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Administrative data

Description of key information

 The key study for skin irritation was guideline study carried out in humans and found the test substance not irritating to skin (Henkel 1996; rel 1). The test procedure was in accordance with generally accepted scientific standards and described in sufficient detail, in compliance with GLP. The study for eye irritation, which was carried out in the rabbit, found the test material irritating to rabbit eye (Scientific Associates 1975; rel 2). The study was conducted according to a protocol that is equivalent to current guideline. It was not compliant with GLP.

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
Reliability:
1 (reliable without restriction)
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:
other: 24/48/72h
Score:
0
Max. score:
4
Reversibility:
other: n/a
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24/48/72h
Score:
0
Max. score:
4
Reversibility:
other: n/a
Irritant / corrosive response data:
The substance was not irritating.
Other effects:
None reported.

No irritation was observed following application to the human skin of undiluted test substance for 4 hours (patch test).

Interpretation of results:
GHS criteria not met
Conclusions:
Undiluted Lorol C12-98 did not produce any skin irritation in human vounteers following a 4 hour semi-occlusive exposure in a test based on OECD 404.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS

- Housing: individually housed in metal cages elevated above the droppings

- Diet: Purina rabbit chow, ad libitum

- Water: tap water, ad libitum


Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): unspecified
- Concentration (if solution): undiluted
Duration of treatment / exposure:
24 hours (single instillation, not washed)
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not washed



Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 24 hours
Score:
26.7
Max. score:
20
Irritant / corrosive response data:
Mild to moderate erythema of the palpebral and bulbar conjunctivae , mild to moderate chemosis, mild mucoid discharge and a mild to moderate corneal opacity involving one-fourth to three-fourths of the corneal surface. By 72 hours, all test eyes showed improvement in the parameters of irritation in all but one animal. That one animal became worse and even developed mild iritis.

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

60 min

0/0/0/0/0/0

0/0/0/0/0/0

 4/6/4/6/6/4

24 h

 5/30/30/20/5/20

0/0/0/0/0/0 

 4/10/10/10/8/8

48 h

 0/30/10/10/0/20

 0/0/0/0/0/0

 4/10/10/10/4/8

72 h

 0/40/5/5/0/5

 0/5/0/0/0/0

 2/14/4/8/2/4

Average 24h, 48h, 72h

          13.05

            0.3 

 7.2

 

 

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The data suggests that if interpreted in terms of EU criteria, the test substance would be a category 2 eye irritant.
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting 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 Perciva; Ltd., Moston, Sandbach, Cheshire, UK.

- Age at study initiation: 12-16 weeks

- Weight at study initiation: 2.53-2.87kg

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

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

- Water: Mains drinking water (ad libitum)

- Acclimation period: Minimum of 5 days.


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 17-20

- Humidity (%): 45-70

- Air changes (per hr): 15

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


Vehicle:
other: warmed to 40C before instillation
Controls:
other: The other eye of each animal served as a control.
Amount / concentration applied:
TEST MATERIAL

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

- Concentration (if solution): undiluted

Duration of treatment / exposure:
A single instillation.
Observation period (in vivo):
1, 24, 48 and 72 hours.
Number of animals or in vitro replicates:
3, male
Details on study design:
REMOVAL OF TEST SUBSTANCE

- Washing (if done): not rinsed.


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


TOOL USED TO ASSESS SCORE: Light source from a standard opthalmoscope.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24/48/72h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24/48/72h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24/48/72h
Score:
0.1
Max. score:
0.3
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24/48/72h
Score:
0
Max. score:
0
Irritant / corrosive response data:
Conjunctival discharge was noted in all animals one hour after instillation. No corneal or iridial effects were noted suring the study. Moderate conjunctival irritation was noted in two treated eyes with minimal conjunctival irritation in the remaining treated eye one hour after treatment.  Minimal conjunctival redness was noted in one treated eye at the 24 hour observation point. The test material produced a maximum group mean score of 8.7. Classified as a minimal eye irritant according to Kay & Callandra (modified).
Other effects:
All scores were 0 at 48 and 72 hours.

AVERAGE SCORE (24+48+72 hour)
- Cornea: All 0
- Iris: All 0
- Conjunctivae (Redness): Individual scores 2 rabbits 0 the remaining rabbit 0.3. (group mean score 0.1)
- Conjunctivae (Chemosis): All 0




Interpretation of results:
GHS criteria not met
Conclusions:
Kalcol 2098 is not irritating to the rabbit eye using either EU or GHS criteria.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key skin irritation study is further supported by two high reliability studies in rabbit (Safepharm Laboratories 1996; rel 1, Hempstock, 1997; rel 1), and another 1 hour study in human (Henkel 1996; rel 1). The supporting studies provide strong evidence for the fact that dodecan-1-ol is not irritating to skin. Human evidence also suggests dodecan-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 dodecan-1-ol to be more pronounced in rabbits than man.

For eye irritation the study by Scientific Associates Inc was selected as key study, even though a more recent, higher reliability source was also available (Safepharm Laboratories, 1996; rel 1), as this gave the more conservative result. The irritation data for the C10 and C14 alcohols which were considered Eye Irrit. Cat 2, suggests that dodecan-1 -ol (C12) is likely to also be irritating to the eye and the results of the more recent study by Safepharm Laboratories (1996) are likely to be a result of biological variation in the test.

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 dodecan-1-ol (derived in the AGW paper) is 155 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.

References:

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, dodecan-1-ol does not require classification or labelling for skin irritation, but it is proposed to be irritating to eye (Cat. 2) in accordance with current EC regulation No 1272/2008 (CLP).