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

Endpoint summary

Description of key information

n-ODSA EC 701-338-8 is irritating to the skin but is not irritating to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 2015- November 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Guideline study under GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

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.

Species:

rabbit

Strain:

other: New Zealand albino

Details on test animals or test system and environmental conditions:

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.
Animal Room Temperature and Relative Humidity Ranges: 19-23ºC and 40-60%, respectively
Animal Room Air Changes/Hour: 12.
Photoperiod: 12-hour light/dark cycle
Acclimation Period: 21 or 28 days
Food: EnvigoTeklad Global High Fiber Rabbit Diet®#2031. A designated amount of the diet (approximately 150 grams/day) and a Premium Timothy Cube (TM) (Ontario Dehy Inc.) were available to each rabbit.
Water: Filtered tap water was supplied adlibitum.

Cage: Each cage was identified with a cage card indicating at least the study number and identification and sex of the animal.
Animal: A number was allocated to each rabbit on receipt and a stainless steel ear tag bearing this number was attached to the animal. This number, together with a sequential animal number assigned to study 41878, constituted unique identification.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

other: 75 % w/w mixture in mineral oil

Controls:

no

Amount / concentration applied:

Five-tenths of a gram of the test substance (0.67g of the prepared test mixture) was placed on a 1-inch x 1-inch, 4-ply gauze pad and applied to one 6-cm2 intact dose site on each animal. The pad and entire trunk of each animal were then wrapped with semi-occlusive 3-inch Micropore tape to avoid dislocation of the pad. Elizabethan collars were placed on each rabbit and they were returned to their designated cages.

Duration of treatment / exposure:

After 4 hours of exposure to the test substance, the pads and collars were removed and the test sites were gently cleansed with a 3% soap solution followed by tap water and a clean paper towel to remove any residual test substance.

Observation period:

Individual dose sites were scored according to the Draize scoring system at approximately 30-60 minutes, 24, 48, and 72 hours and 7, 10 and 14 days after patch removal

Number of animals:

3 female rabbits were used. They were nulliparous and non-pregnant.

Details on study design:

On the day before application, a group of animals was prepared by clipping the dorsal area and the trunk. On the day of dosing, but prior to application, the animals were examined for health and the skin checked for any abnormalities. Three healthy, naive animals (not previously tested) without pre-existing skin irritation were selected for test.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24 h

Score:

3.7

Max. score:

8

Reversibility:

fully reversible within: 14 days

Remarks:

reversible

Remarks on result:

probability of moderate irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

48 h

Score:

3

Max. score:

8

Reversibility:

fully reversible within: 14 days

Remarks:

reversible

Remarks on result:

probability of moderate irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

72 h

Score:

3

Max. score:

8

Reversibility:

fully reversible within: 14 days

Remarks:

reversible

Remarks on result:

probability of moderate irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

7 d

Score:

1

Max. score:

8

Reversibility:

fully reversible within: 14 days

Remarks:

reversible

Remarks on result:

probability of mild irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

10 d

Score:

0.3

Max. score:

8

Reversibility:

fully reversible within: 14 days

Remarks:

reversible

Remarks on result:

probability of weak irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

14 d

Score:

0

Max. score:

8

Reversibility:

fully reversible within: 14 days

Remarks:

reversible

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The Primary Dermal Irritation Index (PDII) calculated for this test substance was 3.2.

Other effects:

Over the first 48 hours after patch removal, all three treated sites exhibited well-defined to moderate to severe erythema and very slight to slight edema. The overall incidence and severity of irritation decreased gradually with time. Desquamation was noted at all three dose sites on Days 7 and 10. All animals were free of dermal irritation by Day 14 (study termination).

Animal No.	Sex	Time After Patch Removal
		30-60 mins	24 hrs	48 hrs	72 hrs	Day 7	Day 10	Day 14
3501	F	2/1	2/2	2/0	2/0	1/0	0/0	0/0
3502	F	2/1	2/2	3/2	3/2	2/0	1/0	0/0
3503	F	2/1	2/1	2/0	2/0	0/0	0/0	0/0
Total		6/3	6/5	7/2	7/2	3/0	1/0	0/0
Mean		2.0/1.0	2.0/1.7	2.3/0.7	2.3/0.7	1.0/0.0	0.3/0.0	0/0

Summed values used for evaluation of irritation:

	Time After Patch Removal
	30-60 min	24 hrs	48 hrs	72 hrs	Day 7	Day 10	Day 14
Erythema	2.0	2.0	2.3	2.3	1.0	0.3	0.0
Edema	1.0	1.7	0.7	0.7	0.0	0.0	0.0
Total (PDI^2)	3.0	3.7	3.0	3.0	1.0	0.3	0.0

The average value was calculated to be 3.2.

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Remarks:

Migrated information: Irritation scores are > 2.3 and < 5 for 2 of 3 animals at 24, 48 and 72 hours after application.

Conclusions:

n-ODSA EC 701-338-8 is moderately irritating to skin according to the Draize scale. The substance is classified as a skin irritant, Category 2.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (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:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

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.

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
.

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.

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

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

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

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

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

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

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

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

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.

	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

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In an OECD 404 GLP study, n-ODSA EC 701-338-8 was found to be moderately irritating to the skin of rabbits after 4 hours of semi-occlusive exposure, displaying erythema and edema throughout 72 hours. The effect was reversible by the end of 14 days.

Transient mild conjunctival irritation after instillation of the substance into eyes of rabbits was observed, resolving in 2 of 3 animals by 48 hours. Mean scores for redness and chemosis did not exceed 2. This mild effect is not considered irritating to the eye.

Justification for selection of skin irritation / corrosion endpoint:
experimental data

Justification for selection of eye irritation endpoint:
experimental data

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

Dermal irritation (erythema and edema) with scores between 2.3 and 5.0 was observed for n-ODSA EC 701-338-8 at 30-60 minutes and 24, 48 and 72 hours after application (in 3 animals). The substance meets the criteria for classification as an irritant according to Regulation EC No. 1272/2008.

Transient ocular (conjunctival) effects do not meet the criteria in Regulation EC No. 1272/2008 for classification for eye irritation.