Registration Dossier

Administrative data

Description of key information

Isophorone is an eye irritant (Esso Research, 1964; human experience: Silverman et al., 1946; Esso, 1965) and an respiratory irritant (human experience: Silverman et al., 1946; Esso, 1965) but does not irritate the skin (Potakar et al., 1985).

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:
no data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1981
GLP compliance:
not specified
Species:
rabbit
Strain:
other: New Zealand
Details on test animals and environmental conditions:
TEST ANIMALS: 
- Strain: New Zealand
- Sex: male / female
- Source: various breeders
- Weight at study initiation: 2-4 kg
- Number of animals: 6 (male plus female)

Environmental conditions
- animals were kept in individual cages under standardized laboratory conditions
Type of coverage:
other: semiocclusive and occlusive
Preparation of test site:
other: shorn
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted, 0.5 ml per patch
Duration of treatment / exposure:
4 hour(s)
Observation period:
Postexposure period: 7 days
Number of animals:
6
Details on study design:
ADMINISTRATION/EXPOSURE 
- Preparation of test substance: none
- Area of exposure: laterally; shorn 15-24 hours in advance;   3 cm x 3 cm gauze pads with test substance
- Two patches were applied (one occlusive, one semi-occlusive):  air-permeable circular bandage (semi-occlusive),   
air-tight plastic foil (occlusive)
- Total volume applied: 0.5 ml per patch (corresponds to ca. 1500 mg/kg  bw)
- Postexposure period: 7 days
- Removal of test substance: each after 4 hours; rinsed with water and dried

EXAMINATIONS
- Scoring system: 5th Amendment to 67/548/EEC (1983)
- Examination time points:  1, 24, 48, 72 hours, and 7 days after removal
Irritation parameter:
other: see remarks
Remarks on result:
other: the report does not mention the scores for edema and erythema; it gives only the classification for skin irritation according to EC Directive 67/548/EEC
Irritant / corrosive response data:
no data
Other effects:
No irritation was observed after occlusive and semi-occlusive application.

no futher remarks

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: EC Directive 67/548/EEC
Conclusions:
Under the present test conditions, none of six rabbits exposed for 4 hours to 1500 mg isophorone per patch and animal (semiocclusive and
occlusive conditions) showed any test item-related changes at the examination time-points 60 minutes, 24, 48 and 72 hours after patch removal.
Executive summary:

The acute skin irritation properties of isophorone were estimated according to OECD Guideline 404. A dose of 1500 mg test item per animal was applied to the shorn, intact dorsal skin of 6 male and female rabbits under semiocclusive and occlusive conditions for 4 hours. After removal of the patches the treated skin areas were rinsed with water and dried. The results were assessed 1, 24, 48 and 72 hr after patch removal. Under the test conditions no significant irritancy to skin were observed. Therefore, isophorone is not irritating to skin.

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:
1964-05-06 - 1964-08-10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Principles of method if other than guideline:
Method: Draize Test based on the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics", FDA (1959)
GLP compliance:
no
Species:
rabbit
Strain:
other: albino rabbits
Details on test animals or tissues and environmental conditions:
TEST ANIMALS: 
- Sex: male/female
- Weight at study initiation: 2.2-2.7 kg
- Number of animals: 6 per dose group and sex
- Controls: untreated eye
Vehicle:
unchanged (no vehicle)
Controls:
other: identical animals, untreated eyes
Amount / concentration applied:
undiluted
Amount applied: 0.1 ml
Duration of treatment / exposure:
not rinsed, no removal of test substance
Observation period (in vivo):
ADMINISTRATION/EXPOSURE 
- Vehicle: undiluted into conjunctival sac of left eye, closed for 30  seconds
- Postexposure period:   1, 4, 24 hours; 2, 3, 4, 7, 10, 14 days
Number of animals or in vitro replicates:
6 albino rabbits of either sex
Details on study design:
EXAMINATIONS
- Scoring system: Draize, 1959;
- Tool used to assess score: sodium fluorescein /UV light / visual inspections
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
26
Max. score:
110
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: see below (other effects)
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.9
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: see: other effects
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.17
Max. score:
2
Reversibility:
fully reversible
Remarks on result:
other: see: other effects
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2.06
Max. score:
3
Reversibility:
fully reversible
Remarks on result:
other: see: other effects
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1.06
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: see: other effects
Irritant / corrosive response data:
AVERAGE Score (6 animals)
- Cornea: 0.9
- Iris: 0.17
- Conjunctivae (Redness): 2.06
- Conjunctivae (Chemosis): 1.06
- Overall irritation score: 26
Other effects:
Immediately following application of the test material, all of the animals exhibited scrambling and preening; phonation was noted in one animal.
Irritation was moderate to severe and generally consisted of moderate or marked erythema, chemosis, and discharge, slight corneal opacity, and  
apparent corneal sloughing. One animal showed slight, transient iritis.  
The sodium fluorescein examination on the seventh day confirmed the presence of corneal lesions in two animals; re-examination at 14 days
revealed no corneal damage.

no remarks

Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: Draize
Conclusions:
Under the present conditions of the study, isophorone is moderately irritating to eyes of 6 albino rabbits. In this study marked irritation was observedwhich reversed within 14 days, but was still present after 7 days.
Executive summary:

The acute eye irritation properties of isophorone were estimated in a Draize test. An amount of 0.1 ml of the undiluted test substance was instilled into the left eye of each of six albino rabbits of either sex, and the untreated right eye served as control. The eyes remained unrinsed and there was no removal of test substance. The animals were observed for 14 days after application. Eye irritation index was assessed using Draize scale.

The test was evaluated as follows (average of evaluation at 24, 48 and 72 hours respectively): cornea: 0.89, iris: 0.17, conjunctivae: redness: 2.06 and chemosis: 1.06 (mean scores on Draize scale). Therefore, isophorone is considered to be moderately irritating to eyes with an overall irritation index of 26 (26 - 56 = moderately irritating).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Animal Data

Skin Irritation

One guideline study (OECD 404) was performed on rabbits with 0.5 mg (corresponds to 1500 mg isophorone/kg bw) and did not result in significant skin irritancy (Potokar et al., 1985). Only slight irritations were seen after application of 0.5 ml according to a modified Draize protocol (24 hours exposure) (Dutertre-Catella, 1976 and Truhaut, 1972). After application of 200 mg/kg isophorone (24 hours exposure) only slight erythema and desquamation during the first four days after 4 hours of exposure was observed (Esso Research, 1964). The findings were fully reversible.

Eye Irritation

Two Draize tests were performed on each 6 male and female rabbits. When applied undiluted to rabbits` eyes isophorone is moderately to severely irritating to the eyes (Esso Research, 1964; Truhaut et al., 1972). In one study marked irritation was observed which reversed within 14 days but was still present after 7 days (irritant scores are not mentioned; Esso Research, 1964), while in the other study, irritant scores of 14/80 (cornea), 0710 (iris) and 6/20 (conjunctiva) were reported and had reversed within 7 days (Truhaut et al., 1972).

Human Data

Eye Irritation

In humans irritating effects in eyes were observed after 7 minutes exposures to concentrations of >= 359 mg/ isophorone / m3 (Esso, 1965; see chapter 7.10.5 of IUCLID 5). The NOAEL for eye irritation in humans is considered to be 199 mg/m3. In a study with 12 volunteers eye irritation was reported at concentrations of 144 mg/m3 (Silverman et al., 1946; see chapter 7.10.5 of IUCLID 5).

Respiratory Irritation

The respiratory irritating potential of isophorone was determined in two investigations with 6 and 12 volunteers respectively. After exposure to 100 up to 230 mg/m3 isophorone for a few minutes, throat irritation was reported at >= 199 mg/m3 (Esso Research, 1965; Smyth and Seaton, 1940; see chapter 7.10.5 of IUCLID 5). Therefore the NOAEL for throat irritation in humans is considered to be 100 mg/m3. In a further investigation 12 volunteers were exposed to isophorone vapors for 15 minutes. At 144 mg/m3 chamber concentration eye, nose and throat irritation were reported (Silverman et al., 1946; see chapter 7.10.5 of IUCLID 5). 40 % of the exposed subjects objected isophorone odor at a concentration of 58 mg/m3 (10 ppm), and this concentration was judged to be the highest tolerable air level for 8 hour exposure.

The current legally binding German occupational exposure limit (TRGS 900) is 11 mg/m3(2 ppm) (Technical Rule for Hazardous Substances 900, German Federal Ministry of Labour and Social Affairs).


Justification for selection of skin irritation / corrosion endpoint:
The key study is a guideline study with Klimisch score 1 (reliable without restriction).

Justification for selection of eye irritation endpoint:
The test procedure of the key study in accordance with generally accepted scientific standards and described in sufficient detail with Klimisch score 1 (reliable without restriction).

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

According to the criteria of CLP Regulation 1272/2008 isophorone is not irritating to skin, but irritating to eyes (Eye Irrit. 2; H319: "Causes serious eye irritation."). Based on human experience isophorone is an respiratory irritant (H335: "May cause respiratory irritation.").