Reaction products of furan-2,5-dione and octadec-1-ene

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 2015- October 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Guideline study under GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

3-[(2E)-octadec-2-en-1-yl]dihydrofuran-2,5-dione

Cas Number:

1628163-42-7

Molecular formula:

C22H38O3

IUPAC Name:

3-[(2E)-octadec-2-en-1-yl]dihydrofuran-2,5-dione

Constituent 2

Reference substance name:

3-[(2Z)-octadec-2-en-1-yl]dihydrofuran-2,5-dione

Molecular formula:

C22H38O3

IUPAC Name:

3-[(2Z)-octadec-2-en-1-yl]dihydrofuran-2,5-dione

Constituent 3

Reference substance name:

3-(octadecenyl)dihydrofuran-2,5-dione excluding 3-(2-octadecen-1-yl)dihydrofuran-2,5-dione

Molecular formula:

C22H38O3

IUPAC Name:

3-(octadecenyl)dihydrofuran-2,5-dione excluding 3-(2-octadecen-1-yl)dihydrofuran-2,5-dione

Constituent 4

Reference substance name:

Hexadecenylsuccinic anhydride

EC Number:

250-911-4

EC Name:

Hexadecenylsuccinic anhydride

Molecular formula:

C20H34O3

IUPAC Name:

3-(hexadecenyl)dihydrofuran-2,5-dione

Constituent 5

Reference substance name:

3-icosenylsuccinic anhydride

EC Number:

258-603-1

EC Name:

3-icosenylsuccinic anhydride

Molecular formula:

C24H42O3

IUPAC Name:

3-icosenyldihydrofuran-2,5-dione

Constituent 6

Reference substance name:

Side products from the reaction of octadec-1-ene and maleic anhydride

Molecular formula:

Not applicable - UVCB component

IUPAC Name:

Side products from the reaction of octadec-1-ene and maleic anhydride

Constituent 7

Reference substance name:

C16-20 (even numbered) alkenes (branched and linear)

Molecular formula:

C16H32, C18H36, C20H40

IUPAC Name:

C16-20 (even numbered) alkenes (branched and linear)

Constituent 8

Reference substance name:

Maleic anhydride

EC Number:

203-571-6

EC Name:

Maleic anhydride

Cas Number:

108-31-6

Molecular formula:

C4H2O3

IUPAC Name:

furan-2,5-dione

Test material form:

solid

Details on test material:

off-white solid, amber liquid at 80 °C. Expected to be stable for duration of testing; Expiration date: not applicable.

Specific details on test material used for the study:

As a result of increasingly rigorous criteria being applied to the analysis of commercial material used in physical property/toxicity testing, the identity of the material has been modified to reveal a more accurate and precise depiction of the commercial substance. This enhancement is reflected in changes in chemical identifiers such as EC and/or CAS numbers from those noted in earlier versions of data records or in study reports.

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Animals: Females, 13-16 weeks of age, 2521-3028 g in weight at beginning of the experiment. Obtained from Robinson Services Inc. (supplier).

Housing: The animals were singly housed in suspended stainless steel caging which conforms
to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011). Enrichment (e.g.,toy) was placed in each cage. Litter paper was placed beneath the cage and was changed at least three times per week.

Temperature: 20-23 degrees C, Humidity: 54-60%

Photoperiod: 12-hour light/dark cycle

Acclimation Period: 12 or 47 days

Food: EnvigoTeklad Global High Fiber Rabbit Diet®#2031, 150 g/day provided to each animal, along with a Premium Timothy Cube(TM) (Ontario Dehy Inc.).

Water: Filtered tap water was supplied ad libitum
.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

One-tenth of a milliliter (0.042 grams) of the test substance was instilled into the eye. The test substance was ground into fine pieces using a spatula.

Duration of treatment / exposure:

0.042 grams of the test substance was instilled into the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing to minimize loss of the test substance. Observations were then taken over the next 72 hours.

Observation period (in vivo):

Ocular irritation was evaluated using a white light source in accordance with the Draize method of scoring 1, 24, 48, and 72 hours post-instillation

Number of animals or in vitro replicates:

3

Details on study design:

Prior to test initiation, both eyes of a group of animals were examined using a white light source and a fluorescein dye procedure. One drop of ophthalmic fluorescein sodium dye was instilled into both eyes of each rabbit. The eyes were rinsed with physiological saline (0.9% NaCl) after instillation of the fluorescein and then evaluated for corneal damage using an ultraviolet light source. Prior to test substance instillation, the eyes were re-examined and scored for abnormalities according to the "Scale for Scoring Ocular Lesions" (Draize et al., 1944). Three healthy, naive animals (not previously tested) without pre-existing ocular irritation were selected for test.
A systemic analgesic (Buprenorphine SR®) was administered to relieve potential discomfort associated with eye irritation which provides therapeutic relief for periods of up to 76 hours. Prior to test substance instillation, 0.1 mg/kg of body weight of the analgesic was administered to the animals and at appropriate intervals to maintain therapeutic blood levels.
The test substance, as received, was a solid. Attempts to grind the test substance with a mortar and pestle prior to instillation were unsuccessful. The test substance was ground into fine pieces using a spatula.
Prior to instillation, 1-2 drops of ocular anesthetic (Tetracaine Hydrochloride Ophthalmic Solution USP, 0.5%) were placed into both the treated and control eye of each animal.
One-tenth of a milliliter (0.042 grams) of the test substance was then instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing to minimize loss of the test substance. The other eye of each rabbit remained untreated with the test substance and served as a control. The rabbits were then returned to their designated cages.
Ocular irritation was evaluated using a white light source in accordance with the Draize method of scoring (Draize et al., 1944) at 1, 24, 48, and 72 hours post-instillation. The fluorescein dye evaluation procedure described in Section 5.A. was used in the treated eye at 24 hours to verify the absence of corneal damage. Individual scores were recorded for each animal. In addition to observations of the cornea, iris and conjunctivae, any other observed lesions were noted. The average score for all rabbits at each scoring period was calculated to aid in data interpretation.
The time interval with the highest mean score (Maximum Mean Total Score - MMTS) for all rabbits was used to classify the test substance by the system of Kay and Calandra (Kay & Calandra, 1962).
The animals were observed for signs of gross toxicity and behavioral changes at least once daily during the test period.
Individual weights of animals were recorded shortly before instillation of the test substance (initial) and at the completion of testing (terminal). Additional body weights were taken to determine the appropriate amount of analgesic. These additional body weights were recorded in the raw data but are not reported.
Once testing was complete, the animals were released for euthanasia and humanely euthanized.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

overall irritation score

Basis:

animal #1

Remarks:

#3401

Time point:

24 h

Score:

8

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

overall irritation score

Basis:

animal #1

Remarks:

#3401

Time point:

48 h

Score:

0

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 3

Irritation parameter:

overall irritation score

Basis:

animal #1

Remarks:

#3401

Time point:

72 h

Score:

0

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 4

Irritation parameter:

overall irritation score

Basis:

animal #2

Remarks:

#3402

Time point:

24 h

Score:

2

Max. score:

110

Reversibility:

fully reversible within: 48 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 5

Irritation parameter:

overall irritation score

Basis:

animal #2

Remarks:

#3402

Time point:

48 h

Score:

4

Max. score:

110

Reversibility:

fully reversible within: 48 hours

Remarks on result:

no indication of irritation

Results 6

Irritation parameter:

overall irritation score

Basis:

animal #2

Remarks:

#3402

Time point:

72 h

Score:

0

Max. score:

110

Reversibility:

fully reversible within: 48 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 7

Irritation parameter:

overall irritation score

Basis:

animal #3

Time point:

72 h

Score:

2

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 8

Irritation parameter:

overall irritation score

Basis:

animal #3

Remarks:

#3403

Time point:

48 h

Score:

0

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Results 9

Irritation parameter:

overall irritation score

Basis:

animal #3

Remarks:

#3403

Time point:

72 h

Score:

0

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks:

reversible

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

There was no corneal opacity or iritis observed in any treated eye during this study. One hour after test substance instillation, two treated eyes exhibited conjunctivitis and one treated eye exhibited minimal conjunctivitis. The overall incidence and severity of irritation decreased with time. Two of three animals were free of ocular irritation at 48 hours, and all animals, by 72 hours.

Other effects:

All animals appeared active and healthy and gained body weight during the study. Apart from the eye irritation noted below, there were no other signs of gross toxicity, adverse clinical effects, or abnormal behavior.

Any other information on results incl. tables

	Rabbit No.: 3401 (Female)				Rabbit No.: 3402 (Female)				Rabbit No.: 3403 (Female)
	Hour				Hour				Hour
	1	24	48	72	1	24	48	72	1	24	48	72
I. Cornea
A. Opacity	0	0	0	0	0	0	0	0	0	0	0	0
B. Area	4	4	4	4	4	4	4	4	4	4	4	4
(AxB)x5	0	0	0	0	0	0	0	0	0	0	0	0
II. Iris
A. Values	0	0	0	0	0	0	0	0	0	0	0	0
Ax5	0	0	0	0	0	0	0	0	0	0	0	0
III. Conjunctivae
A. Redness	2	0	0	0	1	0	1	0	1	0	0	0
B. Chemosis	4	3	0	0	2	0	0	0	0	0	0	0
C. Discharge	2	1	0	0	1	1	1	0	3	1	0	0
(A+B+C)x2	16	8	0	0	8	2	4	0	8	2	0	0
Total	16	8	0	0	8	2	4	0	8	2	0	0

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Mean scores for conjunctival redness and chemosis were < 2. Criteria used for interpretation of results: OECD GHS

Conclusions:

n-ODSA EC 701-338-8 is not considered irritating to the eyes, although mild conjunctivitis was observed in rabbits which resolved by 72 hours after dosing.