12-aminododecanoic acid

Endpoint summary

Description of key information

SKIN
Not irritating, QSAR model prediction, 2011 
E YE 
Not irritating, Rabbit (male), OECD 405, EU Method B.5, EPA OPPTS 870.2400, Stitzinger 2012

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation / corrosion

Remarks:

other: QSAR

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

30 June 2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Calculation done according to a scientifically valid (Q)SAR model.

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May/July 2008

Deviations:

no

Principles of method if other than guideline:

"Nonlinear ANN QSAR Model for Dermal Irritation", Model Version 10.10.2010

GLP compliance:

no

Details on study design:

The Applicability domain (OECD principle 3)
Domains:
- descriptor domain
All descriptor values for 12-aminododecanoic acid fall in the applicability domain (training set value ± 30%).
-structural fragment domain
12-aminododecanoic acid is structurally rather similar to the training set compounds; the training set contains long aliphatic chains, carboxylic acid and amine functionalities. The training set contains compounds of similar size to the studied compound.
-mechanism domain
12-aminododecanoic acid is considered to be in the same mechanistic domain(s) as the molecules in the training set.
 
Structural Analogues
-undec-10-enoic acid
-11-aminoundecanoic acid

Considerations on structural analogues:
The structural analogues are rather similar to the studied compound. The key features in the structure for the studied compound are the two polar functional groups at either end of the aliphatic chain, resulting in a relatively low logP and high water solubility values. Similar compounds with just one polar group at the end of a long chain appear as stronger irritants. The analogues are considered to be within the same mechanistic domain as the studied molecule.

The uncertainty of the prediction (OECD principle 4)
The training set is not from one lab but a collection from several. However, previous and present successful modelling supports its consistency. The statistical quality of the model supports reliable predictions. Skin irritation is a difficult endpoint due to the multitude of possible chemical mechanisms in addition to the variations of permeability, the individual response of test animals may reduce accuracy as well. The studied compound is similar to the training set compounds, adding to prediction reliability. All structural analogues were evaluated correctly within the present model.

The prediction reliability is estimated as 85 %

The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5):
Skin corrosion/irritation is believed to be underpinned by two aspects – reactivity and permeability. Different mechanisms based on chemical reactivity (depending on the chemical’s tendency to behave as an electron donor or acceptor) have been proposed/described. While some models have been designed that rely on the frontier orbital energies, logP, pKa and softness-hardness descriptors, the present model contains a variety of hydrogen bonding and charged surface area (describing the active sites of the molecule) descriptors to characterize the reactivity of the compounds with the epidermis. The complex nature of the ANN model does not allow direct interpretation of the descriptors addressed to the property. However, investigation of the trends in descriptor and endpoint values allows the finding of some trends. It can be roughly estimated that with the increase (slight negative correlation between the descriptors) of count of H-acceptor sites (AM1), HBCA H-bonding charged surface area (AM1), FHACA Fractional HACA (HACA/TMSA) (AM1) the property the PII values increase.

The substance was predicted to have no skin irritation effects.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The model predicts that the test material will not cause significant erythema/eschar or oedema, and also that no inflammation will persist to the end of the observation period. The test material can therefore be considered 'not irritating'.

Executive summary:

The model predicts that the test material will not cause significant erythema/eschar or oedema, and also that no inflammation will persist to the end of the observation period. The test material can therefore be considered 'not irritating'.

The predicted value corresponds to "no category" classification as defined in Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP Regulation).

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:

28 November 2011 - 8 December 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF, 12 Nohsan, Notification No. 8147, April 2011

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: At least 6 weeks.
- Weight at study initiation: At least 1.0 kg.
- Housing: Animals were individually housed in labelled cages with perforated floors (dimensions 67 x 62 x 55 cm) and shelters (dimensions 40 x 32 x 23 cm).
- Diet (e.g. ad libitum): Pelleted diet for rabbits approximately 100 grams per day. Hay and wooden sticks were available during the study period.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0 °C (actual range 19.2 - 20.1 °C).
- Humidity (%): 40 - 70 % (actual range 44 - 65 %)
- Air changes (per hr): Approximately 15 per hour.
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 28 November 2011 To: 8 December 2011

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

A volume of approximately 0.1 mL was applied to the treated eye. The average amount of test material was 40.9 mg (range 40.6 - 41.3 mg).

Duration of treatment / exposure:

After installation of the test material, the lids were gently held together for a second to prevent loss of the test material.

Observation period (in vivo):

72 hours.

Number of animals or in vitro replicates:

3 males

Details on study design:

The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner one week later, after considering the degree of eye irritation observed in the first animal.

REMOVAL OF TEST SUBSTANCE
- Washing: No.

SCORING SYSTEM:

CORNEAL IRRITATION
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal lustre) 0
Scattered or diffuse areas of opacity, details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacreous area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

Area of cornea involved:
No ulceration or opacity 0
One quarter or less but not zero 1
Greater than one quarter, but less than half 2
Greater than half, but less than three quarters 3
Greater than three quarters, up to whole area 4

IRIS
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection,
any of these or combination thereof, iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, haemorrhage, gross destruction (any or all of these) 2

CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris)
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson colour, individual vessels not easily discernible 2
Diffuse beefy red 3

Chemosis (refers to lids and/or nictitating membranes)
No swelling 0
Any swelling above normal (includes nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4

Discharge
No discharge (may include small amounts observed in inner canthus of normal animals) 0
Any amount different from normal and/or lacrimation 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs (considerable area around the eye) 3

TOOL USED TO ASSESS SCORE:
Fluorescein (2 % solution) was used immediately after the observation which took place 24 hours after treatment.
Where standard lighting was considered inadequate for observing minor effects, eye examinations were performed using an ophthalmic examination lamp.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

8

Reversibility:

other: not applicable

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

8

Reversibility:

other: not applicable

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

8

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #2

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #3

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

3

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

3

Reversibility:

other: not applicable

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

Installation of approximately 41 mg of the test material into the eyes resulted in irritation of the conjunctivae, consisting of redness and discharge, at the examination conducted I hour after treatment.
This irritation had completely resolved in two animals at the 24 hour observation and in the remaining animal by the 48 hour observation.

Other effects:

Some remnants of the test material were present in the eye on day 1. No staining of the (peri) ocular tissues by the test substance was observed and there was no evidence of ocular corrosion.
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study, the test material was found to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

A study was carried out to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit, based on the standardised guidelines OECD 405, EU Method B.5, EPA, OPPTS 870.2400 and JMAFF, 12 Nohsan, Notification No. 8147, April 2011.

Approximately 40 mg of the test material was installed into one eye of three rabbits. The animals were observed for 72 hours and the level of irritation assessed. It was concluded that under the conditions of the study the test material was not irritating to eyes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation/corrosion

The model used in the key study ("Nonlinear ANN QSAR Model for Dermal Irritation", Model Version 10.10.2010) predicts that the test material will not cause significant erythema/eschar or oedema, and also that no inflammation will persist to the end of the observation period. The test material can therefore be considered 'not irritating' in accordance with EU criteria.

 

Eye irritation

In the key study, approximately 40 mg of the test material was installed into one eye of three New Zealand White rabbits. The animals were observed for 72 hours and the level of irritation assessed. It was concluded that under the conditions of the study the test material was not irritating to eyes.

 

The supporting QSAR study was conducted in accordance with REACH guidance on QSARs R.6, May/July 2008; it uses the validated QSAR model for Eye irritation (Draize test), Reference to QMRF: Q2-22-1-135 (http://qsardb.jrc.ec.europa.eu/qmrf/).

In accordance with the criteria of Klimisch (1997) this type of study may be awarded a reliability score of 2.

The predicted value corresponds to “weak irritant” on the scale of “non irritant, weak irritant, moderate irritant, strong irritant, very strong irritant” in accordance with the EU acute toxicity hazard categories and acute toxicity estimates (ATE) defining the respective categories according to Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP Regulation). The predicted value would correspond to the “Category 2” classification (Category II weak irritant SP = 2.35) - irritating to eyes [when applied to the eye of an animal, the substance may produce: a positive response of corneal opacity, iritis, and/or conjunctival redness and/or conjunctival oedema (chemosis)]. However this prediction is superseded by the key and supporting in vivo studies and it can therefore be concluded that the test material requires no classification for eye irritation.

Justification for selection of skin irritation / corrosion endpoint:
The key study is a QSAR, conducted in accordance with REACH guidance on QSARs R.6, May/July 2008; it uses the validated "Nonlinear ANN QSAR Model for Dermal Irritation", Model Version 10.10.2010.
In accordance with the criteria of Klimisch (1997) it may be awarded a reliability score of 2 and is considered to be an accurate reflection of the test material.

Justification for selection of eye irritation endpoint:
The key study was performed under GLP and in line with standardised guidelines OECD 405, EU Method B.5, EPA, OPPTS 870.2400 and JMAFF, 12 Nohsan, Notification No. 8147 with a high standard of reporting. The study was assigned a reliability score of 1 according to the principles for assessing data quality set out in Klimisch (1997) and is considered suitable for assessment as an accurate reflection of the test material.

Justification for classification or non-classification

Skin irritation/corrosion

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require

classification for skin irritation.

 

Eye irritation

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for eye irritation.