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Administrative data

Description of key information

Skin Irritation/Corrosion: Not corrosive or Irritating to skin ; OECD 404: B Yasso., 2016

Eye Irritation/Corrosion: Not corrosive or Irritating to the eye; OECD 405: B Yasso., 2016

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:
10 Oct 2016 - 31 March 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study was conducted in accordance with international guidelines and in accordance with GLP. All relevant validity criteria were met.
Qualifier:
according 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: Covance Research Product Inc, Denver, PA
- Females (if applicable) nulliparous and non-pregnant:Not stated
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 2.8 - 2.9 kg
- Fasting period before study: not specified
- Housing: individually housed in suspended wired-bottom cages, absorbent paper was changed at least three times per week.
- Diet (e.g. ad libitum): Fresh PMI Rabbit Chow (Diet No. 5321)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not stated
- Humidity (%): Not stated
- Air changes (per hr): Not stated
- Photoperiod (hrs dark / hrs light): 12 : 12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: Corn oil
Remarks:
test item was moistened with 0.5 ml of corn oil
Controls:
no
Amount / concentration applied:
0.5 g per site
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 & 72 hours
Number of animals:
3
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0.4
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Absent
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
DOT: Not corrosive

Table 3. Results and Discussion

No. of animals

Dermal Responses(Timing post- exposure)

Erythema

Edema

Additional Observations

Three Minutes Exposure

1

0 Minute

Absent

Absent

None

60 Minutes

Absent

Absent

None

One Hour Exposure

2

1-hour

Absent

Absent

None

24-hour

Absent to very slight

Absent

None

48-hour

Absent

Absent

None

72-hour

Absent

Absent

None

Four Hours Exposure

3

1-hour

Very slight

Absent to very slight

None

24-hour

Absent

Absent

None

48-hour

Absent

Absent

None

72-hour

Absent

Absent

None

Systemic Observation

No abnormal physical signs were observed among all three animals.

 

Body weight

Two animals gained weight and one study animal lost weight by study termination.

 

Conclusions

Primary Irritation Index (PII) =0.4Response Category:Practically Non-irritating (Negligible)

DOT:Not corrosive, NoEPA:NotGHS:Not packing group assignment Classified Classified

 

Interpretation of results:
GHS criteria not met
Conclusions:
Under the consition of the study, the primary irritation index (PII) of the test item was 0.4, following exposure to clipped rabbit skin under semi-occlusive condition. The test item does not meet the criteria for classification according to the Globally Harmonized Classification System and to the Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixture.
Executive summary:

OECD 404 (2016) -the irritant or corrosive effects of the test article was assessed following application to the clipped skin of white New Zealand rabbit. The test article (0.5 g) was applied dermally to Site 1 for exposure period of 3 minutes under occlusive patch. Since the reaction of the initial animal did not produce a corrosive or severely irritating effect, two additional animals (one female and one male) were added to the study. All three animals were dosed at Site 2 for an exposure period of one hour and Site 3 for an exposure period of four hours. Erythema and edema were scored at 1, 24, 48 and 72 hours after patch removal for the one and four-hour exposures. Animals were observed for mortality, toxicological and pharmacological effects at least once daily. Body weights were recorded pre-test and at termination.

No abnormal physical or systemic signs were observed among all three animals. Two animals gained weight and one study animal lost weight by study termination. No mortality reported.

Very slight erythema and oedema was noted within 24 hours post exposure and it was fully reversible. The Primary Irritation Index (PII) of theist item was reported as 0.4.

Under the condition of the study, it was concluded that test item was not corrosive and does not cause irritation to the rabbits’ skin. Therefore, the test item does not meet the criteria for classification according to the Globally Harmonized Classification System and to the Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixture.

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:
10 Oct 2016 - 31 March 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study was conducted in accordance with international guidelines and in accordance with GLP. All relevant validity criteria were met.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Covance Research Product Inc, Denver, PA
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 2.7 - 3.2 kg
- Fasting period before study: not specified
- Housing: individually housed in suspended wired-bottom cages, absorbent paper was changed at least three times per week.
- Diet (e.g. ad libitum): Fresh PMI Rabbit Chow (Diet No. 5321)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not stated
- Humidity (%): Not stated
- Air changes (per hr): Not stated
- Photoperiod (hrs dark / hrs light): 12 : 12
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 ml equivalent (36 mg)
Duration of treatment / exposure:
one second
Observation period (in vivo):
1, 24, 48 and 72 hours post-instillation.
Duration of post- treatment incubation (in vitro):
n/a
Number of animals or in vitro replicates:
3
Details on study design:
- Main study: An analgesic, Buprenorphine, was administered at 0.1 mg/kg subcutaneously between the shoulder blades approximately one hour prior to instillation of the test article. A dose of 0.1 ml equivalent (36 mg) of TX16352 was placed into the conjunctival sac of one eye of each rabbit. The eyes were examined pre-test and scored by the Draize technique.
- Duration of observation period following administration: up to 72 hours
- Frequency of observations and weighing: Eyes were examined pre-test and scored by the Draize technique at 1, 24, 48 and 72 hours post-instillation.
- Necropsy of survivors performed: yes
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0.67
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0.33
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0.33
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0.67
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Remarks on result:
no indication of irritation

Table 2. Result and Discussion

No. of Animals

Time Points

ENDPOINTS

Additional Observations

CORNEA

IRIS

CONJUNCTIVAE

3

1-hour

No opacity

No iritis

Redness, chemosis, discharge

Test article residue in conjunctival sac

24-hours

No opacity

No iritis

Redness, chemosis

None

48-hours

No opacity

No iritis

Redness

None

72-hours

No opacity

No iritis

No irritation

None

Systemic Observations:

Diminished fecal output and feed consumption were observed.

Because transient inappetence is frequently observed in rabbits and other animals following administration of Buprenorphine, and the animal appeared otherwise normal and maintained body weight throughout the study, there is no evidence that this finding is test article-related.

Body Weights:

Two animals’ body weights remained the same. One animal gained weight by study termination.

CONCLUSIONS

OECD 405:Ocular Irritant

EU:Not Classified

GHS:Not Classified

US EPA:Category III

Interpretation of results:
GHS criteria not met
Conclusions:
Under the condition of the study the test item did not produce any evidence of ocular irritation or corrosivity and therefore does not meet the criteria for classification according to the Globally Harmonized Classification System and to the Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixture.
Executive summary:

OECD 405 - 2016: Three healthy New Zealand White rabbits (two males and one female), free from evidence of ocular irritation and corneal abnormalities, were placed on the study. An analgesic, Buprenorphine, was administered at 0.1 mg/kg subcutaneously between the shoulder blades approximately one hour prior to instillation of the test article. A dose of 0.1 ml equivalent (36 mg) of the test item was placed into the conjunctival sac of one eye of each rabbit. The eyes were examined pre-test and scored by the Draize technique at 1, 24, 48 and 72 hours post-instillation. The control eyes were observed at the same time periods. Sodium fluorescein dye procedures were used at the 24-hour observation interval. Animals were evaluated for mortality, toxicity and pharmacological effects twice daily. Body weights were recorded pre-test and at termination.

Diminished fecal output and feed consumption were observed. Because transient inappetence is frequently observed in rabbits and other animals following administration of Buprenorphine, and the animal appeared otherwise normal and maintained body weight throughout the study, there is no evidence that this finding is test article-related. Two animals’ body weights remained the same. One animal gained weight by study termination. No evidence of corrosively or irritation was observed.

Under the condition of the study the test item did not produce any evidence of ocular irritation or corrosivity and therefore  does not meet the criteria for classification according to the Globally Harmonized Classification System and to the Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixture.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation/Corrosion: OECD 404: - the irritant or corrosive effects of the test article was assessed following application to the clipped skin of white New Zealand rabbit. The test article (0.5 g) was applied dermally to Site 1 for exposure period of 3 minutes under occlusive patch. Very slight erythema and oedema was noted within 24 hours post exposure and it was fully reversible. The Primary Irritation Index (PII) of theist item was reported as 0.4. Under the condition of the study, it was concluded that the test item was non-corrosive and does not cause irritation to the rabbits’ skin.

Eye Irritation/Corrosion: OECD 405:  - Three healthy New Zealand White rabbits (two males and one female), free from evidence of ocular irritation and corneal abnormalities, were placed on the study. An analgesic, Buprenorphine, was administered at 0.1 mg/kg subcutaneously between the shoulder blades approximately one hour prior to instillation of the test article. A dose of 0.1 ml equivalent (36 mg) of TX16352 was placed into the conjunctival sac of one eye of each rabbit. Conjunctivae redness, chemosis & discharge was observed up 48-hours post exposure but was cleared after 72 hours. No Cornea opacity or iritis observed. Under the condition of the study the test item did not produce any evidence of ocular irritation or corrosivity.

Justification for classification or non-classification

The substance does not meet the criteria for local toxicity classification according to the Globally Harmonized Classification System and to the Regulation (EC) No. 1272/2008; relating to the Classification, Labelling and Packaging of Substances and Mixture.