Octadecanedioic acid, 1,18-dimethyl ester

Endpoint summary

Description of key information

• Non-irritating to skin (OECD 439, read-across from supporting substance, structural analogue EC 662-772-0

• Non-irritating to eyes: Key; BCOP (OECD 437); Supporting (OECD 437 and in-vivo OECD 405, read-across from supporting substance, structural analogue EC 662-772-0)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vitro / ex vivo

Type of information:

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

Adequacy of study:

key study

Study period:

2011-11-15 to 2011-11-21

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

KL2 due to RA

Justification for type of information:

Read-across justification: A comparison target substance (9DDAME) and the read-across substance (9DAME) shows that the two substances share structural similarities, increasing from a chain length of C10 to C12 with similar functional groups and also have ‘mechanistic action’ similarities.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 439 (In vitro skin irritation: reconstructed human epidermis test method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of inspection 2011-07-19 to 2011-07-21; Date of signature 2011-08-31

Species:

other: not applicable

Strain:

not specified

Type of coverage:

other: not applicable

Preparation of test site:

other: not applicable

Vehicle:

not specified

Controls:

other: not applicable

Duration of treatment / exposure:

15 minutes

Observation period:

Not applicable

Number of animals:

Not applicable

Irritation / corrosion parameter:

other: other: relative viability of treated tissues

Value:

68.8

Remarks on result:

other:

Remarks:

Basis: mean. Time point: 15 minutes. Remarks: ± 13.7 Percent . (migrated information)

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material was determined to be non-irritant.

Executive summary:

The skin irritation potential of the test item 9-dodecenoic acid, methyl ester (9DDAME) has been read-across from the substance 9-decenoic acid, methyl ester (9DAME) from the following study.

An in vitro study was performed to assess the skin irritation potential of the test item, using the EPISKIN™ reconstructed human epidermis model, according to OECD Guideline 439, in compliance with GLP. The potential was observed after a treatment period of 15 minutes followed by a postexposure incubation period of 42 hours. The relative mean viability of the test item treated tissues was 68.8 % after the 15 minute exposure period. The test item, 9-decenoic acid, methyl ester was therefore considered to be non-irritant (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar result can be expected for the test item.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

23 January 2012 to 02 February 2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

KL2 due to RA

Justification for type of information:

Read-across justification: A comparison target substance (9DDAME) and the read-across substance (9DAME) shows that the two substances share structural similarities, increasing from a chain length of C10 to C12 with similar functional groups and also have ‘mechanistic action’ similarities.

Reason / purpose for cross-reference:

read-across source

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

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of inspection 2011-07-19 to 2011-07-21; Date of signature 2011-08-31

Species:

rabbit

Strain:

New Zealand White

Vehicle:

unchanged (no vehicle)

Controls:

yes

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

One animal was treated initially. After consideration of the ocular responses produced in the first animal, two additional animals were treated.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.67

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.33

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Reversibility:

fully reversible within: 48 hours

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test item is considered to be not irritating to the rabbit eye and is not classified in accordance with CLP Regulation No (EC) 1272/2008.

Executive summary:

The eye irritation potential of the test item 9-dodecenoic acid, methyl ester (9DDAME) has been read-across from the substance 9-decenoic acid, methyl ester (9DAME) from the following study.

An in vivo study was performed to assess the the eye irritation potential of the test item in New Zealand white rabbit, according to OECD Guideline 405, in compliance with GLP. A single application of the test item to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. One treated eye appeared normal at the 48 hour observation and two treated eyes appeared normal at the 72 hour observation. Based on the classification criteria for eye irritation according to Regulation (EC) No.
1272/2008, 9-decenoic acid, methyl ester is considered to be non-irritating to eyes (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar result can be expected for the test item.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

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

Adequacy of study:

key study

Study period:

20 December 2011 to 22 December 2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Read-across from GLP study performed to accepted scientific standards. Read-across justification: A comparison target substance (9DDAME) and the read-across substance (9DAME) shows that the two substances share structural similarities, increasing from a chain length of C10 to C12 with similar functional groups and also have ‘mechanistic action’ similarities.

Justification for type of information:

Read-across justification: A comparison target substance (9DDAME) and the read-across substance (9DAME) shows that the two substances share structural similarities, increasing from a chain length of C10 to C12 with similar functional groups and also have ‘mechanistic action’ similarities.

Reason / purpose for cross-reference:

read-across source

Qualifier:

no guideline available

Principles of method if other than guideline:

The purpose of this study was to determine the eye irritation potential of the test material using the SkinEthic Reconstituted Human Corneal Epithelium model (HCE, SkinEthic Laboratories, Nice, France) after a treatment period of 10 minutes. The test is based on the hypothesis that irritant chemicals are able to penetrate the corneal epithelial tissue and are sufficiently cytotoxic to cause cell death.

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of inspection 2011-07-19 to 2011-0721; Date of signature 2011-08-31

Species:

other: Reconstituted Corneal Epithelium

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

Cultures were exposed for 10 minutes to the test material.

Observation period (in vivo):

Skin cultures were examined after three hours.

Number of animals or in vitro replicates:

All test substances were tested in triplicate (including controls)

Irritation parameter:

other: relative mean tissue viability

Run / experiment:

10 min

Value:

ca. 113.5

Remarks on result:

other: %

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

According to the protocol followed, the test item was considered to be a Non Irritant The quality criterion required for the acceptance of results in the test was satisfied.

Executive summary:

The eye irritation potential of the test item 9-dodecenoic acid, methyl ester (9DDAME) has been read-across from the substance 9-decenoic acid, methyl ester (9DAME) from the following study.

A in vitro study was performed to assess the eye irritation potential of the test item, using the SkinEthic reconstructed Human Corneal Epithelium model, according to accepted scientific standards, in compliance with GLP. Triplicate SkinEthic tissues were treated with 30 μL of the test item for 10 minutes. Cytotoxicity was determined by the reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyl-tetrazolium bromide) to formazan by viable cells in the test item treated tissues (quantitative
measurement of tissue viability) relative to the negative control. The relative mean viability of the test item treated tissues was 113.5% and hence 9-decenoic acid, methyl ester is considered to be a nonirritant (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar result can be expected for the test item.

Reference 3

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage)

Version / remarks:

October 09, 2017

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Elevance Renewable Sciences, Inc.; Batch/Lot No. 11631837A
- Expiration date of the lot/batch: Indefinitely if stored appropriately
- Purity: 93%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At less than 40 deg C in original containers. Under nitrogen when not in use.

Species:

other: Isolated cornea from the eyes of freshly slaughtered cattle

Details on test animals or tissues and environmental conditions:

SOURCE OF COLLECTED EYES
- Source: Deonar Abattoir slaughter house, Mumbai, Maharashtra
- Number of animals: three corneas per test group
- Characteristics of donor animals (e.g. age, sex, weight): 1 to 5 years of age
- Storage, temperature and transport conditions of ocular tissue (e.g. transport time, transport media and temperature, and other conditions): Transported (in a sealed plastic container) under cold condition in Hanks’ Balanced Salt Solution containing antibiotics [e.g., penicillin at 100 IU/mL and streptomycin at 100 μg/mL]
- Time interval prior to initiating testing: within 24 hours of slaughter
- indication of any existing defects or lesions in ocular tissue samples: Eyes were examined prior to use and corneas free from any visible defects were used. Corneas that have opacity less than seven opacity units or equivalent for the opacitometer were used in the study.

Vehicle:

other: corn oil

Controls:

other: untreated eye

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 750 μL of the prepared test item [20% (w/v) concentration in corn oil]

Duration of treatment / exposure:

4 h at 32 ºC

Duration of post- treatment incubation (in vitro):

Cornea holders were incubated for 90 min at 32 ºC post application.

Number of animals or in vitro replicates:

three corneas per test group

Details on study design:

NEGATIVE CONTROL USED : normal saline

SOLVENT CONTROL USED (if applicable): corn oil

POSITIVE CONTROL USED: Imidazole, 20% (w/v) concentration in normal saline

TREATMENT METHOD: [closed chamber / open chamber] : Selected corneas were mounted on the corneal holders with the endothelial side against the O-ring of the posterior half of the holder. The anterior half of the holder was then placed on the top of the cornea and fixed in place. Both chambers were then filled to excess with pre-warmed phenol red free Eagle's Minimum Essential Medium (EMEM) (the posterior chamber filled first to allow the cornea to return to its natural concave position), ensuring no bubbles were present within the holders. The device was then equilibrated at 32 ± 1°C for at least one hour to allow the corneas to equilibrate with the medium and to achieve normal metabolic activity, to the extent possible. Following equilibration, the medium was removed from both chambers and fresh pre-warmed phenol red free EMEM added to both chambers. A baseline opacity reading was then taken for each cornea.

REMOVAL OF TEST SUBSTANCE
- Number of washing steps after exposure period: the corneal epithelium was washed until no visual evidence of test item was observed using EMEM (containing phenol red). Once the medium was free of test item, the corneas were given a final rinse with EMEM (without phenol red). After opacity measurement the medium was removed from the anterior chamber and filled with 1 mL of 5 mg/mL of fluorescein solution, the posterior chamber was filled with fresh EMEM (without phenol red).

- POST-EXPOSURE INCUBATION: The holders were incubated in a horizontal position for 90 ± 5 min at 32 ± 1 ºC. After incubation the medium in the posterior chamber was transferred in to labelled tubes. An aliquot of the medium from the posterior chamber was transferred to a 96-well plate. The plate reader was set to read at OD490. A reading of EMEM (without phenol red) was also recorded which served as a blank.

METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity: opacitometer
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of [UV/VIS spectrophotometry / microtiter plate reader] (OD490)

SCORING SYSTEM: In Vitro Irritancy Score (IVIS)
IVIS was calculated for each treatment group as follows:
IVIS = mean opacity value + (15 x mean permability OD490 value).
The IVIS was calculated for each individual treatment.

DECISION CRITERIA: as indicated in the TG.
The IVIS cut-off values for identying test item as inducing serious eye damage (UN GHS Category 1) and test item not requiring classification for eye irritation or serious eye damage (UN GHS No Category) are given below:

IVIS:
≤ 3: No category
>3; ≤55: No prediction can be made
<55: Category 1

Irritation parameter:

in vitro irritation score

Run / experiment:

Mean of 3 corneas

Value:

1.35

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Remarks on result:

other: No UN GHS category

Other effects / acceptance of results:

DEMONSTRATION OF TECHNICAL PROFICIENCY: yes

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: yes
- Acceptance criteria met for positive control: yes
The mean IVIS of imidazole (20% w/v) (positive control) treated corneas was found to be 98.35, which is within the range of two standard deviation of the mean of the historical control data, confirming the reliability of the test procedure.

Resutls:
Corneal opacity:
The opacity values for the test item treated corneas (0.66) did not show any observable increase in opacity value in comparison to the vehicle control group (corn oil) (0.20). An observable marked increase in final mean opacity was observed in the corneas trated with the positive control (78.13) in comparison to the control group (normal saline) (0.10).

Corneal Permeability:
The mean final corneal permeability values for the test item treat eyes (0.046) did not show any observable increase in comparison to the vehicle control group (corn oil) (0.021). An observable marked increase in mean final corneal permeability was observed in the corneas treated with the positive control (1.348) in comparison to the control group (normal saline) (0.003).

In vitro Irritancy Score (IVIS):
The mean In-vitro Irritancy Score (IVIS) of normal saline (control), vehicle control (corn oil) and imidazole (20% w/v) (positive controll) treated corneas were found to be 0.15, 0.51 and 98.35, respectively.

The IVIS score for the corneas treated test item at 20% w/v concentration in corn oil were found to be 1.35.

Interpretation of results:

GHS criteria not met

Conclusions:

Octadecanedioic acid, 1,18-dimethyl ester produced a mean in vitro irritancy score of 1.35 under these guideline test conditions, and is therefore not classified for eye irritation or serious eye damage.

Executive summary:

An ex vivo study was performed to assess the eye irritation potential of the test item, using the Bovine corneal opacity and permeability test method, according to OECD Guideline 437, in compliance with GLP.  Octadecanedioic acid, 1,18-dimethyl ester produced a mean in vitro irritancy score of 1.35 under these guideline test conditions, and is therefore not classified for eye irritation or serious eye damage.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

To assess the skin irritation potential and support eye irritation results of the test item octadecanedioic acid, 1,18-dimethyl ester (ODDAME), experimental results have been read-across from a supporting substance, structural analogue 9-decanoic acid, methyl ester (EC 662-772-0):

 

Skin irritation:

An in vitro study was performed to assess the skin irritation potential of the test item, using the EPISKIN™ reconstructed human epidermis model, according to OECD Guideline 439, in compliance with GLP. The potential was observed after a treatment period of 15 minutes followed by a postexposure incubation period of 42 hours. The relative mean viability of the test item treated tissues was 68.8 % after the 15 minute exposure period. The test item, 9-decenoic acid, methyl ester was therefore considered to be non-irritant (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar result can be expected for the test item.

In vitro skin irritation studies performed in accordance with OECD Guideline 439 are considered to be valid replacements for the in vivo skin irritation study (OECD Guideline 404). The result of this study on 9-decenoic acid, methyl ester indicates that the test material is not a skin irritant and is considered to be valid without the need to verify the result by performing additional in vivo studies.

 

Eye irritation:

Key study: 

An ex vivo study was performed to assess the eye irritation potential of the test item, using the Bovine corneal opacity and permeability test method, according to OECD Guideline 437, in compliance with GLP.  Octadecanedioic acid, 1,18-dimethyl ester produced a mean in vitro irritancy score of 1.35 under these guideline test conditions, and is therefore not classified for eye irritation or serious eye damage.

 

Supporting study:

A in vitro study was performed to assess the eye irritation potential of the test item, using the SkinEthic reconstructed Human Corneal Epithelium model, according to accepted scientific standards, in compliance with GLP. Triplicate SkinEthic tissues were treated with 30 μL of the test item for 10 minutes. Cytotoxicity was determined by the reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyl-tetrazolium bromide) to formazan by viable cells in the test item treated tissues (quantitative
measurement of tissue viability) relative to the negative control. The relative mean viability of the test item treated tissues was 113.5% and hence 9-decenoic acid, methyl ester is considered to be a nonirritant (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar result can be expected for the test item.

 

 

An in vivo study was performed to assess the the eye irritation potential of the test item in New Zealand white rabbit, according to OECD Guideline 405, in compliance with GLP. A single application of the test item to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. One treated eye appeared normal at the 48 hour observation and two treated eyes appeared normal at the 72 hour observation. Based on the classification criteria for eye irritation according to Regulation (EC) No.
1272/2008, 9-decenoic acid, methyl ester is considered to be non-irritating to eyes (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar result can be expected for the test item.

 

 

 

Justification for classification or non-classification

The skin irritation potential of the test item octadecanedioic acid, 1,18-dimethyl ester (ODDAME) has been read-across from the substance 9 -decenoic acid, methyl ester. In the in vitro skin irritation, the in vitro eye irritation and the in vivo eye irritation studies, 9-decenoic acid, methyl ester was non-irritant. Therefore the substance octadecanedioic acid, 1,18-dimethyl ester (ODDAME) is also be considered a non-irritant according to Regulation (EC) No. 1272/2008.

The eye irritation potential of the test item octadecanedioic acid, 1,18-dimethyl ester (ODDAME) was assessed in an ex-vivo BCOP study (OECD 437) and under the conditions of this study is no classified for eye irritation according to Regulation (EC) No. 1272/2008.