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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

The substance is not irritating to skin and to eyes.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1981 version
Deviations:
yes
Remarks:
occlusive instead of semi-occlusive conditions as recommended by the Guideline; due to the solubility of the test article the vehicle was changed, which did not affect the validity of the results.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, Fuellinsdorf / Switzerland
- Age at study initiation: 15 - 16 weeks
- Weight at study initiation: 2400 - 2600 g
- Diet (ad libitum): pelleted standard Kliba 341, rabbit maintenance diet
- Water (ad libitum): tap water
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
other: polyethylene glycol 400
Controls:
other: untreated skin area served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g of moistened test article was applied to the skin.
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
3 animals (2 males, 1 female)
Details on study design:
TEST SITE
- Area of exposure: approximately 3.0 cm x 3.0 cm
- Type of wrap if used: occlusive dressing

REMOVAL OF TEST SUBSTANCE
Four hours after application, skin was flushed with luke warm tap water.

SCORING SYSTEM:
Skin reaction was assessed according to the OECD Guidelines 404 (1981) as follows:

ERYTHEMA AND ESCHAR FORMATION
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) or eschar formation (injuries in depth preventing erythema reading) 4

EDEMA FORMATION
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well-defined by definite raising) 2
Moderate edema (edges raised approximately 1 mm) 3
Severe edema (raised more than 1 mm and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
No signs of skin irritation or skin corrosion were observed.
Other effects:
No signs of systemic toxicity and no mortality were observed. A red discoloration of the skin was observed in all animals during the whole observation period. No information was reported on the potential interference of the scoring through the severe red discoloration of the skin.
Interpretation of results:
GHS criteria not met
Conclusions:
After dermal application of 0.5 g of the substance to rabbits for 4 h according to OECD 404 (1981) no erythema or edema were observed. Therefore, the test item is considered to be not irritating to rabbit skin.
Executive summary:

In a primary dermal irritation GLP-compliant study according to guideline OECD 404, threee New Zealand White rabbits (15 -16 weeks old, approx. 2.5 kg) were dermally exposed to 0.5 mL of substance. Test sites were shaved and covered with a occlusive dressing for 4 hours.

Neither erythema, nor edema were observed in any rabbits at any timepoint (24, 48 and 72h). Therefore, the substance was not irritating when applied to rabbit skin.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is performed between two forms of the same substance. The identities of the two forms are describe below.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source form is 3,6-bis(4-chlorophenyl)-2,5-dihydropyrrolo[3,4-c]pyrrol-1,4-dione (EC-no. 401-540-3), referred to here as PR254. PR254 is an organic mono-constituent substance with a typical purity of > 99.5% (w/w). It does not contain any impurity relevant for classification or labelling of the substance. The target form is the nanoform of the source substance, referred to here as PR254 nanoform. As the source form, it has a typical purity of > 99.5% (w/w) and it does not contain any impurity relevant for classification or labelling of the substance. The PR254 nanoform is spheroidal with a pure polyhedral shape and is not surface-treated.

3. ANALOGUE APPROACH JUSTIFICATION
The two analogue forms have the same structure. Under ambient atmosphere, the specific surface energy of particles increases with decreasing particle size. Therefore, particle aggregate to reach an energy minimum. The driving forces are hydrogen bonds and van der Waals forces (π-π interaction). Substantial energy is required to disperse the PR254 nanoform aggregates to particles that fall under the nanoform definition.
PR254 was been tested extensively addressing information requirements of Annexes VII to IX without identifying any biological target. PR254 nanoform could potentially have biological targets due to the different particle size distribution, which would require processes capable of dispersing the aggregates, e.g. in aqueous milieu. However, both forms have been tested according to OECD Test Guideline 318, demonstrating that PR254 nanoform cannot be dispersed under the condition of the study, i.e. immediately after sonification re-forms aggregates. Also, PR254 aggregates to a large extent, but can be more easily dispersed than the nanoform. The experiments demonstrated that exposure in aqueous milieu will be primarily to aggregates, regardless of the PR254 form.
Therefore, it is concluded that both forms will behave identically in studies, in which they are applied under atmospheric conditions and/or in aqueous milieus, so that for the PR254 nano-form no specific biological targets need to be considered.
As both forms form non-dispersible aggregates in aqueous milieu and under ambient conditions, read-across of toxicological studies from the source to the target form is scientifically justified.

4. DATA MATRIX
The data matrix is included as Annex 1 in the assessment report ‘PR254 bulk nano analogue approach 210111’ attached here below under ‘Attached justification’.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1981 version
Deviations:
yes
Remarks:
occlusive instead of semi-occlusive conditions as recommended by the Guideline; due to the solubility of the test article the vehicle was changed, which did not affect the validity of the results.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, Fuellinsdorf / Switzerland
- Age at study initiation: 15 - 16 weeks
- Weight at study initiation: 2400 - 2600 g
- Diet (ad libitum): pelleted standard Kliba 341, rabbit maintenance diet
- Water (ad libitum): tap water
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
other: polyethylene glycol 400
Controls:
other: untreated skin area served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g of moistened test article was applied to the skin.
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
3 animals (2 males, 1 female)
Details on study design:
TEST SITE
- Area of exposure: approximately 3.0 cm x 3.0 cm
- Type of wrap if used: occlusive dressing

REMOVAL OF TEST SUBSTANCE
Four hours after application, skin was flushed with luke warm tap water.

SCORING SYSTEM:
Skin reaction was assessed according to the OECD Guidelines 404 (1981) as follows:

ERYTHEMA AND ESCHAR FORMATION
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) or eschar formation (injuries in depth preventing erythema reading) 4

EDEMA FORMATION
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well-defined by definite raising) 2
Moderate edema (edges raised approximately 1 mm) 3
Severe edema (raised more than 1 mm and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
No signs of skin irritation or skin corrosion were observed.
Other effects:
No signs of systemic toxicity and no mortality were observed. A red discoloration of the skin was observed in all animals during the whole observation period. No information was reported on the potential interference of the scoring through the severe red discoloration of the skin.
Interpretation of results:
GHS criteria not met
Conclusions:
After dermal application of 0.5 g of the substance to rabbits for 4 h according to OECD 404 (1981) no erythema or edema were observed. Therefore, the test item is considered to be not irritating to rabbit skin.
Executive summary:

In a primary dermal irritation GLP-compliant study according to guideline OECD 404, threee New Zealand White rabbits (15 -16 weeks old, approx. 2.5 kg) were dermally exposed to 0.5 mL of substance. Test sites were shaved and covered with a occlusive dressing for 4 hours.

Neither erythema, nor edema were observed in any rabbits at any timepoint (24, 48 and 72h). Therefore, the substance was not irritating when applied to rabbit skin.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
1981 version
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, Fuellinsdorf / Switzerland
- Age at study initiation: 15 - 16 weeks
- Weight at study initiation: 2600 g - 2800 g
- Housing: individually in stainless steel cages.
- Diet (ad libitum): pelleted standard Kliba 341, rabbit maintenance diet.
- Water (ad libitum): tap water
- Acclimation period: four days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
0.1 g of undiluted test article was applied to the left eye of each animal.
Duration of treatment / exposure:
The eye was not rinsed after application.
Observation period (in vivo):
Scoring of irritation effects was performed approximately 1 h, 24 h, 48 h and 72 h after application.
Number of animals or in vitro replicates:
3 animals ( 1 male, 2 females)
Details on study design:
SCORING SYSTEM according to OECD 405 (1981):

CORNEA
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacreous area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

IRIS
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, hemorrhage, gross destruction (any or all of these) 2

CONJUNCTIVAE
Redness (refers to most severe reading of palpebral and bulbar conjunctivae when compared with control eye)
Blood vessels normal 0
Some blood vessels definitely hyperemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

CHEMOSIS: lids and/or nictitating membranes
No swelling 0
Any swelling above normal (including nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half-closed 3
Swelling with lids more than half-closed 4
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
No signs of irritation were observed in all rabbits and at all time points.
Other effects:
No clinical signs of systemic toxicity were observed and no mortality occurred. Red residues were observed at 1 h in all animals. No discoloration of the cornea and conjunctivae was observed.
Interpretation of results:
GHS criteria not met
Conclusions:
After dermal application of 0.5 g of the substance to rabbits for 4 h according to OECD 404 (1981) no erythema or edema were observed. Therefore, the test item is considered to be not irritating to rabbit skin.
Executive summary:

In an eye irritation/corrosion GLP-compliant study according to guideline OECD 405, threee New Zealand White rabbits (15 -16 weeks old, approx. 2.5 kg) were exposed by applying 0.1 g of undiluted test article to the left eye of each animal. Eyes wre not rinsed and irritation was evaluated at 1, 24, 48 and 72h.

Since no effects were observed at 24, 48 and 72 hours after treatment, the substance was not irritating to the rabbit eye.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is performed between two forms of the same substance. The identities of the two forms are describe below.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source form is 3,6-bis(4-chlorophenyl)-2,5-dihydropyrrolo[3,4-c]pyrrol-1,4-dione (EC-no. 401-540-3), referred to here as PR254. PR254 is an organic mono-constituent substance with a typical purity of > 99.5% (w/w). It does not contain any impurity relevant for classification or labelling of the substance. The target form is the nanoform of the source substance, referred to here as PR254 nanoform. As the source form, it has a typical purity of > 99.5% (w/w) and it does not contain any impurity relevant for classification or labelling of the substance. The PR254 nanoform is spheroidal with a pure polyhedral shape and is not surface-treated.

3. ANALOGUE APPROACH JUSTIFICATION
The two analogue forms have the same structure. Under ambient atmosphere, the specific surface energy of particles increases with decreasing particle size. Therefore, particle aggregate to reach an energy minimum. The driving forces are hydrogen bonds and van der Waals forces (π-π interaction). Substantial energy is required to disperse the PR254 nanoform aggregates to particles that fall under the nanoform definition.
PR254 was been tested extensively addressing information requirements of Annexes VII to IX without identifying any biological target. PR254 nanoform could potentially have biological targets due to the different particle size distribution, which would require processes capable of dispersing the aggregates, e.g. in aqueous milieu. However, both forms have been tested according to OECD Test Guideline 318, demonstrating that PR254 nanoform cannot be dispersed under the condition of the study, i.e. immediately after sonification re-forms aggregates. Also, PR254 aggregates to a large extent, but can be more easily dispersed than the nanoform. The experiments demonstrated that exposure in aqueous milieu will be primarily to aggregates, regardless of the PR254 form.
Therefore, it is concluded that both forms will behave identically in studies, in which they are applied under atmospheric conditions and/or in aqueous milieus, so that for the PR254 nano-form no specific biological targets need to be considered.
As both forms form non-dispersible aggregates in aqueous milieu and under ambient conditions, read-across of toxicological studies from the source to the target form is scientifically justified.

4. DATA MATRIX
The data matrix is included as Annex 1 in the assessment report ‘PR254 bulk nano analogue approach 210111’ attached here below under ‘Attached justification’.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
1981 version
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, Fuellinsdorf / Switzerland
- Age at study initiation: 15 - 16 weeks
- Weight at study initiation: 2600 g - 2800 g
- Housing: individually in stainless steel cages.
- Diet (ad libitum): pelleted standard Kliba 341, rabbit maintenance diet.
- Water (ad libitum): tap water
- Acclimation period: four days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
0.1 g of undiluted test article was applied to the left eye of each animal.
Duration of treatment / exposure:
The eye was not rinsed after application.
Observation period (in vivo):
Scoring of irritation effects was performed approximately 1 h, 24 h, 48 h and 72 h after application.
Number of animals or in vitro replicates:
3 animals ( 1 male, 2 females)
Details on study design:
SCORING SYSTEM according to OECD 405 (1981):

CORNEA
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacreous area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

IRIS
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, hemorrhage, gross destruction (any or all of these) 2

CONJUNCTIVAE
Redness (refers to most severe reading of palpebral and bulbar conjunctivae when compared with control eye)
Blood vessels normal 0
Some blood vessels definitely hyperemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

CHEMOSIS: lids and/or nictitating membranes
No swelling 0
Any swelling above normal (including nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half-closed 3
Swelling with lids more than half-closed 4
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
No signs of irritation were observed in all rabbits and at all time points.
Other effects:
No clinical signs of systemic toxicity were observed and no mortality occurred. Red residues were observed at 1 h in all animals. No discoloration of the cornea and conjunctivae was observed.
Interpretation of results:
GHS criteria not met
Conclusions:
After dermal application of 0.5 g of the substance to rabbits for 4 h according to OECD 404 (1981) no erythema or edema were observed. Therefore, the test item is considered to be not irritating to rabbit skin.
Executive summary:

In an eye irritation/corrosion GLP-compliant study according to guideline OECD 405, threee New Zealand White rabbits (15 -16 weeks old, approx. 2.5 kg) were exposed by applying 0.1 g of undiluted test article to the left eye of each animal. Eyes wre not rinsed and irritation was evaluated at 1, 24, 48 and 72h.

Since no effects were observed at 24, 48 and 72 hours after treatment, the substance was not irritating to the rabbit eye.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

As the substance did not induce any irritating effects, classification for skin and eye irritaion/corrosion are not warranted.