Reaction mass of undec-8-enal and undec-9-enal and undec-10-enal

Endpoint summary

Description of key information

Skin sensitisation: sensitizing, based on read-across from Pino acetald tested in OECD TG 429.

Respiratory sensitisation: non-sensitising in absence of human data and absence of structural alerts for respiratory sensitisation.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The result derived from read across is sufficiently reliable because all Annex XI criteria are met.

Justification for type of information:

The read across justification is presented in the Endpoint summary and the accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Positive control results:

The positive control item, α-Hexylcinnamaldehyde, gave a Stimulation Index of greater than 3 (9.4) when tested at a concentration of 35% v/v.

Key result

Parameter:

EC3

Remarks:

% v/v

Value:

25

Parameter:

SI

Value:

1.8

Remarks on result:

other: 2.5%

Parameter:

SI

Value:

1.1

Remarks on result:

other: 5%

Parameter:

SI

Value:

1.7

Remarks on result:

other: 10%

Parameter:

SI

Value:

3

Remarks on result:

other: 25%

Parameter:

SI

Value:

4.5

Remarks on result:

other: 50%

Interpretation of results:

other: Skin Sensitiser 1B

Remarks:

According to the CLP Regulation EC 1272/2008 and its updates

Conclusions:

Based on the results of the study for read-across substance Pino Acetald, Intreleven aldehyde was considered to be a sensitiser based on the EC3 value of 25%.

Reference 2

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15-06-2009 to 14-07-2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The information is used for read across to Intreleven aldehyde.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

GLP compliance:

yes

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

other: CBA/J

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Jackson Laboratories, Bar Harbor, ME 04609
- Age at study initiation: 8 weeks
- Weight at study initiation: 19 to 23 g
- Housing: 5 animals/cage (randomly allocated)
- Diet (e.g. ad libitum): ad libitum (Harlan Teklad Certified Rodent Chow 7012C)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21
- Humidity (%): 44-62
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

other: Ethanol/diethyl phthalate 1:3

Concentration:

2.5%, 5%, 10%, 25% and 50% v/v

No. of animals per dose:

5

Details on study design:

MAIN STUDY

Test Item Administration
Groups of five mice were treated with the test item at concentrations of 2.5%, 5%, 10%, 25% or 50% v/v in EtOH/DEP. No justification on the choice of vehicle is provided. The doses were chosen on the basis of avoiding systemic toxicity and overtly induced skin irritation, according to reported uses of the test material. 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, 2, 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 positive control animals were similarly treated to the test animals except that 25 µl of the positive control item, α Hexylcinnamaldehyde, at a concentration of 5%, 15% and 35% v/v in ethanol/diethyl phthalate 1:3 was applied to the dorsal surface of each ear.

3H-Methyl Thymidine Administration
On day 6, all mice were injected via the tail vein with 250 µl of phosphate buffered saline (PBS) containing 3H methyl thymidine (3HTdR:80µCi/ml, specific activity 2.0 Ci/mmol, ARC UK Ltd) giving a total of 20 µCi to each mouse.

Observations
Clinical Observations: All animals were observed before and after dosing, and on a daily basis on Days 4, 5 and 6. Any signs of toxicity or signs of ill health during the test were recorded. The animals were also examined daily for erythema and edema on the site of application.

Bodyweights: The bodyweight of each mouse was recorded on Day 1 (prior to dosing) and Day 6 (prior to termination).

Terminal Procedures
Termination: Five hours following the administration of 3HTdR all mice were killed by carbon dioxide asphyxiation. For each individual animal of each group the draining auricular lymph nodes were excised and processed.

Preparation of Single Cell Suspension: A single cell suspension of the lymph node cells for each individual animal was prepared. The lymph node cells were rinsed with PBS and precipitated with 5% trichloroacetic acid during night. The lymph node cells suspension was transferred to a centrifuge tube and thereafter, the pellets were resuspended in 1 ml TCA and transferred to scintillation fluid vials for the measurement of the radioactive material.

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. Increases in the radioactivity compared to the vehicle control were recorded. Individual DPM values were analyzed with log values. Dunett's test was used to determine significance when required. The EC3 was calculated as follows:

EC3=c+[(3-d)/(b-d)](a-c),

data points between the SI=3 lie in the coordinates (a,b) and (c,d)

Positive control results:

The positive control item, α-Hexylcinnamaldehyde, gave a Stimulation Index of greater than 3 (which was 9.4) when tested at a concentration of 35% v/v.

Key result

Parameter:

EC3

Remarks:

% v/v

Value:

25

Parameter:

SI

Value:

1.8

Remarks on result:

other: 2.5%

Parameter:

SI

Value:

1.1

Remarks on result:

other: 5%

Parameter:

SI

Value:

1.7

Remarks on result:

other: 10%

Parameter:

SI

Value:

3

Remarks on result:

other: 25%

Parameter:

SI

Value:

4.5

Remarks on result:

other: 50%

Cellular proliferation data / Observations:

Disintegrations per minute (DPM)

Test material: Mean DPM at 0 (vehicle), 2.5, 5, 10, 25, and 50% were 468.3, 842.6, 507.4, 801.7, 1400.1 and 2095.1, respectively.
Positive control: Mean DPM at 0 (vehicle), 5, 15, 35% were 320.7, 380.4, 602.4, 3027.4, respectively.

No erythema or edema was noted. There were no deaths. No signs of systemic toxicity were noted in the test or control animals during the test. Bodyweight changes of the test animals between Day 1 and Day 6 were comparable to those observed in the corresponding control group animals over the same period.

Interpretation of results:

other: Skin Sensitiser 1B

Remarks:

According to the CLP Regulation EC 1272/2008 and its updates

Conclusions:

The test item testing resulted in an EC3 value of 25% and therefore it is considered to be a skin sensitiser.

Executive summary:

The skin sensitisation potential of Pino Acetald was tested according to OECD TG 429 (Local Lymph Node Assay). At 2.5, 5, 10, 25 and 50% the substance showed SI values of 1.8, 1.1, 1.7, 3.0 and 4.5, respectively. An EC3 value of 25% was derived. The substance was found to be a skin sensitiser under the conditions of this test.

Reference 3

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

The skin sensitisation potential of Intreleven Aldehyde was assessed by using read across from Pino Acetald. First the experimental skin sensitisation information of Pino Acetald will be summarised. Thereafter the read across justification is presented, the accompanying files are attached in the present endpoint summary.

Skin sensitisation study (LLNA) with Pino Acetald

The skin sensitisation potential of Pino Acetald was tested according to OECD TG 429 (Local Lymph Node Assay). At 2.5, 5, 10, 25 and 50% the substance showed SI values of 1.8, 1.1, 1.7, 3.0 and 4.5, respectively. An EC3 value of 25% was derived. The substance was found to be a skin sensitiser under the conditions of this test.

The skin sensitisation properties of Intreleven aldehyde (CAS 58296-81-4; Target) using read across from Pino ACETALD (CAS 33885-51-7; Source)

 

Introduction and hypothesis for the read across

Intreleven aldehyde is a multi-constituent which consists of the following main constituents: Undec-10 -enal, (9E) Undec-9 -enal, (9Z) Undec-9 -enal and (8E) Undec-8 -enal. These constituents are aldehydes with a linear carbon backbone and contain one C=C double bond at various positions ranging from C 8 to 10. For this substance no skin sensitisation data are available. Therefore additional information is used in accordance with Article 13 of REACH where it is said that lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, SARs, grouping and read-across. For assessing the skin sensitisation of Intreleven aldehyde, the analogue approach is selected because for one closely related analogue, Pino ACETALD, skin sensitisation data are available which can be used for read-across.

Hypothesis: Intreleven aldehyde is expected to have the same skin sensitisation properties as Pino ACETALD.

Available information: For the target substance, Intreleven aldehyde, no sensitization information is available. Based on the substance being an aldehyde, skin sensitization is expected. For the source chemical, Pino ACETALD, an OECD TG 429 (Local Lymph Node Assay, K1) is available. At 2.5, 5, 10, 25 and 50% the substance showed SI values of 1.8, 1.1, 1.7, 3.0 and 4.5, respectively. An EC3 value of 25% was derived.

Target and Source chemical(s):

Chemical structures of the target chemical (Intreleven aldehyde) and the source chemical (Pino ACETALD) are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for skin sensitisation.

Purity / Impurities:

The components and impurities of the target chemical do not indicate skin sensitisation properties other than indicated by the parent substance. The constituents are known for at least 95% and therefore this substance is well characterized.

Analogue justification

According to REACH Annex XI an analogue approach and structural alert information can be used to replace testing when information from different sources provides sufficient evidence to conclude that this substance has or does not have a particular dangerous property. The result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.

Analogue selection: Pino ACETALD was selected as analogue based on the structural similarity with Intreleven aldehyde and because it is a substance from IFF portfolio, for which suitable information on skin sensitization was available.

Structural similarities and differences: The target chemical, Intreleven aldehyde, and source chemical Pino ACETALD have the same hydrocarbon backbone with one double C=C bond and aldehyde functional group. The difference between the target and source substance is that Pino ACETALD has a cyclic ring in its tail, while Intreleven aldehyde has it linear.

Toxicokinetics: To some extent skin absorption is needed for skin sensitisation. Intreleven aldehyde and Pino Acetald are likely to be absorbed in skin, based on the fact that they are both liquids, the similarity in chemical structure and physico-chemical properties (similar molecular weights and logKow).

Toxicodynamics: Reactivity is the key parameter for assessing the skin sensitization potential. Both Intreleven aldehyde and Pino Acetald are expected to have the same reactivity based on the fact that they both have the same functional alkyl aldehyde group, which is the key structural parameter for skin sensitisation potential. Pino acetald can, however, be a bit more reactive based on skin and eye irritation information, where it was demonstrated to be an irritant, while Intreleven aldehyde was not.

Remaining uncertainties: There are no remaining uncertainties as presented above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix in Table 1.

Conclusions for skin sensitisation

For the target substance Intreleven aldehyde, the potential for skin sensitisation was derived from Pino Acetald using read across. The results of this read-across assessment based on OECD TG 429 (Local Lymph Node Assay) indicated senstitisation potential (EC3 value of 25%). This information can also be used for Intreleven aldehyde based on the similarity in structure, toxicokinetics and reactivity.

Final conclusion on hazard and application in the risk assessment: From analogue information and structural alert information, it can be concluded that Intreleven aldehyde is expected to exert skin sensitising properties and it is a sensitizer 1B.

 

Data matrix for the read across from Pino ACETALD to Intreleven aldehyde 

CHEMICAL NAME	Intreleven aldehyde (Undec-8-enal)	Pino ACETALD
Molecular structure
CAS	58296-81-4	33885-51-7
REACH registration	To be registered (Annex VIII)	Registered (Annex VII)
Einecs	261-202-4	251-717-2
Molecular formula	C11H20O	C12H18O
Molecular weight	168.28	178.27
Physico-chemical properties
Appearance	Liquid	Liquid
Melting point (°C)	<-20 (IFF, 2016)	<-20 (IFF, 2015)
Boiling point (°C)	239.1 (IFF, 2016)	243.9 (IFF, 2015)
Vapour pressure (Pa)	6.04 (IFF, 2016)	4.4 (IFF, 2015)
Water solubility (mg/L)	26.1 (IFF, 2016)	61.0 (IFF, 2015)
LogKow	4.47 (IFF, 2017)	4.3 (IFF, 2015)
Human health
Skin irritation	Not irritating (OECD TG 439)	Skin Irrit. 2 (OECD TG 439)
Eye irritation	Not irritating (OECD TG 438)	Eye Irrit. 2 (OECD TG 438)
Skin sensitisation	Read Across from Pino ACETALD	Skin Sens. 1B (OECD TG 429)
Genotoxicity – Ames test	Negative (OECD TG471)	Negative (OECD TG471)

For testing data, see the IUCLID under the relevant endpoint.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

This endpoint can be assessed using human data such as indicated in R7.3.5.2 of the ECHA guidance (2015) that indicate respiratory reactions e. g. from consumer experience or occupational exposure. In case no such data are available, the respiratory sensitisation can be assessed using the integrated evaluation strategy for respiratory sensitisation data in the ECHA guidance (R7A, Fig. 7.3-2, 2015).

The substance is not a respiratory sensitiser in absence of human data indicating such effects, and in addition:

1)     The substance is a skin sensitiser;

2)     The substance does not belong to the di-isocyanates;

3)     The substance has no structural alerts or is structurally related to chemicals causing respiratory sensitisation as presented in Table R.7.3-1 in the ECHA guidance of 2015 or those provided in the following document: http://ec.europa.eu/health/scientific_committees/docs/annex6_respiratory.pdf

Based on this stategy, Intreleven aldehyde is not considered to be a respiratory sensitiser.

Justification for classification or non-classification

Based on the available data, the substance needs to be classified as skin sensitiser (Skin Sens. 1B / H317) in accordance with the criteria outlined in the EU CLP Regulation (EC No. 1272/2008 and its updates).

In absence of human data indicating respiratory sensitisation and using the ITS in the ECHA guidance (R.7a, 2014), the substance is not considered to be a respiratory sensitiser in accordance with the criteria outlined in the EU CLP Regulation (EC No. 1272/2008 and its updates).