Registration Dossier

Administrative data

Description of key information

1 TEST: With 4 hours of exposure, slight irritation, with scores not meeting the criteria for classification.  Ddesquamation  was also noted which had not resolved in all animals by day 14.

2 TEST: With 24 hours of exposure,  the substance caused severe skin irritation. Its dermal effects observed after 24 hours generaly consisted of well-defined erythema, slight to distinct ischemia and very slight to slight edema. The dermal effects observed after 72 hours generally consisted of slight to distinct incrustation and very slight edema.

Slight conjunctival effects were noted in two eye irritation studies; however, they were not severe enough to warrant classification.

A study for respiratory irritation is not available.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 September 1994 - 2 November 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-conducted and documented study performed under GLP; however, no CoA for the test material is included in the report.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Myrtle's Rabbitry, Thompson Station, TN.
- Age at study initiation: adult
- Weight at study initiation:2.0 to 3.5 kg
- Housing: The animals were housed individually in suspended stainless steel cages. All housing and care were based on the standards recommended by the Guide for the Care and Use of Laboratory Animals
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow #5322 was provided ad libitum to the animals throughout the study. The lot number and expiration date of each batch of diet used during the study were recorded. The feed was analyzed by the supplier for nutritional components and environmental contaminants. Dietary limitations for various environmental contaminants, including heavy metals, pesticides, polychlorinated biphenyls and total aflatoxin are set by the manufacturer. Within these limits, contaminants which may have been present were not expected to compromise the purpose of this study. Results of the dietary analyses (Certificates of Analysis) are provided by the manufacturer for each lot of diet. These are maintained by SLS.
- Water (e.g. ad libitum): Municipal tap water treated by reverse osmosis or deionization (back-up system) was available to the animals ad libitum throughout the study. The purified water was supplied by an automatic watering system. Monitoring of the drinking water for contaminants was conducted by SLS and the records are available for inspection. Within generally accepted limits, contaminants which may have been present were not expected to compromise the purpose of this study.
- Acclimation period: Upon receipt, animals were examined, identified with plastic ear tags and then quarantined for a minimum of five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):± 19-21
- Humidity (%): 46-64
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 29 September 1994 - 2 November 1994
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
Duration of treatment / exposure:
4 hours
Observation period:
Animals were examined for signs of erythema and edema and the responses scored at approximately 1, 24, 48 and 72 hours and up to 14 days after patch removal
Number of animals:
3 males and 3 females
Details on study design:
TEST SITE
- Area of exposure: 1" X 1" square 4 ply gauze patch
- % coverage:-
- Type of wrap if used: The test article was administered under the gauze patch. The gauze patch was held in contact with the skin at the cut edges with a non-irritating tape. Removal and ingestion of the test article was prevented by placing an elastic wrap over the trunk and test area (semi-occlusive binding). The elastic wrap was then further secured with adhesive tape around the trunk at the cranial and caudal ends.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test article was removed using gauze moistened with distilled water.
- Time after start of exposure: immediatly after the 4 hour exposure.

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
mean
Remarks:
all
Time point:
other: 24-48-72 hours
Score:
1.22
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: in 5/6 animals desquamation was observed
Irritation parameter:
edema score
Basis:
mean
Remarks:
all
Time point:
other: 24-48-72 hours
Score:
0.94
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: in 5/6 animals desquamation was observed
Irritant / corrosive response data:
Exposure to the test article produced very slight to well-defined erythema and very slight to slight edema on 6/6 test sites at the 1 hour scoring interval. The dermal irritation resolved completely in all animals by study day 14. Additional dermal findings noted during the period included desquamation, which was noted on 5/6 test sites.

Summary of dermal lesions

 

no.

Effect

Hour

Days after application

Mean score erythema

24/48/72 h *

Mean score oedema

24/48/72 h *

1

1

2

3

7

10

14

51403/M

Erythema/ eschar

Oedema

1

1

1

1

1

1

1

0

1**

0

2

1

0**

0

1

 

0.66

51411/F

Erythema/ eschar

Oedema

1

1

2

1

1

1

1

0

0

0

-

-

-

-

1.33

 

0.66

51387/M

Erythema/ eschar

Oedema

2

1

2

1

1

1

0

1

0**

0

-

-

-

-

1

 

1

51388/M

Erythema/ eschar

Oedema

2

2

2

1

1

1

1

1

1

0

1**

0

0**

0

1.33

 

1

51427/F

Erythema/ eschar

Oedema

2

1

2

1

1

1

1

1

1**

1

2

1

0**

0

1.33

 

1

51430/F

Erythema/ eschar

Oedema

2

2

2

2

2

1

1

1

1

1

2

1

0**

0

1.66

 

1.33

Mean Group

1.22

0.94

* Mean score based on 24, 48 and 72 h after application

**desquamation

 

Executive summary:

The potential irritant and/or corrosive effects of the substance were evaluated on the skin of New Zealand White rabbits. Each of six rabbits received a 0.5 ml dose of the test article as a single dermal application. The dose was held in contact with the skin under a semi-occlusive binder for an exposure period of four hours. Following the exposure period, the binder was removed and the remaining test article was wiped from the skin using gauze moistened with distilled water. Test sites were subsequently examined and scored for dermal irritation for up to 14 days following patch removal. Exposure to the test article produced very slight to well-defined erythema and very slight to slight edema on 6/6 test sites at the 1 hour scoring interval. The dermal irritation resolved completely in all animals by study day 14. Additional dermal findings noted during the period included desquamation, which was noted on 5/6 test sites. Under the conditions of this test the substance is considered to be an irritant to the skin of the rabbit.

Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 September 1994 - 27 October 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-conducted and documented study performed under GLP; however, no CoA for the test material is included in the report.
Qualifier:
according to
Guideline:
EPA OTS 798.4500 (Acute Eye Irritation)
Deviations:
yes
Remarks:
One mortality check was not conducted and one was conducted but not documented. However, no mortality occurred during the study and the occurences are considered to have had no apparent impact on the outcome of the study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Adult, New Zealand White rabbits were received at SLS from Myrtle's Rabbitry, Thompson Station, TN. Upon receipt, plastic ear tags displaing unique identification numbers were used to individually identify the animals. Cage cards displaying at least the study number, animal number and sex were affixed to each cage. The animals were housed individually in suspsended stainles steel cages. All housing and care were based on the standards recommended by the Guide for the Care and Use of Laboratory Animals.

The animal room temperature and relative humidity rnages were 68 - 70 °F and 46 - 59%, respecitvely. Environmental contrl equipment was monitored and adjusted as necessary to minimize fluctuations in the animal room environment. Light timers were set to maintain a 12-hour light/12-hour dark cycle. There were ten to twelve air changes in the animal room per hour. the animal room temperature and relative humidity were recorded a minimum of once daily.

Purina Certified Rabbit chow #5322 was provided ad libitum to the animals throughout the study. the lot number and expiration date of each batch of diet used during the study were recorded. The feed was analyzed by the supplier for nutritional components and environmental contaminants. Dietary limitation for various environmental contaminants, including heavy metals. pesticides, polychlorinated biphenyls and total aflatoxi are set by the manufacturer. Within these limits, contaminnats which may have bee present were not expected to compromise the purpose of this study. Results of the dietary analyses (Certificates of Analysis) are provided by the manufacturer for each lot of diet. These are maintained by SLS.

Municipal tap water treated by reverse osmosis or deionization (back-up system) was available to the animals ad libitum throughout the study. the purified water was supplied by an automatic watering system. Monitoring of the drinking water for contaminants was conducted by SLS and the records are available for inspetion. Within generally accepted limits, contaminants which may have been present were notexpected to compromise the purpose of this study.

Upon receipt, animals were examined, identified with plastic ear tags and then quarantined for a minimum of five days. The animals chosen for study use were arbitrarily selected from healthy stock animals to avoid potential bias. All animals received a detailed pretest observation prior to dosin. Onlyhealthy animals were chosen for study use. Females were nulliparous and nonpregnant.
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
Once.
Observation period (in vivo):
The eyes were macroscopically examined with the aid of an auxiliary light source for signs of irritation at 1, 24, 48 and 72 hours after dosing according to the Ocular Grading System presented in Appendix B which is based on Draize. Following macroscopic observations at the 24 hour scoring interval, the fluorescein examination procedure was repeated on all test and control eyes and any residual etst article was gently rinsed from the eye at this time (if possible) using 0.9% physiological saline. If positive fluorescein dye retention was noted at 24 hours, a flurescein exam was conducted on the affected eyes at each subsequent interval until a negative response was obtained.
Number of animals or in vitro replicates:
six
Details on study design:
The test article was instilled into the conjunctival sac of the right eye of each animals after gently pulling the lower lid away from the eye. Following instillation, the eyelids were gently heald together for approximately one second in order to limit test article loss and the animal was returned to its cage. The contralateral eye remained untreated to serve as a control.
Irritation parameter:
conjunctivae score
Remarks:
(redness + swelling + discharge) x 2
Basis:
mean
Remarks:
mean of all six animals
Time point:
other: 1 hour
Score:
5
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Remarks:
(redness + swelling + discharge) x 2
Basis:
mean
Remarks:
mean of all six animals
Time point:
other: 24 hours
Score:
2.33
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Remarks:
(redness + swelling + discharge) x 2
Basis:
mean
Remarks:
mean of all six animals
Time point:
other: 48 hours
Score:
0.33
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Remarks:
(redness + swelling + discharge) x 2
Basis:
mean
Time point:
other: 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: all
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
other: all
Score:
0
Max. score:
0
Irritant / corrosive response data:
Exposure to the test article produced conjunctivitis (redness, swelling and/or discharge) in 6/6 test eyes at the 1 hour scoring interval. The conjunctival irritation resolved completely in all animals by the 72 hour scoring interval.
Normal background positive fluorescein dye retention was observed in 1/6 control eyes (stippling) at the 24 hour scoring interval. This finding was resolved by 48 hours and was not considered significant. No corneal opacityI iritis or conjunctivitis was observed in the control eyes.

Summary of ocular lesions

Anim.

No.

Effect

Hours

Days after application

Mean

score cornea

Days

1/2/3

Mean score iritis

Days 1/2/3

Mean score redness Days 1/2/3

Mean score chemosis Days 1/2/3

1

1

2

3

7

14

51369/F

Cornea

Iris

Redness

Chemosis

Discharge

0

0

1

1

1

0

0

1

1

0

0

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

-

-

0

 

0

 

 

0.33

 

 

 

0

51370/F

Cornea

Iris

Redness

Chemosis

Discharge

0

0

1

1

1

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

-

-

0

 

0

 

 

0

 

 

 

0

51364/F

Cornea

Iris

Redness

Chemosis

Discharge

0

0

1

1

1

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

-

-

0

 

0

 

 

0.33

 

 

 

0

51337/F

Cornea

Iris

Redness

Chemosis

Discharge

0

0

1

1

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

-

-

0

 

0

 

 

0.33

 

 

 

0

51362/F

Cornea

Iris

Redness

Chemosis

Discharge

0

0

1

1

0

0

0

1

0

0

0

0

1

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

-

-

0

 

0

 

 

0.66

 

 

 

0

51275/F

Cornea

Iris

Redness

Chemosis

Discharge

0

0

1

1

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

-

-

0

 

0

 

 

0.33

 

 

 

0

Mean all anim.

0

0

0.33

0

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Slight conjunctival effects were noted in this study; however, they were not severe enough to warrant classification under the former EU Dangerous Substances Directive or any implementation of the Globally Harmonized System of Classification and Labeling of Chemicals.
Executive summary:

The potential eye irritant and/or corrosive effects of the substance were evaluated on New Zealand White rabbits. Each of six rabbits received a 0.1 ml dose of the test article in the conjunctival sac of the right eye. The conralateral eye of each animal remained untreated and served as a control. Test and control eyes were examined for signs of irritation for up to 72 hours following dosing.

Exposure to the test article produced conjunctivitis (redness, swelling and/or discharge) in 6/6 test eyes at the 1 hour scoring interval. The conjunctival irritation resolved completely in all animals by the 72 hour scoring interval.

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
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

On the basis of the result from 2 studies it can be concluded that the substance is a severe primary skin irritant after 24 hour exposure under occlusion. Mean values of > 2.3 - < 4.0 for erythema in all animals from gradings at 24, 48 and 72 hours after patch removal. Reversibilty of these effects cannot be judged from this study since the observations stopped after 72 hours. However corrosion was not observed and the animals were exposed for 24 hours instead of 4 hours.

While the two available studies, conducted with 24 hours of exposure reported severe irritation, in the study conducted in accordance with current guideline, using a 4 hour exposure, the registered substance was slightly irritating to skin with desquamation noted which had not resolved by day 14.

Effects on skin irritation/corrosion: highly irritating

Justification for classification or non-classification

The registered substance was classified as a skin irritatant based on studies conducted using severe exposure conditions (i.e. 24 -hour exposure occlusive) even though the study conducted in accordance with current guidelines resulted in irritation scores which did not warrant classificaiton.

However, desquamation was reported in this study.

Slight conjunctival effects were noted in two eye irritation studies; however, they were not severe enough to warrant classification.

Data to conclude on respiratory irritation is not available.