Registration Dossier

Administrative data

Description of key information

The key study for skin irritation in human, which is based on a protocol similar to current guideline reports the test substance not to be irritating to skin (Henkel, 1996; rel 2).
The key study for eye irritation, conducted according to the appropriate OECD test guideline, and in compliance with GLP, reports tetradecan-1-ol to be irritating to eye (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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
(based on)
GLP compliance:
yes
Species:
human
Strain:
other: n/a
Details on test animals and environmental conditions:
Age of the subjects was 22 - 53 years with an average of 34.9 years. 
Type of coverage:
semiocclusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
Readings of erythema, edema, scaling and fissures were taken 1, 24, 48 and 72 hours after application.
Number of animals:
20
Details on study design:
15 drops/plaster of undiluted test substance were added to a semi-occlusive plaster (diameter: 1.5 cm) and applied for 4 hours to the backs of 
healthy volunteers.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: n/a
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: n/a
Irritant / corrosive response data:
No irritation was observed following application to the human skin of undiluted test substance for 4 hours (patch test).
Other effects:
None reported.
Interpretation of results:
GHS criteria not met
Conclusions:
Lorol C12-98 is not irritating to human skin following a 4 hour semi-occlusive exposure. The study was conducted accordint to GLP.
Executive summary:

In the skin irritation study, undiluted test material was applied onto human skin and kept in contact to the skin under semi-occlusive dressing for 4 hours. Erythema and oedema scores were recorded at 1, 24, 48 and 72 hours after application.

No erythema and oedema were observed during the study period.

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:
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: 2.67-2.94 kg

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

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

- Water: Mains water (ad libitum).

- Acclimation period: Minimum of five days.


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 17-20C

- Humidity (%): 43-70

- Air changes (per hr): 15

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

Vehicle:
other: The test material was ground to a fine powder before use.
Controls:
other: The other eye of each animal was used as a control.
Amount / concentration applied:
TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 0.1ml

- Concentration (if solution): 46 mg (as measured by gently compacting the required volume into an adapted syringe)


Duration of treatment / exposure:
Single instillation of the test material.
Observation period (in vivo):
Assesment of ocular damage/irritation was made approximately 1 hour, 24, 48 and 72 hours following treatment. Total observation period was 14 days.
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE

- Washing (if done): not rinsed


SCORING SYSTEM: Draize J H (1977) "Dermal and Eye Toxicity tests" modified Kay and Callandra.


TOOL USED TO ASSESS SCORE: Standard optalmoscope.
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.4
Max. score:
2
Reversibility:
fully reversible
Remarks:
14 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible
Remarks:
14 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.5
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Diffuse corneal opacity was noted in 2 treated eyes at the 24, 48, and 72 hour observations. Iridial inflammation was noted in 2 treated eyes at the 24 hour observation and persisted in 1 treated eye at the 48 and 72 hour observations.  Moderate conjunctival irritation was noted in all treated eyes 1 hour after treatment and persisted in 2 treated eyes at the 24 and 48 hour observations. Minimal conjunctival irritation was noted in 1 treated eye at the 24 and 48 hour observations and in 2 treated eyes at the 72 hour and 7 day observation. Overall irritation score: Maximum group mean score 27.3 at 24 hours.

All corneal and iridial scores and scores for conjunctival chemosis were normal by day 7. Conjunctival redness persisted in 2 
rabbits through day 7 but scores were 0 by day 14. The effects were therefore fully reversible.  
Other effects:
Discharge was observed from all treated eyes 1 hour after instillation and persisted in one eye for 48 hours and in another for 72  hours. 

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

0/0/0

0/0/0 

2/2/2 

 2/2/1

24 h

 0/1/1

 0/1/1

 1/2/2

 1/2/2

48 h

 0/1/1

 0/1/0

 1/2/2

 0/2/2

72 h

 0/1/1

 0/1/0

 0/2/1

 0/1/1

Average 24h, 48h, 72h

 0/1/1

 0/1/0.3

 0.7/2/1.7

 0.3/1.7/1.7

Reversibility*)

 c

Average time (unit) for reversion

Day 14 

Day 14  

Day 14  

Day 14  

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

 

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Based on cornea scores of 1 in all animals and conjunctivae redness and chemosis reading of 2 in two of the animals, the test material would be a category 2 irritant according to current guidelines.
Executive summary:

In the eye irritation study, fine powder of test material was applied into the eyes of 3 rabbits. Assesment of ocular damage/irritation was made approximately 1 hour, 24, 48 and 72 hours following treatment. Total observation period was 14 days.

Diffuse corneal opacity was noted in 2 treated eyes at the 24, 48, and 72 hour observations.

Iridial inflammation was noted in 2 treated eyes at the 24 hour observation and persisted in 1 treated eye at the 48 and 72 hour observations.  Moderate conjunctival irritation was noted in all treated eyes 1 hour after treatment and persisted in 2 treated eyes at the 24 and 48 hour observations. Minimal conjunctival irritation was noted in 1 treated eye at the 24 and 48 hour observations and in 2 treated eyes at the 72 hour and 7 day observation. Overall irritation score: Maximum group mean score 27.3 at 24 hours.

All corneal and iridial scores and scores for conjunctival chemosis were normal by day 7. Conjunctival redness persisted in 2 

rabbits through day 7 but scores were 0 by day 14. The effects were therefore fully reversible.  

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key study for skin irritation was chosen as it was the most recent, high reliability study available with data from man. However, a supporting study was also available, with results in rabbit which finds tetradecan-1-ol a class 2 irritant when interpreted according to EU criteria (Scientific Associates, 1977; rel 2). The rest of the supporting studies are reliability 4 and may not be used for classification purposes; however, they support the existing key study by finding the test material at the most slightly irritating to skin. Human evidence also suggests tetradecan-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 tetradecan-1 -ol to be more pronounced in rabbits than man.

The key study for eye irritation by SafePharm Laboratories (1996) was chosen as key study as it is the most recent study with tetradecan-1 -ol. The key study reports the test material to be irritating to eyes.

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 tetradecan-1 -ol (derived in the AGW paper) is 178 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 from the key skin irritation study, no classification is proposed for skin irritation for tetradecan-1-ol. Based on the key study for eye irritation and the current EU guideline, tetradecan-1-ol is a category 2 eye irritant according to Regulation (EC) No 1272/2008.