Octadecan-1-ol

Endpoint summary

Description of key information

The key skin irritation study, conducted according OECD TG 404, and in compliance with GLP, reports octadecan-1-ol to be not irritating to skin (Safepharm Laboratories, 1996a). The key eye irritation study, conducted according OECD TG 405, and in compliance with GLP, reports octadecan-1-ol to be not irritating to eyes (Safepharm Laboratories, 1996b).

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:

1996/03/13-1996/03/16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: David Percival Ltd., Moston, Sandbach, Cheshire, UK

- Age at study initiation: 12 to 16 weeks

- Weight at study initiation: 2.56 to 2.73 kg

- Housing: The animals were individually housed in suspended metal cages.

- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK (ad libitum)

- Water: Tap water (ad libitum)

- Acclimation period: 5 days minimum


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 18-19C

- Humidity (%): 49-60%

- Air changes: 15 changes per hour

- Photoperiod (hrs dark / hrs light): 12h/12h


IN-LIFE DATES: Not stated.

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped free of fur

Vehicle:

other: 0.5 g test material moistened with 0.5 ml water

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 0.5g of test material, moistened with 0.5ml of distilled water

Duration of treatment / exposure:

4 hour(s)

Observation period:

1h, 24h, 48h, 72h

Number of animals:

3

Details on study design:

TEST SITE

- Area of exposure: The back of the rabbit

- % coverage: 2.5x2.5cm patch

- Type of wrap if used: A cotton gauze patch was secured in position with surgical adhesive tape (BLENDERM) approximate size 2.5x4.0cm. To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in elasticated corset (TUBIGRIP).


REMOVAL OF TEST SUBSTANCE

- Washing (if done): Patches were removed and any residual test material removed by gentle swabbing with cotton.

- Time after start of exposure: 4 hours


SCORING SYSTEM: Draize J H 1977 "Dermal and Eye Toxicity Tests"

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: No corrosive effects were noted.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The test material produced a primary irritation index of 0.0. No evidence of skin irritation was noted during the study, all scores were 0.

Interpretation of results:

GHS criteria not met

Conclusions:

Following a 4 hour semi-occlusive exposure to rabbits skin Kalcol 8098 was non-irritating to rabbit skin.

Executive summary:

In a skin irritation study, 0.5 g test material moistened with 0.5 ml water was applied onto the skin of 3 rabbits and kept in contact to the skin under semi-occlusive dressing for 4 hours. The primary dermal iritation index was scored at 1, 24, 48 and 72 hours post-appliaction.

The test material produced a primary irritation index of 0.0. No evidence of skin irritation was noted during the study, all scores were 0.

The study was conducted according the appropriate OECD test guideline and in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS

- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK.

- Age at study initiation: 12-16 weeks

- Weight at study initiation: 2.9-3.23kg

- Housing: individually housed in suspended metal cages

- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK (ad libitum)

- Water: mains drinking water (ad libitum)

- Acclimation period: minimum of five days


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 17-19

- Air changes (per hr): 15

- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye of each animal

Amount / concentration applied:

TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 0.1ml (ca.82mg)

- Concentration (if solution): undiluted

Duration of treatment / exposure:

The application of the test material was a single instillation followed by no washing. An assessment of the initial pain reaction was made immediately after the administration of the test material, followed by assessment of ocular damage/irritation first at 1 hour.

Observation period (in vivo):

1 hour, 24, 48 and 72 hours.

Number of animals or in vitro replicates:

3 (1M,2F)

Details on study design:

REMOVAL OF TEST SUBSTANCE

- Washing (if done): not rinsed

SCORING SYSTEM: Draize and modified Kay and Callandra.


TOOL USED TO ASSESS SCORE: opthalmoscope

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: 48 hours

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

AVERAGE SCORE (24+48+72 hour)
- Cornea: 0, 0, 0.3 (group mean score 0.1)
- Iris: 0, 0, 0.3 (group mean score 0.1)
- Conjunctivae (Redness): 0.3, 0, 1 (group mean score 0.43)
- Conjunctivae (Chemosis): 0, 0, 0.3 (group mean score 0.1)
- Overall irritation score: maximum group mean score 10.0 at 1 hour post instillation. Classified as a mild irritant.

Other effects:

The application of the test material produced diffuse corneal opacity restricted to one treated eye at 24 hours. Iridial inflammation was noted in 2 eyes at 1 hour and one at 24 hours. Minimal to moderate conjunctival irritation was reported at 1 hour with minimal conjunctivitis in 2 eyes at 24 hours. All eyes scored 0 at 48 and 72 hours post instillation.  Residual test material noted around all eyes at the 1 hour observation period.

Table 1: Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Score at time point / Reversibility	Cornea	Iris	Conjunctivae	Chemosis
	Max. score: 4	Max. score: 2	Max. score: 3	Max. score: 4
60 min
24 h	0/0/1	0/0/1	1/0/2	0/0/1
48 h	0/0/0	0/0/0	0/0/1	0/0/0
72 h	0/0/0	0/0/0	0/0/0	0/0/0
Average 24h, 48h, 72h	0/0/0.3	0/0/0.3	0.3/0/1	0/0/0.3
Reversibility*)	c	c	c	c
Average time (unit) for reversion	48 h	48 h	48 h	48 h

 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

 

Interpretation of results:

GHS criteria not met

Conclusions:

Kalcol 8098 is not an eye irritant according to EU or GHS criteria.

Executive summary:

In an acute eye irritation study, 0.1 ml of test material was applied to one eye of 1 male and 2 female rabbits. The untreated eye was used as a negative control group. The application of the test material was a single instillation followed by no washing. An assessment of the initial pain reaction was made immediately after the administration of the test material, followed by assessment of ocular damage/irritation first at 1 hour, and then at 24, 48 and 72 hours post-application.

The application of the test material produced diffuse corneal opacity restricted to one treated eye at 24 hours. Iridial inflammation was noted in 2 eyes at 1 hour and one at 24 hours. Minimal to moderate conjunctival irritation was reported at 1 hour with minimal conjunctivitis in 2 eyes at 24 hours. All eyes scored 0 at 48 and 72 hours post instillation.  Residual test material noted around all eyes at the 1 hour observation period. The study reports the test material to be not irritating to eyes. The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The key skin irritation study reports the test material to be not irritating, when tested on rabbit skin for 4 hours under semi-occlusive dressing (Safepharm Laboratories, 1996a). Human evidence also suggests octadecan-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 octadecan-1-ol to be more pronounced in rabbits than man.

The key eye irritation study reports the test material to be not irritating, following 1-hour exposure (Safepharm Laboratories, 1996b).

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; tetradecanol 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 octadecan-1-ol (derived in the AGW paper) is 224 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 data, octadecan-1 -ol does not require classification for skin and eye irritation according to Regulation (EC) No 1272/2008.