Registration Dossier

Administrative data

Description of key information

Skin irritation: 
One GLP, FIFRA- EPA guideline Section 81-5 and TSCA August 1982 study available for DPO, all other studies were not conducted according to a guideline.
Eye irritation:
In vivo eye irritation pre-guideline study.

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:
1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
other: FIFRA: Pesticide Assessment Guidelines, Subdivision F; Hazard Evaluation : Human and Domestic Animals; Office of Pesticide Programs, U.S. Envi ronmental Protection Agency, Nov. 1982, Section 81-5, Primary Dermal Irritation Study
Deviations:
no
Remarks:
Not specified in report
Qualifier:
according to
Guideline:
other: TSCA: Health Effects Test Guidelines; Office of Toxic Substances; Office of Pesticide and Toxic Substances; United States Environmental Protection Agency, August 1982; Acute Exposure, Primary Dermal Irritation
Deviations:
no
Remarks:
Not specified in report
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Supplier: Summit View Farm, Hazleton , Pennsylvania
Number: Six (1 male, 5 females)
Age: Young adults ( at least 8 weeks old at study initiation)
Acclimation Period: 41 days
Observations: All animals were checked for viability twice daily. Prior to assignment to study all animals were examined to ascertain suitability for study.
Husbandry: Currently acceptable practices of good animal husbandry were followed, e.g., Guide for the Care and Use of Laboratory Animals. DHEW Publication No. ( NIH ) 78-23 Revised 1978.
Housing: Individually housed
Cages: Suspended, stainless steel
Environmental Conditions:
Temperature: 60-70°F is considered an acceptable temperature range for rabbits; room temperature was monitored and recorded twice daily and maintained within this range to the maximum extent possible.

Humidity: 30-70% is considered an acceptable humidity range for rabbits; room humidity was monitored and recorded daily and maintained within this range to the maximum extent possible.

Light Cycle: 12 hours light, 12 hours dark (controlled by an automatic timer).

Food: Lab Rabbit Chow HF (Purina #5326), -ad libitum.

Water: Automatic watering system, ad libitum, Municipal water supply (Elizabethtown Water Co.).

Contaminates: There were no known contaminants reasonably expected to be found in food or water which would interfere with the results of this study.

Identification: Each animal was identified with a monel ear tag, bearing a unique number, prior to testing.

Selection: Animals were randomly placed in cages upon receipt, and were placed on study as available at the time of study initiation. Any animals considered unsuitable for study because of poor health or unacceptable skin were excluded from selection.
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 ml of test material per site. (The material was applied to two intact sites on each animal.)
Duration of treatment / exposure:
4 hours/single application
Observation period:
3-14 days
Number of animals:
Six (1 male, 5 females)
Details on study design:
Preparation o f Animals
On the day before dosing the hair of each rabbit was closely clipped from the dorsal area of the trunk with an electric clipper, so as to expose at least 10% of the body surface area. Care was taken to avoid abrading the skin. Only animals with intact, healthy skin were used.

Preparation of Test Material
The test material was administered as received; no preparation was necessary.

Administration of Test Material:
The appropriate amount of the test material was applied beneath a gauze square, 1 "x1", placed directly on each of two test sites nearest the
head of the rabbits and held in place with non - irritating tape. Gauze was then wrapped around the animal and covered with porous tape, to semi-occlude the test sites.
Elizabethan collars were placed on each animal prior to or at the time of dosing in order to prevent the animal from disturbing the coverings and test sites.

Following 4 hours of exposure, the wrappings and gauze squares were removed and the test site was gently wiped free of excess test material using water and gauze. After approximately 30 minutes, dermal observations were made.

LXPERIMENTAL EVALUATION
A. Viability Check:
Twice Daily

B. Evaluation of Dermal Irritation:
1. Intervals:
Approximately 30 minutes and 24, 48 and 72 hours after patch removal. If there were any signs of irritation noted at the 72 hour observation, observations were made again at each affected site 7, 10 and 14 days after treatment or until no signs of irritation were present. Each site was treated independently, i.e., if irritation was no longer present at a site at 72 hours or any interval thereafter, no further scoring was performed on that site.
2. Methods:
At each interval all sites were evaluated for erythema and edema or other evidence of dermal irritation according to the Draize scoring system. The most severely affected area was scored. Adjacent areas of untreated skin were used for comparison.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 0.5 h
Score:
0.83
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 48 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 h
Score:
1.8
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 7 days
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 14 days
Score:
0.17
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 0.5 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 h
Score:
0.17
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 48 h
Score:
0.17
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 72 h
Score:
0.17
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Right side (worst case)
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 7 and 14 days
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Right side (worst case)
Irritant / corrosive response data:
Diphenyl Oxide produced generally mild reversible dermal irritation. Five of the six animals exhibited very slight ( barely perceptible ) erythema with
little or no edema, at 0.5 hours; the remaining animal was free of dermal irritation. By 24 or 48 hours, most animals exhibited slight erythema. By study termination (Day 14), five of the six animals were free of dermal irritation; one animal continued to exhibit only very slight erythema at one test site The individual animal Average Dermal Irritation Score of Diphenyl Oxide is 1.4.
Other effects:
No data

None

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Diphenyl Oxide produced generally mild reversible dermal irritation. Five of the six animals exhibited very slight ( barely perceptible ) erythema with
little or no edema, at 0.5 hours; the remaining animal was free of dermal irritation. By 24 or 48 hours, most animals exhibited slight erythema. By study termination (Day 14), five of the six animals were free of dermal irritation; one animal continued to exhibit only very slight erythema at one test site The Average Dermal Irritation Score of Diphenyl Oxide is 1.4.
Executive summary:

A primary dermal irritation study was conducted in six rabbits (4-hour exposure/semi-occlusive covering) according to FIFRA: Pesticide Assessment Guidelines, Subdivision F; Nov. 1982, Section 81-5 and TSCA: Health Effects Test Guidelines; Office of Toxic Substances; Office of Pesticide and Toxic Substances; United States Environmental Protection Agency, August 1982.

Diphenyl Oxide produced generally mild reversible dermal irritation. Five of the six animals exhibited very slight ( barely perceptible ) erythema with little or no edema, at 0.5 hours; the remaining animal was free of dermal irritation. By 24 or 48 hours, most animals exhibited slight erythema. By study termination (Day 14), five of the six animals were free of dermal irritation; one animal continued to exhibit only very slight erythema at one test site The individual animal Average Dermal Irritation Score of Diphenyl Oxide is 1.4.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not 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:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
no guideline available
Principles of method if other than guideline:
Two drops of material was instilled into the right eye and then washed (within 30 s) with a flowing stream of tepid water for 2 minutes. The left eye was treated the same but was left unwashed. Observations were made within 2-3 minutes, at 1, 24, and 48 hours and 6 to 8 days after treatment.
GLP compliance:
no
Species:
other: Although not specified, rabbits were typically used for this study.
Strain:
not specified
Details on test animals or tissues and environmental conditions:
No data
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
2 drops of undiluted material/eye
Duration of treatment / exposure:
Single exposure
Right eye was washed after 30 s of exposure, left eye was left unwashed
Observation period (in vivo):
Observed immediately for pain. Observations for conjunctival and corneal responses were made within 2-3 minutes, at 1, 24, and 48 hours and 6-8 days.
Number of animals or in vitro replicates:
3
Details on study design:
No additional information
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: immediate (2-3 minutes)
Score:
2
Max. score:
6
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: washed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1 h
Score:
2
Max. score:
6
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: washed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 h, 48 h and 7 days
Score:
1
Max. score:
6
Remarks on result:
other: washed
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: immediate (2-3minutes)
Score:
1
Max. score:
6
Remarks on result:
other: washed
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1 h
Score:
3
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 h
Score:
1.67
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 48 h
Score:
1.3
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 7 days
Score:
2
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed and after stain
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: immediate (2-3 minutes)
Score:
1
Max. score:
6
Remarks on result:
other: not washed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1 h
Score:
2
Max. score:
6
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: not washed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 and 48 h and 7 days
Score:
1
Max. score:
6
Remarks on result:
other: not washed
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: immediate (2-3 minutes)
Score:
1
Max. score:
6
Remarks on result:
other: not washed
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1 h
Score:
1.67
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: not washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 h
Score:
1
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: not washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 48 h
Score:
1.3
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: not washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 7 days
Score:
1.67
Max. score:
6
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: not washed and after stain
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: All time points
Score:
1
Max. score:
6
Remarks on result:
other: Before stain, washed and unwashed
Irritant / corrosive response data:
Pain response was a 2 out of 6 or very slight (time point- immediate).
Other effects:
None

None

Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Eye contact with the test material would likely result in very slight pain, very slight transient conjunctival inflammation, and possibly a slight transient corneal injury.
Executive summary:

A sample of industrial grade diphenyl oxide XA-1075-L, was submitted to Chemical Biology Research for evaluation of acute oral lethality, eye and skin irritation properties, and for definition of industrial handling hazards involving acute exposures. The test material is in the early stages of application development. The objective of this study was to provide initial toxicological information on the industrial grade material. As applications are developed, additional appropriate toxicological tests may be required.

Eye contact with the test material would likely result in very slight pain, very slight transient conjunctival inflammation, and possibly a slight transient corneal injury. Safety glasses are recommended whenever the likelihood of eye contact exists.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In the GLP, guideline 1988 key study (ks) (Klimisch 1), Diphenyl Oxide (DPO) produced generally mild reversible dermal irritation following a single 4 hour exposure. Five of the six animals exhibited very slight (barely perceptible) erythema with little or no edema, at 0.5 hours; the remaining animal was free of dermal irritation. By 24 or 48 hours, most animals exhibited slight erythema. By study termination (Day 14), five of the six animals were free of dermal irritation; one animal continued to exhibit only very slight erythema at one test site. The mean scores for 24, 48 and 72 hours were not high enough to warrant classification as an irritant to the skin.

Eye Irritation

In the 1973 ks (Klimisch 2), two drops of material was instilled into the right eye and then washed (within 30 s) with a flowing stream of tepid water for 2 minutes. The left eye was treated the same but was left unwashed. Very slight, corneal opacity (after staining) was present in all three animals after 7 days.

Results indicated eye contact with the test material would likely result in very slight pain, very slight transient conjunctival inflammation, and possibly a slight transient corneal injury. In the two supporting studies, slight corneal injury was present; however, all signs of irritation were essentially absent after 24 hours. In one of the supporting studies, the mean observed conjunctiva score at 24 hours of 8.7 out of 10 (redness+chemosis+discharge) was fully reversible within 120 hours. Overall, the weight of evidence suggests that this material is only minimally irritating to the eyes, however due to the persistence of effects in all three animals at 7 days in the ks, DPO is considered as irritating to the eyes.

However, it should be understood that in the key study, the study period was only 7 days and effects may therefore have resolved within 14 or 21 days (the normal length of the guideline study).


Effects on eye irritation: irritating

Justification for classification or non-classification

The mean scores for 24, 48 and 72 hours for DPO were not high enough to warrant classification as an irritant to the skin.

The eye irritation classification of Category 2 (irritating to eyes) (CLP) was based on very slight, corneal opacity (after staining) that persisted to the end of the study in all three animals.