Registration Dossier

Administrative data

Description of key information

 The key study for skin irritation was conducted according to OECD TG 404, and in compliance with GLP. The study reporst the tested substance (docosan-1-ol) to be not irritating to skin (Safepharm Laboratory, 1997). The key study for eye irritation was conducted according to OECD TG 405, and in compliance with GLP. The study reports the tested substance (docosan-1-ol) to be not irritating to eye (Safepharm Laboratory, 1997).

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:
18/06/1997-21/06/1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Cheshire, UK
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.81 - 3.15 kg
- Housing:individually housed in suspended metal cages
- Diet: STANRAB SQC Rabbit diet, ad libitum
- Water: mains water, ad libitum
- Acclimation period:minimum 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-20
- Humidity (%): 59-62
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
no
Amount / concentration applied:
TEST MATERIAL

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



Duration of treatment / exposure:
4 hour(s)
Observation period:
Ca. 1h, 24h, 48h, 72h after patch removal
Number of animals:
3F
Details on study design:
TEST SITE
- Area of exposure: shorn dorsal  surface of the skin,  2.5 x 2.5 cm
- Type of wrap if used: gauze patch secured in position with a strip of surgical adhesive tape, wrapped in an elastic corset.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water.
- Time after start of exposure: 4h


SCORING SYSTEM: Draize
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: n/a
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. 
Other effects:
No evidence of skin irritation was noted during the study other than very slight  erythema at one test site at 1 hour after patch removal. All other scores  were 0.
Interpretation of results:
GHS criteria not met
Conclusions:
Kalcol 220-80 is not a skin irritant when applied to rabbit skin undiluted in a 4 hour semi-occlusive exposure. Group mean 24+48+72 hours were 0.
Executive summary:

In the skin irritation study 0.5g of test material was moistened with 0.5ml distilled water and applied onto the skin of 3 female rabbits and kept under semi-occlusive dressing for 4 hours. The exposure area was shaved from hair prior to the treatment. After 4 -hour exposure any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water. The skin reaction was evaluated at 1h, 24 h, 48 h, 72 h after patch removal according to Draize scoring system. The mean primary dermal irritation index was 0. The study was conducted according to an 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:
1997
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, Cheshire, UK
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.80-2.90kg
- Housing: individually suspended metal cages.
- Diet: Stanrab SQC Rabbit diets, ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: minimum 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-19
- Humidity (%): 58-69
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light):12/12


Vehicle:
unchanged (no vehicle)
Controls:
other: Untreated eye used as control
Amount / concentration applied:
Amount applied: 0.1 ml (ca. 62mg)
Duration of treatment / exposure:
single instillation, not rinsed
Observation period (in vivo):
Assessment of ocular damage was made approximately 1h, 24h, 48h and 72h following treatment.
Number of animals or in vitro replicates:
1F, 2M
Details on study design:
Comment: not rinsed
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24/48/72h
Score:
10.7
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
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
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 48h
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
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:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48h
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Moderate conjunctival irritation was reported in  all animals one  hour after treatment with minimal to moderate  conjunctival irritation at the 24 hour observation time. At 48 hours minimal conjunctival redness was observed in one animal only. All scores were 0 at 72 hours.
Other effects:
None reported.
Interpretation of results:
GHS criteria not met
Conclusions:
Kalcol is not classifiable as an eye irritant according to EU or GHS criteria.

Executive summary:

In the eye irritation study, single instillation of 0.1 ml of solid test material was performed into one eye of 1 female and 3 male rabbits. No washing was performed after exposure. The untreated eye was used as negative control. The test area was examined at 1, 24, 48 and 72 hours post-application. Draize scoring system was used to evaluate the eye irritation response.

Moderate conjuctival irritation was observed in all animals 1 hour post-application. At 24 hours, mild to moderate conjuctival redness was observed and by 72 hours post-treatment the redness was not evident. The study reports the test material to be not irritating to eye. The study was conducted according to an 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 was the most recent available study, conducted according to an appropriate OECD test guideline, and in compliance with GLP (Safepharm Laboratories, 1997).

Following application of 0.5g of test material moistened with 0.5ml distilled water onto the skin of 3 female rabbits for 4 hours under occlusive dressing, slight erythema was observed in one animal. The study reports the test material to be not irritating to skin. Human evidence also suggests docosan-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 docosan-1 -ol to be more pronounced in rabbits than man.

The key eye irritation study was the most recent available study, conducted according to an appropriate OECD test guideline, and in compliance with GLP (Safepharm Laboratories, 1997).

Following a single instillation of 0.1 ml of test material into the eyes of 1 female and 2 male rabbits, moderate conjunctival irritation was observed at 1 after exposure and was fully reversible within 48 hours post application.

The available eye irritation supporting study confirms the findings of the key study.

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 docosan-1 -ol (not derived in the AGW paper) is 267 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, docosan-1 -ol does not require classification for skin and eye irritation according to Regulation (EC) No 1272/2008.