be considered to be key data. The summary is included for completeness only.

The approaches and findings from the three studies (in brief) are as follows.

C. van Thriel, A. Seeber, E. Kiesswetter, M. Blaszkewicz, K. Golka, G.A. Wiesmüller (2003). Physiological and psychological approaches to chemosensory effects of solvents. Toxicology Letters 140-141 (2003) 261-271

- Both 2-Ethylhexanol and octan-1-ol were examined in this study. The AGW ultimately derives from the high-concentration exposure of 2-ethylhexanol.

- In additional to self-reported symptoms, physiological measurements (including anterior active rhinomanometry and biochemical analysis of nasal secretions (lavage)) were also investigated and compared with the subjective scores. The physiological responses studied are not necessarily indicative of damage.

- 24 subjects exposed for up to 4 hours at “high” min/max octanol concentrations of 0.4/12.5 ppm (mean 6.4 ppm). Lower ranges also tested.

- Min/max “high” 2-ethylhexanol concentrations were 1.76/42.07 ppm (mean 21.88 ppm). Lower ranges also tested.

- No information is given in the paper regarding the method for generating the dose or whether it would have comprised vapour or aerosol.

- Statistical analysis was done

- Based on the effects reported, the concentration(s) examined do not result in high scores for chemosensory irritation.

- The subjective (self reported) and objective (physiological) responses did not correlate strongly.

- This paper is in a relevant and peer reviewed journal (3 months elapsed between being submitted and published)

Andreas Seeber, Christoph van Thriel, Katja Haumann, Ernst Kiesswetter, Meinolf Blaszkewicz, Klaus Golka (2002). Psychological reactions related to chemosensory irritation. Int Arch Occup Environ Health (2002) 75: 314–325:

- 8 substances were investigated, including octan-1-ol, at up to 12 ppm.

- The paper is primarily concerned with the investigation of chemosensory irritation based on perceived symptoms and self-reported changes of well-being - i.e. not measured physiological responses. As such the paper is not an investigation into “safe” (inhalatory) concentrations of the substances investigated. These are local and not systemic effects.

- For octanol, 24 volunteers were exposed for periods up to 4 hours at peak concentrations of up to 12 ppm. Based on the effects reported, the concentration(s) examined do not result in high scores for chemosensory irritation.

- No information is given in the paper regarding the method for generating the dose or whether it would have comprised vapour or aerosol.

- Statistical analysis was done, the paper does not report this in detail. We have to presume that appropriate and suitably powered methodology was used.

- This paper is in a relevant and peer reviewed journal (5 months elapsed between being submitted and published)

J. Enrique Cometto-Muñiz, William S. Cain (1998). Trigeminal and olfactory sensitivity: comparison of modalities and methods of measurement. Int Arch Occup Environ Health (1998) 71: 105-110

- Primary aim of the study was to investigate sensitivity to nasal irritation by psychophysical methods (common detection procedure vs nasal lateralisation)

- Study group comprised 5 anosmics (no sense of smell) and 4 normosmic (normal sense of smell)

- 1-propanol, 1-butanol, 1-hexanol and 1-octanol investigated, concentrations were 100% and subsequent 3-fold dilutions (100%, 33.3%, 11.1% and 3.7%)

- Again this study was not intended or powered to identify a “safe” concentration of any of the substances.

In view of the non-standard test design, subjective assessment of results, and lack of relationship between the reported effects and evidence of harmfulness, these results cannot be considered to be key data. The above summary is included for completeness only.

Kaestner, W. 1977. Zur Speziesabhangigkeit der Hautvertraglichkeit von Kosmetikgrundstoffen. J. Soc. Cos. Chem. 28:741-754.

Motoyoshi, K; et al. 1979 Comparative studies on the irritancy of oils and synthetic perfumes to the skin of rabbit, guinea pig, rat, miniature swine and man. Cosmetics and Toiletries 94: 41-48.

Justification for classification or non-classification

Based on the available information, undecan-1-ol is proposed to be a category 2 irritant to eye, but not classified as irritating to skin in accordance with Regulation (EC) No. 1272/2008.