Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. residues

Endpoint summary

Description of key information

Skin irritation: In a rabbit skin irritation/corrosion test according to OECD TG 404 and EC B.4, the test substance was mildly irritating according to the Draize classification scheme (Allen, 1996), but is not to be classified as irritant to the skin according to the CLP Regulation.
Eye irritation: Based on the data of the key study (performed according to EPA OPPTS 870.2400 and EC Method B.5) and according to the criteria of the CLP Regulation, the test substance is classified as serious eye damage (category 1).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

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

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-11-01 - 1994-11-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

- Name of test material (as cited in study report): AMINE C-8
- Substance type: dark brown slightly viscous liquid with crystalline sediment
- Physical state: liquid
- Analytical purity: no data
- Composition of test material, percentage of components: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: responsibility of the sponsor
- Storage condition of test material: at room temperature

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.23-2.29 kg
- Housing: individually in suspended metal cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-20 °C
- Humidity (%): 58-65%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1 November 1994 To: 4 November 1994

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): not applicable

Duration of treatment / exposure:

patches were removed after exposure periods of 3 min, 1 h and 4 h.

Observation period:

One hour after removal of the patches, and 24, 48 and 72 h.

Number of animals:

3 animals, with 3 test sites each

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- % coverage: no data
- Type of wrap if used: gauze patches secured with strips of surgical adhesive tape and wrapped in an elasticated corset.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with cotton wool soaked in distilled water
- Time after start of exposure: 3 min, 1 hour and 4 hour

SCORING SYSTEM: Draize (1977) Primary Irritation Index.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.2

Max. score:

1

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Classification: mild irritant

Remarks:

4 hours exposure

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: after 1 hour exposure

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: after 3 minutes exposure

Irritation parameter:

edema score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Remarks on result:

other: after 3 minutes, 1 hour and 4 hours of exposure

Irritation parameter:

erythema score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: after 4 hours of exposure

Irritant / corrosive response data:

After 3 min and 1 hour exposure: no erythema/eschar formation and no oedema formation.
After 4 hours exposure: very slight erythema in all three animals and very slight oedema in two animals, but fully reversible within 24-48 hours.

Interpretation of results:

GHS criteria not met

Conclusions:

The test material does not need to be classified as a skin irritant according to the CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

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

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The in vivo eye irritation study was performed in 2010, according to EU method B.5 and OPPTS 870.2400. This type of data is intended to fulfill the testing requirements for the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136, et seq.) and the Toxic Substances Control Act (TSCA) (15 U.S.C. 2601).

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): Amine C8
- Substance type: no data
- Physical state: viscous amber liquid
- Storage condition of test material: 15-30 °C, room temperature

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan or any other USDA approved vendor
- Age at study initiation: young adult (12-18 weeks) at start of dosing; records of dates of birth for animals used in this study will be retained in the Calvert archives.
- Weight at study initiation: 2.0-3.0 kilograms at the outset (Day 1) of the study.
- Housing: Animals are housed individually in compliance with USDA Guidelines. The room in which the animals will be kept will be documented in the study records. no other species will be kept in the same room.
- Diet (e.g. ad libitum): All animals will have access to PMI certified Hi-Fiber Rabbit Diet or equivalent as per Calvert SOP, unless otherwise specified. The lot number and specifications of each lot used are archived in the facility records at Calvert. No contaminants are known to be present in the certified diet at levels that would be expected to interfere with the results of this study. analysis of the diet was limited to that performed by the manufacturer, records of which will be maintained in the Calvert archives.
- Water (e.g. ad libitum): Tap water is available ad libitum, to each animal via an automatic watering device. The water is routinely analyzed for contaminants as per Calvert SOP's. No contaminants are known to be present in the water at levels that would be expected to interfere with the results of this study. Results of the water analysis will be maintained in the Calvert archives.
- Acclimation period: study animals were acclimated to their housing for a minimum of seven days prior to their first day of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 21°C
- Humidity (%): 30-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Vehicle:

not specified

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

Only once instilled

Observation period (in vivo):

mortality/morbidity: once daily
clinical observations: prior to dose administration and then daily
ocular observations: at 1 (± 15 minutes), 24, 48 and 72 hours (± 1 hour); if there is no evidence of irritation at 72 hours, the study will be complete. Extended observations may be necessary if there is persistent corneal involvement or other ocular irritation is observed to determine the progress of the lesions and their reversibility or irreversibility. If the cornea, iris or conjunctivae have not healed completely by Day 8, the unhealed animals will be retained and reexamined on Days 15 and 22, if injury persists. In addition to the observations of the cornea, iris and conjunctivae, any other lesions, which are noted, will be recorded and reported. The grades of ocular reaction according to Draize will be manually recorded at each examination.
Body weight: prior to dose administration

Number of animals or in vitro replicates:

Three

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated eyes of the animals will remain un-rinsed for at least 24 hours after instillation of the test article. The treated eyes may be gently washed out (if necessary) using room temperature physiological saline.
- Time after start of exposure: see above

SCORING SYSTEM: An animal has exhibited a positive reaction if the test article has produced at any observation one or more of the following signs: opacity of the cornea (other than a slight dulling of the normal luster), inflammation of the iris (other than a slight deepening of the rugae or light hyperemia of the circum corneal blood vessels) or an obvious swelling in the conjunctivae (excluding the cornea and iris) with partial eversion of the eyelids or a diffuse crimson color with individual vessels not easily discernible.
EEC classification of ocular irritants: The total ocular irritation score for the 24, 48 and 72 hour invertvals are individually added for corneal opacity, iris lesion, conjunctival redness and conjunctival edema. For a group of the three animals, the calculated mean scores will remain expressed individually and compared to the EEC ocular evaluation criteria. Scores for two or more animals above the appropriate mean will classify the test article in that particular category. A test substance will be classified as a nonirritant, irritating to the eyes (R36) or risk of serious damage to eye (R41 Risk Phrase) based on the EEC Ocular Evaluation Criteria.

Globally harmonized system of classification evaluation criteria: for this classification system, the 24-, 48- and 72- hours scores will be added separately for each animal and each total divided by 3 (three time points) to yield the individual mean scores for each animal.

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 22 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 15 days

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 15 days

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 15 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 22 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

not fully reversible within: 22 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 15 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Remarks:

of 3 animals

Time point:

other: 24 hours post dose

Score:

26

Max. score:

110

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Remarks:

of 3 animals

Time point:

other: 48 hours

Score:

31

Max. score:

110

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Remarks:

of 3 animals

Time point:

other: 72 hours

Score:

32.67

Max. score:

110

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Remarks:

of 3 animals

Time point:

other: day 5

Score:

30.67

Max. score:

110

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Remarks:

of 3 animals

Time point:

other: 8 days

Score:

28.67

Max. score:

110

Reversibility:

fully reversible

Irritant / corrosive response data:

No corneal, iris or conjunctival irritation was observed in the untreated eyes of the rabbit at any time point. In the first animal, scattered to diffuse corneal opacity covering 1/4 or less of the eye was observed at 24 hours post dose. Iritis (grade 1) was observed at 1 hour after dosing, at 24, 48 and 72 hours post dose, on Days 5 through 8. Conjunctival redness (grade 1) was noted at 1 hour after dosing up until study termination on Day 22. Chemosis (grades 3 to 4) was also seen starting at 1 hour post dose and throughout the study until it diminished to grade 1 on Day 22. Discharge (grade 3) was observed in the rabbit throughout the entire duration of the study.
In the second animal, scattered to diffuse corneal opacity covering 1/4 to 1/2 of the total surface area of the eye was observed from 24 hours post dose out to Day 8. Iritis (grade 1) was observed at 1 hour after dosing through to day 8. Conjunctival redness (grade 1) was noted at 1 hour after dosing up until Day 15. Chemosis (grades 3 to 4) was also seen from 1 hour post dose until Day 5. From Days 6-8, chemosis declined to grade 2 and was not apparent by Day 15. Discharge (grade 3) was observed from 1 hour post dose until Day 5. On Days 6-8, discharge decreased to grade 2 and by Day 15 further lowered to grade 1. At Day 22, no discharge was noted.
For the third animal, scattered or diffuse areas of corneal opacity with details of the iris clearly visible covering greater than 1/2 to 3/4 of the whole area of the eye was observed from 48 hrs post dose until Day 15. On Day 22, no ulceration or opacity was observed. Iritis (grade 1) was observed at 1 hour after dosing through to Day 22. Conjunctival redness (grade 1) was noted at 1 hour after dosing through to study termination on Day 22. Chemosis (grades 3 to 4) was also seen from 1 hour post dose through to Day 5. From Days 6 to 22, chemosis declined to grade 2. Discharge (grade 3) was observed from 1 hour post dose until study termination on Day 22.

Other effects:

No mortality or adverse clinical signs were observed in the animals during the study

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Based on the data of this EPA OPPTS 870.2400 and EC Method B.5 study and according to the criteria of the CLP Regulation, the test substance is classified as serious eye damage (category 1).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

The skin irritation potential of the test substance is investigated in a key, reliable study performed according to OECD guideline 404 (Allen, 1994; Klimisch 1) in 3 rabbits. Semiocclusive patches were removed from shaved test sites after exposure periods of 3 min, 1h, and 4h to 0.5mL of the test substance. The Draize scoring system was used to evaluate the results. No erythema/eschar formation and no oedema formation is observed after 3 min and 1 hour exposure. After 4 hours of exposure, very slight erythema in all 3 animals and very slight oedema in 2 animals was observed, but this was fully reversible within 24 -48 hrs.

No in vitro skin irritation studies were performed as adequate data from an in vivo study was available.

 

Eye irritation:

Calvert Laboratories, Inc. (2010) investigated the eye irritation potential of the test substance in a key, reliable study performed according to EU method B.5 (Klimisch 1) in 3 rabbits. The treated eyes (with 0.1mL test substance) will remain unrinsed for at least 24 hours after instillation. The 24 -, 48- and 72 -hours scores will be added seperately for each animal and each total divided by 3 to yield the individual mean scores for each animal. Based on the data and according to the criterial of the CLP regulation, the test substance is classified as serious eye damage (category 1).

No in vitro eye irritation studies were performed as adequate data from an in vivo study was available.

Justification for classification or non-classification

Based on the available data and according to the criteria laid down in the CLP Regulation (EC) 1272/2008, the test substance is not to be classified as irritant to skin. The test substance does not need to be classified for skin irritation or skin corrosion, as the substance proved to be only mildly irritating in a rabbit skin irritation/corrosion study.

Based on the data and according to the criteria of the CLP Regulation, the test substance is classified as serious eye damage (category 1).