Hexadecan-1-ol

Endpoint summary

Description of key information

The key skin irritation study for hexadecan-1-ol, conducted according to OECD Test Guideline 404 and in compliance with GLP, reports the substance to be not irritating to skin when tested in rabbits (Safepharm Laboratories, 1996; rel 1).

The key eye irritation study for hexadecan-1-ol, conducted according to OECD Test Guideline 405 and in compliance with GLP, reports the substance to be not irritating to eyes when tested in rabbits (Safepharm Laboratories, 1996; rel 1).

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: 12-16 weeks old

- Weight at study initiation: 2.36-2.54 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: Minimum of 5 days.


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 18-19C

- Humidity (%): 49-60%

- Air changes (per hr): 15

- 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:

water

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 0.5g test material

VEHICLE

- Amount(s) applied (volume or weight with unit): 0.5ml of distilled water

Duration of treatment / exposure:

4 hour(s)

Observation period:

Examinations at 1h, 24h, 48h, 72h. Post-exposure period 16 hours

Number of animals:

2 male, 1 female

Details on study design:

TEST SITE

- Area of exposure: dorsal flank

- % coverage: 2.5x2.5cm

- Type of wrap if used: cotton gauze patch was secured in position with a strip of surgical adhesive tape. 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): When the corset and patches were removed at the end of the 4 hour exposure period, any residual test material was removed by gentle swabbing with cotton.

- Time after start of exposure: 4 hours


SCORING SYSTEM: Draize J H (1977) "Dermal and Eye Toxicity Tests" In Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31

Irritation parameter:

primary dermal irritation index (PDII)

Score:

0

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:

AVERAGE SCORE

- Erythema: Erythema (grade 1) observed at 1 hour after removal of dressings. All scores at other time points 0. 
- Oedema: No oedema observed.

REVERSIBILITY: Initial erythema regressed in the first 24 hours. All scores at 24, 48 and 72 hours were 0.

Other effects:

None reported.

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	Erythema	Edema
	Max. score: 4	Max. score: 2
60 min	1/1/1	0/0/0
24 h	0/0/0	0/0/0
48 h	0/0/0	0/0/0
72 h	0/0/0	0/0/0
Average 24h, 48h, 72h	0.25	0
Reversibility*)	c	-

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

 

Interpretation of results:

GHS criteria not met

Conclusions:

Following a 4 hour semi-occlusive exposure of Kalcol 6098 to rabbit skin there was no evidence of skin irritation between 24 and 72 hours after patch removal. Kalcol 6098 is not a skin irritant according to EU or GHs criteria.

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:

1996/04/09-1996/04/13

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:

other: New Zealand White rabbit

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: 2.69-3.01kg

- 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: minimum of five days


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 17-19C

- Humidity (%): 56-61%

- Air changes (per hr): 15

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

Vehicle:

unchanged (no vehicle)

Controls:

other: The other eye of each rabbit was used as a control.

Amount / concentration applied:

TEST MATERIAL

- Amount(s) applied (volume or weight with unit): A volume of 0.1ml of the test material which was found to weight approximately78mg was applied to the eye.


VEHICLE

-No vehicle.

Duration of treatment / exposure:

72 hours

Observation period (in vivo):

1h, 24h, 48h, 72h

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE

- Washing (if done): No washing reported.


SCORING SYSTEM: Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the toxicity of Household Substances,National Academy of Sciences, Washington DC p. 48 to 49. Classification According to a Modified Version of the Kay and Calandra System

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by the use of the light source from a standard opthalmoscope.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: No initial effect.

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: No initial effect.

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: No initial effect.

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

other: No initial effect.

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: No initial effect.

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: No initial effect.

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: No initial effect.

Irritant / corrosive response data:

The numerical values corresponding to each animal, tissue and observation time were recorded. The data relating to the conjunctivae were designated by the letters A (redness), B (chemosis) and C (discharge), those relating to the iris designated by the letter D and those relating to the cornea by the letter E (degree of opacity) and F (area of opacity). For each tissue the score was calculated as follows:

Score for the conjunctivae - (A+B+C)x2
Score for iris - Dx5
Score for cornea - (ExF)x5

Using the numerical data obtained a modified version of the system described by Kay J H and Calandra J C, J.Soc.Cosmet Chem., 1962 13 281-289 wasused to classify the ocular irritancy potential of the test material. This was achieved by adding together the scores for the cornea, iris and conjunctivae for each time point for each rabbit. The group means of the total scores for each observation were calculated. If any rabbit shows irreversible oculardamage the test material will be classified as corrosive to the eye.

Overall irritation score: Maximum group mean score 15.3 at 1 hour post instillation. Classified as a mild irritant according to a modified Kay and 
Calandra system.

Other effects:

DESCRIPTION OF LESIONS: Dulling of the cornea noted in 2 animals 1 hour after instillation, diffuse corneal opacity noted in 1 rabbit at 24 hours 
post instillation. Iridial inflammation noted in 2 animals at 1 hour post instillation only. Moderate conjunctival irritation noted in all eyes at 1 hour 
which reduced to minimal conjunctival irritation at 24 hours.
REVERSIBILITY: All eyes were normal at 48 and 72 hours post instillation.
OTHER EFFECTS: Residual test material noted around the treated eyes at 1 hour post instillation.

Interpretation of results:

GHS criteria not met

Conclusions:

Kalcol 6098 is not an eye irritant according to EU or GHS criteria. The result is a read across from hexadecanol (CAS 36653-82-4).

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 for hexadecan-1-ol, conducted according to OECD Test Guideline 404 and in compliance with GLP, reports the substance to be not irritating to skin when tested in rabbits (Safepharm Laboratories, 1996; rel 1).

In the study, 0.5 g of hexadecan-1-ol in water were applied onto the skin of 2 male and 1 female rabbits for 4 hours under semiocclusive dressing. Skin reactions were assessed at 1, 24, 48, 72 hours, then daily up to 16 days post exposure. No erythema or oedema were observed at any of the observation timepoints.

The supporting studies were in accordance with the key findings. The key studies were the most recent high reliability studies available, and were selected for that reason. Human evidence also suggests hexadecan-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 hexadecan-1-ol to be more pronounced in rabbits than man.

The key eye irritation study for hexadecan-1-ol, conducted according to OECD Test Guideline 405 and in compliance with GLP, reports the substance to be not irritating to eyes when tested in rabbits (Safepharm Laboratories, 1996; rel 1).

In the study, 0.1 ml of undiluted hexadecan-1-ol were instilled into the eyes of 3 rabbits. Ocular reactions were assessed at 1, 24, 48 and 72 hours post exposure. No erythema or oedema were observed at any of the observation timepoints. Dulling of the cornea was noted in 2 animals at 1 hour after instillation, diffuse corneal opacity was noted in 1 rabbit at 24 hours post instillation. Iridial inflammation was noted in 2 animals at 1 hour post instillation only. Moderate conjunctival irritation was noted in all eyes at 1 hour which reduced to minimal conjunctival irritation at 24 hours. All eyes were normal at 48 and 72 hours post instillation.

The supporting study was in accordance with the key findings. The key study was the most recent high reliability studies available, and was selected for that reason.

A full discussion of the Category and considerations of RAAF Assessment Entities can be found in the Human Health Alcohols C6-24 Category report (PFA, 2016).

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 hexadecan-1 -ol (derived in the AGW paper) is 200 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 for hexadecan-1-ol, no classification is required for skin and eye irritation according to Regulation (EC) No 1272/2008.