Registration Dossier

Administrative data

Description of key information

Under the test conditions for skin irritation, PM 343 is classified as ‘Category 2: Irritant’ according to the CLP Regulation and as ‘R38 Irritating to skin’ according to the Directive 67/548/EEC.
Under the test conditions for eye irritation, PM 343 Pivaloxycyclene is classified as ‘Irritating to eyes (Category 2)’ according to the CLP Regulation. It is not classified as irritating to eyes according to the Directive 67/548/EEC.

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:
1979-05-21 to 1979-06-06
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Non-GLP study conducted similarly to OECD Guideline 404 with deviations: no data about purity and no certificate of analysis of the test substance; no details on housing conditions of animals; observations not followed until the reversibility of the effects; different scoring system was followed in the study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
non-GLP study; no data about purity and no certificate of analysis of the test substance; no details on housing conditions of animals; observations not followed until the reversibility of the effects; different scoring system was followed in the study
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Specific details on test material used for the study:
- Name of test material (as cited in study report): PM 343
- Source: PPL, UK
- Physical state: Clear liquid
- Date received: 29 March 1979
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
- Age at study initiation: 9-12 weeks
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): 100 %
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
Eight
Details on study design:
- Area of exposure: Dorsum
- % coverage: Test substance (0.5 mL) was applied under a semi-occlusive patch to the clipped skin and the patches were held in place with an adhesive tape.
- Type of wrap used: Animals were immobilised in a canvas body sleeve for 4 h after application of the patch.

REMOVAL OF TEST SUBSTANCE
- After the removal of the patches, the application site was wiped clean of excess material.

SCORING SYSTEM: Skin reactions were observed immediately after removal of the patch and after 24, 48 and 72 h and graded according to the following 8-point anchored ordinate scale:
1 = marginal / very slight
2 = slight
3 = fairly distinct
4 = quite distinct
6 = becoming well developed
8 = well developed
10 = becoming severe
12 = severe
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of 8 animals
Time point:
other: average of 24, 48 and 72 h
Score:
3.4
Max. score:
12
Reversibility:
no data
Irritation parameter:
edema score
Basis:
mean
Remarks:
of 8 animals
Time point:
other: average of 24, 48 and 72 h
Score:
2.8
Max. score:
12
Reversibility:
no data
Irritation parameter:
overall irritation score
Basis:
other: sum of scores observed in 8 animals
Time point:
other: 24, 48 and 72 h
Score:
225
Max. score:
1 152
Reversibility:
no data
Irritant / corrosive response data:
- At 24 h, generally fairly distinct to distinct erythema and oedema were noted in test animals.
- By 48 and 72 h, fairly distinct to distinct erythema and slight to fairly distinct oedema with marginal to slight cracking were noted in most animals.
- The response produced by PM 343 was greater than that produced by Diethyl Phthalate which produced a generally marginal to slight response in some animals, although one animal had distinct erythema and oedema at 24 h.
- The response produced by PM 343 was slightly less than that produced by the controls, Cyclamen Aldehyde and Geraniol, which produced similar responses showing fairly distinct to fairly well developed erythema and oedema at 24 h and fairly distinct to well-developed erythema and oedema with slight cracking in some animals by 48 and 72 h.
Other effects:
None

Table 7.3.1/1: Skin irritation data for individual rabbits

Rabbit number

Irritation scores*

24 h

48 h

72 h

Mean (24, 48 and 72 h)

Erythema

Oedema

Erythema

Oedema

Erythema

Oedema

Erythema

Oedema

1

3#

3

3#

2

3# α

2

3.0

2.3

2

4

3

4#

3

3#

2

3.7

2.7

3

4

3

3#

3

3#

2

3.3

2.7

4

2

2

3#

2

2#

1

2.3

1.7

5

4

3

4

4

4# α

4

4.0

3.7

6

4

4

4

3

3#

3

3.7

3.3

7

4# α

4

4# α

2

3# α

2

3.7

2.7

8

4

3

4

3

3#

3

3.7

3.0

Mean (all 8 animals)

3.4

2.8

*Reaction grades and scores:

1 = marginal / very slight

2 = slight

3 = fairly distinct

4 = quite distinct

6 = becoming well developed

8 = well developed

10 = becoming severe

12 = severe

#Very slight to fairly distinct cracking

αVery slight scaling

Interpretation of results:
Category 2 (irritant)
Conclusions:
Under the test conditions, PM 343 is classified as ‘Category 2: Irritant’ according to the CLP Regulation and as ‘R38 Irritating to skin’ according to the Directive 67/548/EEC.
Executive summary:

In a primary dermal irritation study performed similarly to OECD Guideline 404, 0.5 mL of the test item, PM 343, was applied under a semi-occlusive patch to clipped dorsum of eight New Zealand White rabbits. After an exposure period of 4 h, the patches and the applied material were removed and skin reactions were scored immediately after removal of the patch and after 24, 48 and 72 h, according to the 8-point anchored ordinate scale ranging from very slight (score = 1) to severe reactions (score = 12).

At 24 h, generally fairly distinct to distinct erythema and oedema were noted in test animals. By 48 and 72 h, fairly distinct to distinct erythema and slight to fairly distinct oedema with marginal to slight cracking were noted in most animals. Very slight scaling was noted in 3/8 animals at 72 h. The calculated mean scores for each individual lesion for all animals within three scoring times (24, 48 and 72 h) on the 8-point anchored ordinate scale were 3.4 for erythema score and 2.8 for oedema score.

After comparing the scores with the scale in OECD Guideline, the calculated mean scores for all animals within three scoring times (24, 48 and 72 h) were as follows: 2 for erythema score and 2 for oedema score.

Under the test conditions, PM 343 is classified as ‘Category 2: Irritant’ according to the CLP Regulation and as ‘R38 Irritating to skin’ according to the Directive 67/548/EEC.

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:
1979-05-21 to 1979-06-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Non-GLP study conducted similarly to OECD Guideline 405 with deviations: no data about purity and no certificate of analysis of the test substance; no details on environmental conditions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
non-GLP study; no data about purity and no certificate of analysis of the test substance; no details on environmental conditions
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Specific details on test material used for the study:
- Name of test material (as cited in study report): PM 343 Pivaloxycyclene
- Source: PPL, UK
- Physical state: Very pale clear yellow liquid
- Date received: 29 March 1979
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
- Age at study initiation: 8 weeks
- Weight at study initiation: 1-2 kg
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
No washing was done.
Observation period (in vivo):
15 days
Number of animals or in vitro replicates:
Three
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM: Ocular lesions were scored at 15 min, 4, 24, 48 and 72 h and on Days 5, 8, 9, 10, 11, 12 and 15 according to the following scale:
CORNEA
Normal……0
Any change from normal, including slight dulling of corneal luster.......0.5 (can be considered as equivalent to 1 as recommended in OECD Guideline 405)
Scattered or diffuse areas of opacity, or loss of corneal epithelium, iris clearly visible….…1
Easily discernible, greyish, translucent areas, details of iris slightly obscured….…2
Grey-white areas, no details of iris visible, size of pupil barely discernible……..3
Complete corneal opacity, iris not discernible…..…4

IRIS
Normal…0
Any divergence from normal, congestion of iridial vessels, deepening on folds……+ (can be considered as equivalent to 1 as recommended in OECD Guideline 405)

CONJUNCTIVAE
Redness (palpebral and bulbar conjunctivae and nictitating membrane)
Vessel normal……0
Some vessel definitely injected……1
Diffusion, crimson red, individual vessel not easily discernible……2
Diffuse beefy red……3

CHEMOSIS
No swelling……0
Any swelling above normal……1
Obvious swelling with partial eversion of eyelids……2
Swelling with lids about half closed…..…3
Swelling with lids more than half closed………4

TOOL USED TO ASSESS SCORE: Slit lamp
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: for undiluted test item
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1.3
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 2 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: for undiluted test item
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 2 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: for undiluted test item
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: for undiluted test item
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 2 days
Remarks on result:
other: for undiluted test item
Irritant / corrosive response data:
- Moderate corneal opacities, affecting up to all cornea, were noted in all 3 rabbits. These reactions were associated with moderate corneal swelling.
- All animals had slight to moderate conjunctivitis and 2/3 animals had slight to moderate discharge.
- One animal healed by Day 4, one by Day 9 and one by Day 15.
Other effects:
None

Table 7.3.2/1: Individual ocular examinations and mean values of the scores recorded for each animal (24, 48 and 72 h) after instillation of undiluted test item

 Rabbit No.

Region of eye

Scores

15 min

4 h

24 h

48 h

72 h

Day 5

Day 8

Days 9-12

Day 15

Mean

(24, 48 and 72 h)

1

Corneal opacity

-

-

1

1

1

1

-

1

N

1.0

Iris

-

-

0

0

0

0

-

0

0

0.0

Conjunctivae: Redness

1

1

1

2

1

1

-

0

0

1.3

Conjunctivae: Chemosis

0

0

1

0

0

0

-

0

0

0.3

2

Corneal opacity

-

-

1

1

N

-

-

-

-

0.7

Iris

-

-

0

0

0

-

-

-

-

0.0

Conjunctivae: Redness

1

1

1

1

0

-

-

-

-

0.7

Conjunctivae: Chemosis

0

1

1

0

0

-

-

-

-

0.3

3

Corneal opacity

-

-

1

1

1

-

N

-

-

1.0

Iris

-

-

0

0

0

-

0

-

-

0.0

Conjunctivae: Redness

1

1

1

1

0

-

0

-

-

0.7

Conjunctivae: Chemosis

0

1

1

0

0

-

0

-

-

0.3

 N: No information about the symbol was reported by the author. In the text, it was mentioned that one animal healed by Day 4, one by Day 9 and one by Day 15 therefore 'N' was considered as equivalent to zero for the calculation of mean scores.

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Under the test conditions, PM 343 Pivaloxycyclene is classified as ‘Irritating to eyes (Category 2)’ according to the CLP Regulation. It is not classified as irritating to eyes according to the Directive 67/548/EEC.
Executive summary:

In an eye irritation study conducted similarly to the OECD Guideline 405, 0.1 mL of the undiluted test item, PM 343 Pivaloxycyclene, was instilled into one eye of 3 rabbits. The eyes were examined and the changes were scored at 15 min, 4, 24, 48 and 72 h and on Days 5, 8, 9, 10, 11, 12 and 15.

Single application of the undiluted preparation caused moderate corneal opacities, affecting up to all cornea, in all 3 rabbits. These reactions were associated with moderate corneal swelling. All animals had slight to moderate conjunctivitis and 2/3 animals had slight to moderate discharge. One animal healed by Day 4, one by Day 9 and one by Day 15. Mean individual scores at 24, 48 and 72 h for the 3 animals after exposure to undiluted item were 1.0, 0.7, 1.0 for cornea score; 0, 0, 0 for iris score; 1.3, 0.7, 0.7 for conjunctivae score and 0.3, 0.3, 0.3 for chemosis score.

Under the test conditions, PM 343 Pivaloxycyclene is classified as ‘Irritating to eyes (Category 2)’ according to the CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of skin irritation / corrosion endpoint:
Reliable in vivo study

Justification for selection of eye irritation endpoint:
Reliable in vivo study

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Based on the results of reliable in vivo skin and eye irritation studies, Pivacyclene is classified as a ‘Category 2: Irritant’ and ‘Irritating to eyes (Category 2)’ according to the EU DSD or CLP Regulation.