Registration Dossier

Administrative data

Description of key information

In-vivo studies are available for both skin and eye irritation, and thus in-vitro studies are waived.

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:
October 30th, 2018 - February 27th, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Principles of method if other than guideline:
Additional tests at 3 min and 1hr exposure time as well as exposure of 2 animals for 4 hours according to OECD 404
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
HCFO-1233yd(Z)
Purity 92.5%
7.3% (E)-1-chloro-2,3,3-trifluoropropene
0.2% unknown impurity
stable at room temperature
Expiry date Oct 17th, 2019
Species:
rabbit
Strain:
other: Japanese White (Jla:JW)
Remarks:
female animals - more easily handled. No sex differences in skin irritation responses.
Details on test animals and environmental conditions:
Age at start of test 16 weeks, 3 females. Received into the test facility at 14 weeks and allowed 14 days to acclimatise before commencement of the test. Body weight range 3.22-3.86 kg. Normal weight gain and good dermal condition before start of test. Potential contaminants in feed were
within acceptable range. Animals were maintained within a room 21-25 deg Centigrade and humidity
38-77%, with air exchange 11-14 times per hour, lighting from 07:00-19:00 each day. Animals were accommodated individually in aluminium cages 560(W)x 550(D) x 410mm(H) and allowed free access to LRC4 pelleted diet for rabbits and guinea pigs (Lot 180828 Oriental Yeast Co.) and tap water on automatic supply. Environmental enrichments were provided according to IUCAC recommendations.
Type of coverage:
other: Nichiyu Linseed Oil Paper;
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.5mL unmodified (no vehicle)
Duration of treatment / exposure:
3 min, 1hr, 4hr
Observation period:
14 days
Number of animals:
1 animal for 3 min, 1 animal for 1 hour, 3 for 4 hour exposure (initially 1 animal then a further 2 animals).
Details on study design:
At step 1, the pre-clipped dorsal area of 1 animal was divided into 4 application areas. 0.5ml of the test substance was uniformly put on a 2.5x2.5 cm lint sheet (Nishio Eisei Zairyo Co Ltd), on the applied side, Nichiyu Linseed Oil Paper (Nichiyu Co. Ltd) and applied to the application site A. The patch was covered with Tegaderm tape (3M Healthcare) and fixed. After 3 minutes, the patch on the application site A was removed and the site wiped with cotton soaked with water for injection (Lot 7C92, Otsuka Pharmaceutical Factory Inc.).

At step 2 the test substance was applied in the same manner as step 1, but left in place for 1 hour, then removed and the site (B) wiped as above.

At step 3, the test substance was applied to application site C in the same manner as above, with a control (untreated) patch applied to application site D. After application, all application sits were covered with a lint sheet and the area wrapped with self-adhesive elastic bandage (3M Coban Self-adherent wrap, 3M health care) and fixed by polyethylene film tape (Keepore A; Nichaban Co. Ltd). After 4hours of application, patches on the application sites were removed and the sites wiped with cotton soaked with water for injection, as above.

At step 4, the day after after steps 1-3, the pre-clipped dorsal areas of 2 new animals were both divided into right and left along the median line and 2 application sites, E and F, were designated. The test substance was applied to the application site E in the same manner as the first application in steps 1-3. A control patch 2.5 cm x 2.5 cm was applied to application site F. After application, the patch was covered with tape, wrapped in self adhesive elastic bandage and fixed by polyethylene film tape. After 4 hours of application. Patches were all removed and the sites wiped with cotton and water for injection as above.

Observation and measurement was performed on day 3, day 4 and day 10.
Animals were observed for clinical signs immediately after each application and at 1hr after removal of application for the animals in step 1-4; From the day following application, clinical signs were observed once each day until the final observation day (day 3 (animal 1103), day 4 (animal 1101) or day 10 (animal 1102).

Dermal reactions were observed at 1, 24, 48 and 72 hr after removal of the patch(es). Thereafter observations were performed once daily until dermal reactions disappeared in the animal (up to day 10 after application at the longest). For steps 1 and 2, observations were only continued up to 72 hours. Dermal reactions erythema or oedema were scored and recorded according to Draize's Criteria (1959). After the final observation, animals were euthanized by an overdose of pentobarbital sodium (Somnopentyl, Kyoritsu Seiyaku Corporation).


Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
>= 1 - <= 2
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
>= 0 - <= 2
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
>= 1 - <= 3
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
>= 0 - <= 2
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
>= 0 - <= 1
Max. score:
1
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
>= 0 - <= 1
Max. score:
1
Reversibility:
fully reversible
Irritant / corrosive response data:
P.I.I. 2.0 moderate irritant. By the GHS classification the test substrance was judged as not classified
Interpretation of results:
GHS criteria not met
Conclusions:
Results showed fully reversible erythema and edema in 3 female Japanese White rabbits; slight edema reversible within 72 hours across all animals; moderate to severe erythema reversible within 10 days for one animal, well-defined erythema fully reversible within 3-4 days for the other two animals. Based on the above results the test substance showed no corrosion to rabbit dermis and was judged as a "moderate irritant" according to Primary Irritation Index criteria and as "not classified" according to GHS criteria under the conditions of this study.
Executive summary:

Exposure of Japanese white rabbits to the test substance for 4hr resulted in moderate erythema and mild edema, fully reversible. The test substance is classified as a moderate irritant according to the Primary Irritation Index and "not classified" according to GHS criteria.

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:
30/10/2018 - 19/11/2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
other: Japanese White (Jla:JW)
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent negative control
Amount / concentration applied:
0.1ml
Duration of treatment / exposure:
Single administration followed by closing the eyelid for 1 second.
Observation period (in vivo):
1, 3 and 6 hours after treatment, for 4 days.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
>= 0 - <= 1
Max. score:
1
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
>= 0 - <= 1
Max. score:
1
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the above results, HCFO-1233yd(Z) showed no corrosion to rabbit eye and it was judged as "Mildly irritating" and regarded as ''Not classified" according to the GHS classification under the conditions of this study.
Executive summary:

The eye irritation/corrosion potential of the HCFO-1233yd(Z) (the test substance) was examined in Japanese White rabbits (lla:JW, female). The test substance (0.1 mL) was applied to the left eye of one (initial test) and two animals ( confirmatory test), and the eye reactions were observed for the longest 96 hours after application and the eye corrosion/irritation potential was evaluated. The results are summarised as follows:

There were no corrosive changes in any animal during the observation period. Conjunctival redness, chemosis and discharge were observed in 3/3 or 2/3 animals at 1 hour after application. Eye irritation reactions were alleviated with the passage of time and all changes disappeared by 96 hours after application. The maximum mean total score (MMTS) was recorded at 1 hour after application and the value was 7.3. In the evaluation by the Kay and Calandra classification, the value of mean total score at 48 hours after application (MTS 48) was 0.7 and higher than 0, thus the test substance was classified as "Mildly irritating". In the evaluation of irritation by the GHS classification criteria, the test substance was regarded as ''Not classified" since there were no animals that showed positive response for corneal opacity (degree), iritis, conjunctival redness or chemosis. There were no abnormalities in clinical signs or body weight of any animal.

Based on the above results, HCFO-1233yd(Z) showed no corrosion to rabbit eye and it was judged as "Mildly irritating" and regarded as ''Not classified" according to the GHS classification under the conditions of this study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin Irritation

Results showed fully reversible erythema and edema in 3 female Japanese White rabbits; slight edema reversible within 72 hours across all animals; moderate to severe erythema reversible within 10 days for one animal, well-defined erythema fully reversible within 3-4 days for the other two animals. Based on the above results the test substance showed no corrosion to rabbit dermis and was judged as a "moderate irritant" according to Primary Irritation Index criteria and as "not classified" according to GHS criteria under the conditions of this study.  

Eye Irritation

The eye irritation/corrosion potential of the HCFO-1233yd(Z) (the test substance) was examined in Japanese White rabbits (lla:JW, female). The test substance (0.1 mL) was applied to the left eye of one (initial test) and two animals (confirmatory test), and the eye reactions were observed for the longest 96 hours after application and the eye corrosion/irritation potential was evaluated. The results are summarized as follows:

There were no corrosive changes in any animal during the observation period. Conjunctival redness, chemosis and discharge were observed in 3/3 or 2/3 animals at 1 hour after application. Eye irritation reactions were alleviated with the passage of time and all changes disappeared by 96 hours after application. The maximum mean total score (MMTS) was recorded at 1 hour after application and the value was 7.3. In the evaluation by the Kay and Calandra classification, the value of mean total score at 48 hours after application (MTS 48) was 0.7 and higher than 0, thus the test substance was classified as "Mildly irritating". In the evaluation of irritation by the GHS classification criteria, the test substance was regarded as ''Not classified" since there were no animals that showed positive response for corneal opacity (degree), iritis, conjunctival redness or chemosis. There were no abnormalities in clinical signs or body weight of any animal.

Justification for classification or non-classification

The available data indicates that classification for both skin and eye irritation is not warranted.

HCFO-1233yd(Z) is not classified according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).