Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From October 08, 2015 to November 04, 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted in compliance with OECD Guideline No. 429 without any deviation
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on June 17, 2015/ signed on September 24, 2015)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
other: CBA/Ca
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS B.V., Inc., Horst, The Netherlands.
- Age at study initiation: Approximately 8-12 weeks
- Weight at study initiation: 15-23g
- Housing: Animals were housed in suspended solid floor polypropylene cages furnished with softwood woodflakes.
- Diet: Standard rodent diet (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK), ad libitum
- Water: Potable water taken from the public supply, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 %
- Air changes: The rate of air exchange was approximately 15 changes/ h.
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES:
From October 08, 2015 to November 04, 2015
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
Main test: 25, 50 % v/v in acetone/olive oil 4:1 and undiluted
No. of animals per dose:
5
Details on study design:
PRELIMINARY STUDY:
- Using available information regarding the systemic toxicity/irritancy potential of the test item, a preliminary screening test was performed using one mouse. The mouse was treated by daily application of 25 μL of the undiluted test item to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3).
- Based on the results of this preliminary test, the undiluted test item and the test item at concentrations of 50% and 25% v/v in acetone/olive oil 4:1 were selected for the main test.

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: Local Lymph Node Assay
- Criteria used to consider a positive response: If the SI is 3 or more, the test substance is regarded as a skin sensitizer with a consideration given to dose response and statistical significance.

TREATMENT PREPARATION AND ADMINISTRATION:
- For the purpose of the study, the test item was used undiluted and freshly prepared as a solution in acetone/olive oil 4:1. This vehicle was chosen as it produced a solution at the required concentration.
- The mice were treated by daily application of 25 μL of the appropriate concentration of the test item to the dorsal surface of each ear for three consecutive days (Days 1 to 3). The test item formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette. A further group of five mice received the vehicle alone in the same manner. The thickness of each ear was measured and recorded as described in the preliminary screening test. Local skin irritation was scored daily. Five days following the first topical application of the test item (Day 6) all mice were injected via the tail vein with 250 μL of phosphate buffered saline (PBS) containing 3H-methyl thymidine (3HTdR: 80 μCi/mL, specific activity 2.0 Ci/mmoL, ARC UK Ltd) giving a total of 20 μCi to each mouse. Five hours following the administration of 3HTdR all mice were killed by carbon dioxide asphyxiation followed by cervical separation. For each individual animal of each group the draining auricular lymph nodes were excised and placed in 1 mL of PBS. A single cell suspension of the lymph node cells (LNC) for each individual animal was prepared by gentle mechanical disaggregation through a 200-mesh stainless steel gauze. The LNC were rinsed through the gauze with 9 mL of PBS, transferred to a centrifuge tube, pelleted at 1400 rpm (approximately 190 g) for 10 minutes and resuspended in 10 mL of PBS and re-pelleted. The pellet was re-suspended in 3 mL of 5% Trichloroacetic acid (TCA). After approximately 18 hours incubation at approximately 4 °C, the precipitate was recovered by centrifugation at 2100 rpm (approximately 450 g) for 10 minutes, re-suspended in 1 mL of TCA 5% and transferred to 10 mL of scintillation fluid. 3HTdR incorporation was measured by β-scintillation counting. The proliferation response of LNC was expressed as the number of radioactive disintegrations per minute per animal (dpm/animal) and as the ratio of 3HTdR incorporation into lymph node cells of test nodes relative to that recorded for the control nodes (Stimulation Index).

- Stimulation Index: Results for each treatment group were expressed as the Stimulation Index (SI).
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
Data was processed to give group mean values for disintegrations per minute and standard deviations where appropriate. Individual and group mean disintegrations per minute values were assessed for dose response relationships. Data was first assessed for suitability by analysis of normality and homogeneity of variance. If the assumptions that the data are both normally distributed and has homogeneity of variances, then parametric one way analysis of variance (ANOVA) and Dunnett’s multiple comparison procedure were used to determine statistical significance. If the assumptions were not met, non-parametric Kruskal-Wallis Rank Sum and Mann-Whitney U test procedures were used.
Probability values (p) are presented as follows:
P<0.001 ***
P<0.01 **
P<0.05 *
P>0.05 (not significant)
Positive control results:
SI for the positive control substance α-Hexylcinnamaldehyde (HCA) 25% v/v in vehicle, was 5.83 which demonstrates the validity of this study.
Parameter:
SI
Remarks on result:
other: see Remark
Remarks:
- Stimulation index for 25 and 50 % v/v and undiluted material were 3.10, 8.85 and 17.83, respectively. - As a SI of 3 or more was recorded for all of the concentrations tested, test item was considered to have the potential to cause skin sensitization. The concentration of test item expected to cause a 3 fold increase in 3HTdR incorporation (extrapolated EC3 value) was calculated to be 24.7%.
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Mean DPM/animal for 25, 50 % v/v and undiluted material were, 6870.78, 19637.09 and 39532.59, respectively.

Preliminary investigation

Mortality and clinical signs: There were no deaths and no signs of systemic toxicity was noted during the study.

Dermal reactions: Very slight erythema was noted on both ears of the animals receiving undiluted test item on Day 3 (score of 1/4).

Measurement of ear thickness: No signs of irritation indicated by the increase in mean ear thickness were noted.

Body weight : There was no indication of an effect of treatment on body weight gain. A minor loss in body weight was noted

Based on this information the undiluted test item and the test item at concentrations of 50% and 25% v/v in acetone/olive oil 4:1 were selected for the main test.

 

Main phase

Mortality and clinical signs: There were no deaths and no signs of systemic toxicity were noted in the test or control animals during the test.

Dermal reactions: No signs of dermal irritation were seen on the ear during the study.

Measurement of ear thickness: No signs of irritation indicated by the increase in mean ear thickness were noted.

Body weight: There was no indication of an effect of treatment on body weight gain. Body weight change of the test animals between Day 1 and Day 6 were comparable to that observed in the corresponding control group animals over the same period.

Table 7.4.1/1 : Individual Disintegrations per Minute and Stimulation Indices

Treatment Group

Animal Number

dpm/ Animala

Mean dpm/Animal (Standard Deviation)

Stimulation Indexb

Result

Vehicle acetone/olive oil 4:1

1-1

2108.49

2217.80 (±203.05)

na

na

1-2

2298.16

1-3

2535.86

1-4

2115.36

1-5

2031.12

Test Item 25% v/v in acetone/olive oil 4:1

2-1

7472.53

6870.78** (±720.83)

3.10

Positive

2-2

6342.71

2-3

6277.67

2-4

7819.96

2-5

6441.01

Test Item 50% v/v in acetone/olive oil 4:1

3-1

14710.36

19637.09** (±5036.07)

8.85

Positive

3-2

25912.11

3-3

18322.54

3-4

23867.04

3-5

15373.41

Test Item 100%

4-1

34319.39

39532.59** (±7449.68)

17.83

Positive

4-2

46971.60

4-3

29440.18

4-4

45292.91

4-5

41638.87

Positive Control Item

25% v/v in acetone/olive oil 4:1

5-1

20309.44

12922.88** (±7257.76)

5.83

Positive

5-2

21265.82

5-3

7030.16

5-4

9313.81

5-5

6695.15

dpm = Disintegrations per minute

a = Total number of lymph nodes per animal is 2

b = Stimulation Index of 3.0 or greater indicates a positive result

na = Not applicable

** = Significantly different from vehicle control group p<0.01 

Interpretation of results:
sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, test material is classified as a skin sensitizer 1B according to the annex VI of the Regulation EC No. 1272/2008 (CLP).
Executive summary:

A study was performed to assess the skin sensitisation potential of test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. The method was conducted according to the OECD test guideline No 429 and in compliance with GLP.

The study comprised three treated groups, each comprising five female mice receiving test item at concentrations of 25, 50% v/v or the undiluted test item. Similarly constituted groups received the vehicle 4:1 v/v acetone: olive oil or positive control substance (25% v/v α-Hexylcinnamaldehyde). The mice were treated by daily application of 25mL of the appropriate concentration or control (vehicle or positive), to the dorsal surface of both ears for three consecutive days.The proliferative response of the lymph node cells (LNC) from the draining auricular lymph nodes was assessed five days following the initial application, by measurement of the incorporation of3H-methyl Thymidine (3HTdR) by β-scintillation counting of LNC suspensions. The proliferation response of lymph node cells was expressed as the number of radioactive disintegrations per minute per animal and as the ratio of 3HTdR incorporation into lymph node cells of test nodes relative to that recorded for the control nodes (Stimulation Index).

The SI obtained for 25, 50% v/v and for the undiluted test item were 3.10, 8.85 and 17.83 respectively which indicates that test item showed the potential to induce skin sensitization. The EC3 value was calculated to be 24.7% v/v. No sign of systemic toxicity or excessive local skin irritation were noted at the concentrations of 25 and 50 v/v, nor for the undiluted test item.

 

The SI for the positive control substance α-Hexylcinnamaldehyde was 5.83, which demonstrates the validity of this study.

 

Under the test conditions, test material is classified as a skin sensitizer 1B in the Local Lymph Node Assay according to the annex VI of the Regulation (EC) No. 1272/2008 (CLP).

 

This study is considered as acceptable and satisfies the requirement for sensitisation endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Existing human data concluded that the registered substance has no to mild skin sensitization potential. The reliability of those data was not considered adequate to meet the REACH requirements and to make a conclusion on classification and labelling. Moreover QSAR (ToxTree v2.6.6) identified skin sensitisation potential (Michael acceptors and Schiff base formation alerts) for one component (CAS n°28387-62-4) which is present between 1 to 3% in the UVCB substance.

Therefore, a new LLNA study was performed according to the OECD test guideline No. 429 and in compliance with GLP (Envigo, 2016).

The study comprised three treated groups, each comprising five female mice receiving test item at concentrations of 25, 50% v/v or the undiluted test item. Similarly constituted groups received the vehicle 4:1 v/v acetone: olive oil (AOO) or positive control substance (25% v/v hexyl cinnamic aldehyde). Mice were treated by daily application of 25mL of the appropriate concentration or control (vehicle or positive), to the dorsal surface of both ears for three consecutive days.The proliferative response of the lymph node cells (LNC) from the draining auricular lymph nodes was assessed five days following the initial application, by measurement of the incorporation of 3H-methyl Thymidine (3HTdR) by β-scintillation counting of LNC suspensions. The response was expressed as radioactive disintegrations per minute per animal and as the ratio of 3HTdR incorporation into LNC of test nodes relative to that recorded for control nodes (test/control ratio), termed as Stimulation Index (SI).

The SI obtained for 25, 50% v/v and for the undiluted test item were 3.10, 8.85 and 17.83, respectively, which indicates that test item showed the potential to induce skin sensitization. The EC3 value was calculated to be 24.7% v/v. No sign of systemic toxicity or excessive local skin irritation were noted at the concentrations of 25 and 50 % v/v, nor for the undiluted test item.

The SI for the positive control substance hexyl cinnamic aldehyde was 5.83, which demonstrates the validity of this study.

 

Under the test conditions, test material is classified as a skin sensitizer.



Migrated from Short description of key information:
LLNA, skin sensitizer (OECD 429, GLP, K, Rel. 1)

Justification for selection of skin sensitisation endpoint:
GLP-compliant and of high quality (Klimisch score = 1).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

Under the REACH regulation there is no legal standard information requirement in Annexes VII to X to perform any specific test for respiratory sensitisation. However, guidance document Chapter R.7.a endpoint specific guidance (paragraphs 7.3.5-7.3.9) describes how to use human and non-human data. As regards non-human data there is:

No definitive guidance on use of QSARs

No specific in vitro method

The role on LLNA, cytokine fingerprints, total IgE/specific IgE methods are described. However, it is widely appreciated that, in both humans and animals, the accurate evaluation of antibody responses against chemical allergens in the form of hapten–protein conjugates can be technically demanding and highly variable between laboratories.

Assessment should be case-by-case

Nonetheless, the registrant recognises that further information can be requested beyond the information mentioned in Annexes VII to X of REACH, if there is a concern that a given substance may constitute a risk to human health or the environment, and further information is needed to clarify such concern. The substance has been identified as a weak skin sensitizer and hence there is potential for a risk of respiratory sensitization effects following inhalation exposure; either as a cause of respiratory sensitization or as a route of exposure to elicit dermal and/or respiratory effects in an individual that is already sensitized via the dermal exposure route.

The case-by-case risk assessment for the potential for respiratory sensitization for this substance is addressed as follows.

Prevalence.Compared with contact allergens, of which a few thousand have been identified, far fewer chemicals have been implicated as having the potential to cause sensitisation of the respiratory tract, the number being no more than 80, all are associated with occupational exposures (Kimber and Dearman, 1997; Bakerly et al., 2008; Health and Safety Executive, 2001; Baur, 2013; Baur and Bakehe, 2014).

Mechanistic Factors.Most chemicals are too small in terms of molecular size to induce an adaptive immune response. To acquire immunogenic potential they must form stable associations with protein (hapten–protein conjugates). Mechanistic chemistry studies have revealed that chemical respiratory allergens can be assigned to one of six electrophilic mechanistic domains, with harder (stronger) electrophilic mechanisms such as acylation being more prevalent than softer (weaker) mechanisms, with the hypothesis being that the harder nucleophile lysine is the favoured biological nucleophile for sensitization of the respiratory tract (Enoch et al., 2012). The substance is not-predicted to react with skin proteins directly, but may act as a pro-hapten (OECD toolbox v3.1). The substance or its’ metabolites are expected to react via covalent binding with a cysteine peptide under the metabolic conditions of the peroxidase peptide reactivity assay (PPRA) (Gerberick, 2009), which is the first step of the adverse outcome pathway (AOP) of sensitization. The possible importance of lysine reactivity (in comparison to cysteine binding) in sensitization of the respiratory tract by chemical allergens is supported by some in chemico and in vitro studies (Hopkins et al., 2005; Lalko et al., 2011, 2012, 2013b). Hence, as the substance or its’ metabolites preferentially react with cysteine it is unlikely to be a respiratory sensitizer, which seem to be those chemicals that are more likely to react with lysine.

Antigenic Response.A positive response in the LLNA does not imply that a chemical will cause respiratory sensitisation because the immune responses induced by contact allergens and chemical respiratory allergens begin to diverge in a qualitative sense after the initial activation of T lymphocytes (Cochrane et al., 2015). Chemical respiratory allergens result in the development of a selective Th2-type immune response characterised by the increased expression of type 2 cytokines such as IL-4, IL-5 and IL-13. In contrast, under the same conditions, skin sensitising chemicals elicit Th1-selective immune responses.

Threshold Effects.There is evidence that thresholds of elicitation can be defined for IgE mediated allergies and in the case of human respiratory sensitisation to proteins there is evidence for thresholds even if it is not currently possible to be specific in numerical terms (Basketter et al., 2010, 2012; Peters et al., 2001; Sarlo, 2003).

As an example for chemical respiratory sensitizers, over the past 30 years evidence has accumulated of occupational asthma associated with the use of glutaraldehyde, including the involvement of IgE antibody, and in particular in endoscopy, radiography and pathology suites. The evidence suggests that brief exposures to high levels of glutaraldehyde are required to induce allergic sensitization, this is consistent with the probability that peak exposures to chemicals may drive sensitisation (Arts et al., 2006; Vyas et al., 2000).

Experimental Evidence.A study was conducted with patients with confirmed contact allergy to isoeugenol (an analogue of eugenol) or hydroxyisohexyl-3-carboxaldehyde (HICC). These patients were exposed to the chemical to which they were sensitized by inhalation using an exposure chamber, with skin contact being shielded by protective clothing. No significant changes in lung function were observed suggesting the absence of respiratory sensitization (Schnuch et al., 2010). This study provides evidence that individuals already sensitised to a substance via the dermal route do not experience symptoms of sensitization when exposed via the inhalation route. Also of relevance is a study of lung function among employees in the fragrance industry (Dix, 2013). A group of workers exposed to fragrance materials during production or similar operations was compared with a non-exposed control group of office workers. There were no significant differences in lung function as determined by measurement of forced expiratory volume, forced vital capacity of peak expiratory flow (Dix, 2013). The relevance of these studies and other work has been recently reviewed (Basketter and Kimber, 2015).

Consumer Exposure Levels.Irrespective of whether sensitisation is acquired via dermal contact or inhalation exposure, current mechanistic understanding of allergic sensitisation is such that it can be assumed there will be threshold effects for immunological priming, in the skin or respiratory tract, respectively. This means that for both the skin and respiratory tract there will be levels of exposure below which sensitisation will fail to develop (Cochrane et al, 2015). Furthermore, inhalation exposure may, in some circumstances at least, induce immunological tolerance rather than priming or sensitisation (Kimber and Dearman, 2002). As for the majority of fragrance materials the consumer exposure levels to the substance are estimated to be very low.

Worker Exposure.The substance is identified as a skin sensitizer and the workplace environmental controls, standard personal protection equipment and safety procedures (risk management measures) are considered adequate to limit the risk of respiratory sensitization in workers.

Conclusion.The current identified mechanisms of dermal and respiratory sensitization may be sufficiently different, and exposure levels are significantly lower than the probable minimum threshold level required for induction and/or elicitation to prevent any risk of respiratory sensitization. This conclusion is based on various elements of scientific evidence that together constitute a robust argument and obviate the need to conduct further specific studies to investigate the potential for respiratory sensitization of this substance.

References

Arts, J.H.E., Mommers, C., de Heer, C., 2006. Dose-response relationships and threshold levels in skin and respiratory allergy. Crit. Rev. Toxicol. 36, 219–251.

Bakerly, N.D., Morre, V.C., Vellore, A.D., Jaakkola, M.S., Robertson, A.S., Burge, P.S., 2008. Fifteen-year trends in occupational asthma: data from the shield surveillance scheme. Occup. Med. 58, 69-174.

Baur, X., 2013. A compendium of causative agents of occupational asthma. J. Occup. Med. Toxicol. 8, 1-8.

Baur, X., Bakehe, P., 2014. Allergens causing occupational asthma: an evidence based evaluation of the literature. Int. Arch. Occup. Environ. Health 87, 339-363.

Basketter, D.A., Broekhuizen, C., Fieldsend, M., Kirkwood, S., Mascarenhas, R., Maurer, K., Pedersen, C., Rodriguez, C., Schiff, H.-E., 2010. Defining occupational consumer exposure limits for enzyme protein respiratory allergens under REACH. Toxicology 268, 165–170.

Basketter, D.A., Berg, N., Kruszewski, F.H., Sarlo, K., Concoby, B., 2012. Relevance of sensitization to occupational allergy and asthma in the detergent industry. J. Immunotoxicol. 9, 314–319.

Basketter, D.A. and Kimber, I., 2015. Fragrance sensitisers: Is inhalation an allergy risk? Regul. Toxicol. Pharmacol. 73(3): 897-902.

Cochrane, SA., Arts, J.H.E., Ehnes, C., Hindle, S., Hollnagel, H.M., Poole, A., Suto, H., and Kimber, I., 2015. Thresholds in chemical respiratory sensitisation. Toxicology, 333, 179-194.

Dix, G.R., 2013. Lung function in fragrance industry employees. Occup. Med. (Lond.) 63, 377-379.

Enoch, S.J., Seed, M.J., Roberts, D.W., Cronin, M.T., Stocks, S.J., Agius, R.M., 2012. Development of mechanism-based structural alerts for respiratory sensitization hazard identification. Chem. Res. Toxicol. 25, 2490–2498.

Gerberick GF1, Troutman JA, Foertsch LM, Vassallo JD, Quijano M, Dobson RL, Goebel C, Lepoittevin JP. Investigation of peptide reactivity of pro-hapten skin sensitizers using a peroxidase-peroxide oxidation system. Toxicol Sci. 2009, 112(1):164-74.

Hopkins, J.E., Naisbitt, D.J., Kitteringham, N.R., Dearman, R.J., Kimber, I., Park, B.K., 2005. Selective haptenation of cellular and extracellular protein by chemical allergens: association with cytokine polarization. Chem. Res. Toxicol. 18, 375–381.

HSE (Health and Safety Executive), 2001. Asthmagen? Critical Assessments of the Evidence for Agents Implicated in Occupational Asthma. UK Health and Safety Executive.

Kimber, I., Dearman, R.J., 1997. Chemical respiratory allergy: an introduction. In: Kimber, I., Dearman, R.J. (Eds.), Toxicology of Chemical Respiratory Hypersensitivity. Taylor & Francis, London, UK, pp. 1-6.

Kimber, I., Dearman, R.J., 2002. Chemical respiratory allergy: role of IgE antibody and relevance of route of exposure. Toxicology 181–182, 311–315.

Lalko, J.F., Kimber, I., Dearman, R.J., Gerberick, G.F., Sarlo, K., Api, A.M., 2011. Chemical reactivity measurements: potential for characterization of respiratory chemical allergens. Toxicol. In Vitro 25, 433–445.

Lalko, J.F., Kimber, I., Gerberick, G.F., Foertsch, L.M., Api, A.M., Dearman, R.J., 2012. The direct peptide reactivity assay: selectivity of chemical respiratory allergens. Toxicol. Sci. 129, 421–431.

Lalko, J.F., Dearman, R.J., Gerberick, G.F., Troutman, J.A., Api, A.M., Kimber, I., 2013a. Reactivity of chemical respiratory allergens in the peroxidase peptide reactivity assay. Toxicol. In Vitro 27, 651–661.

Lalko, J.F., Kimber, I., Dearman, R.J., Api, A.M., Gerberick, G.F., 2013b. The selective peptide reactivity of chemical respiratory allergens under competitive and noncompetitive conditions. J. Immunotoxicol. 10, 292–301.

Peters, G., Johnson, G.Q., Golembiewski, A., 2001. Safe use of detergent enzymes in the workplace. Appl. Occup. Environ. Hyg. 16, 389–396.

Sarlo, K., 2003. Control of occupational asthma and allergy in the detergent industry. Ann. Allergy Asthma Immunol. 90, 32–34.

Schnuch, A., Oppel, E., Oppel, T., Rommelt, H., Kramer, M., Riu, E., Darsow, U., Przybilla, B., Nowak, D., Jorres, R.A., 2010. Experimental inhalation of fragrance allergen in predisposed subjects: effects on skin and airways. Br. J. Dermatol. 162, 598-606.

Vyas, A., Pickering, S.A.C., Oldham, L.A., Francis, H.C., Fletcher, A.M., Merrett, T., Niven, R.M., 2000. Survey of symptoms respiratory function, and immunology and their relation to glutaraldehyde and other occupational exposures among endoscopy nursing staff. Occup. Environ. Med. 57, 752–759.


Migrated from Short description of key information:
A robust evaluation of the available evidence for skin and respiratory sensitization, focussing on the mechanisms of dermal and respiratory sensitization. A conclusion is reached, based on various elements of scientific evidence, that together constitute a robust argument and obviate the need to conduct further specific studies to investigate the potential for respiratory sensitization of this substance.

Justification for selection of respiratory sensitisation endpoint:
The current identified mechanisms of dermal and respiratory sensitization may be sufficiently different, and exposure levels are significantly lower than the probable minimum threshold level required for induction and/or elicitation to prevent any risk of respiratory sensitization. This conclusion is based on various elements of scientific evidence that together constitute a robust argument and obviate the need to conduct further specific studies to investigate the potential for respiratory sensitization of this substance.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self-classification:

Based on the available data, the substance is classified as Skin Sens. 1B, H317 (May cause an allergic skin reaction) according to the Regulation (EC) No. 1272/2008 (CLP), since EC3 is > 2% (24.7%).

No direct scientific data are available on the substance to address respiratory sensitisation. However, a scientific argument using mechanistic information has been constructed and is detailed in the discussion of the endpoint summary. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.4.