Registration Dossier

Administrative data

Description of key information

Skin Irritation, rabbit: non-irritating (Huels, Muermann 1992)
Skin Irritation, rabbit: non-irritating (DuPont Haskell, Majkut 1966)
Eye irritation, rabbit: irritant, average scores day 1-3: cornea 0.78, iris 0.45, erythema 2.67, chemosis 1.67, reversible in 20 days (Huels, Muermann 1992)
Eye Irritation, rabbit: irritant, moderate corneal injury, reversible (DuPont Haskell, Reinke 1966)
Respiratory irritation: clear signs of irritation noted in acute inhalation toxicity (cf. 7.2.2)

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
Study period:
1992-11-09 to 1992-11-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: Kleine Weisse Russen, strain Chbb:HM, SPF
Details on test animals and environmental conditions:
TEST ANIMALS
- Kleine Weisse Russen, strain Chbb:HM, SPF
- Age at study initiation: adult
- Weight at study initiation: 2 - 3 kg
- Housing: conventional, individual animals in stainless steel cages
- Diet: ad libitum, Ssniff K 4 Alleindiaet fuer Kaninchen
- Water: communal drinking water ad libitum
- Acclimation period: > 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: From: 1992-11-09 To: 1992-11-13
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume): 0.5 cm3
- Concentration (if solution): undiluted

VEHICLE
- none
Duration of treatment / exposure:
4 hours
Observation period:
30-60 min, 24 h, 48 h, and 72 h after removal of patch

Number of animals:
3 males

Details on study design:
TEST SITE
- Area of exposure: approximately 6cm2
- Type of wrap: gauze patch, held in place with non-irritating tape, semi-occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing: with warm water
- Time after start of exposure: 4 hours

SCORING SYSTEM: OECD Guideline 404: Table: Grading of skin reactions
Irritation parameter:
erythema score
Basis:
mean
Remarks:
all animals had score 0 at all times
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks:
no erythema or eschar formation at any time
Irritation parameter:
edema score
Basis:
mean
Remarks:
all animals had score 0 at all times
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks:
no edema formation at any time
Irritant / corrosive response data:
No signs of dermal irritation were observed 30-60 min after the removal of the patches. Neither were any skin reactions (erythema or edema) found at the later observation time points (24, 48, and 72 hours)
Other effects:
none observed
Interpretation of results:
GHS criteria not met
Conclusions:
The substance does not meet GHS classification criteria for skin irritation.
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1966
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Clipped dorsal rabbit skin was wrapped with impervious film (secured by tape). Test substance was introduced through an opening (which was then sealed). Animals immobilized in FDA-type wooden stocks for up to 60 min. or 6 hours, then fitted with collars for 24 hrs to prevent oral uptake. 14-day observation with assessment of skin reactions, necropsy.
GLP compliance:
no
Species:
rabbit
Strain:
other: Albino, not otherwise specified
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
1) 2250 mg/kg bw (4.6 ml per animal, application site loosely covered)
2) 2250 mg/kg bw (5.9 ml per animal, application site wrapped with occlusive patch)
3) 3400 mg/kg bw (11.2 ml per animal, application site wrapped with occlusive patch)
- Concentration (if solution): 100% undiluted

VEHICLE
-none
Duration of treatment / exposure:
1) 55 minutes: 2250 mg/kg bw (application site loosely covered)
2) 1 hour: 2250 mg/kg bw (application site wrapped with occlusive patch)
3) 6 hours: 3400 mg/kg bw (application site wrapped with occlusive patch)
Observation period:
14 days
Number of animals:
3 (one per dose and type of coverage)
Details on study design:
TEST SITE
- Area of exposure and % coverage: no data
- Type of wrap if used: impervious film, secured at each end with Elastoplast. Opening in the center back to introduce test substance, then closed with strip of adhesive
- 2-inch polyethylene collars to prevent oral uptake during first 24 hours (before washing)
- One experiment with 2250 mg/kg bw performed without occlusive wrap, loosely covered

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water, then dried
- Time after start of exposure: 24 hours

SCORING SYSTEM:
- none; verbal descriptions of findings
Irritation parameter:
erythema score
Remarks:
derived from verbal description of effects
Basis:
animal #3
Remarks:
3400 mg/kg bw, 6 hours exposure, occlusive
Time point:
other: days 1-5
Score:
>= 1 - <= 2
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: mild to moderate on day 1, diminishing
Irritant / corrosive response data:
No corrosion observed
Other effects:
No systemic effects observable
Interpretation of results:
slightly irritating
Remarks:
Criteria used for interpretation of results: EU
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:
supporting study
Study period:
1966
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
Simple screening test, right eyes of two animals instilled, one washed after 20 seconds
GLP compliance:
no
Species:
rabbit
Strain:
other: Albino, not otherwise specified
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): 100% (used as received)

VEHICLE
- none
Duration of treatment / exposure:
Animal 1: washed 20 seconds after instillation with tap water for 1 minute
Animal 2: not washed
Observation period (in vivo):
1 hour after instillation, 1, 2, 3, 4, 7, and 14 days thereafter
Number of animals or in vitro replicates:
2 (one washed)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): in 1 animal, 1 minute with tap water
- Time after start of exposure: 20 seconds

SCORING SYSTEM:
- no formal scoring (detailed description of findings and rating in the summary)

TOOL USED TO ASSESS SCORE:
- hand-slit lamp
- biomicroscope with fluorescein 5% (after the day of treatment)
Irritation parameter:
cornea opacity score
Remarks:
derived from verbal description of findings
Basis:
animal #2
Remarks:
not washed
Time point:
other: days 1 + 2
Score:
ca. 2
Max. score:
4
Reversibility:
not fully reversible within: 14 days (trace microscopic change)
Remarks on result:
other: Localized injury on day 1, moderate edema on day 2
Irritation parameter:
cornea opacity score
Remarks:
derived from verbal description of findings
Basis:
animal #2
Remarks:
not washed
Time point:
other: days 3 - 4
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 14 days (trace microscopic change)
Remarks on result:
other: slight microscopic change
Irritation parameter:
iris score
Remarks:
derived from verbal description of findings
Basis:
animal #2
Remarks:
not washed
Time point:
other: days 1 + 2
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 3 days
Remarks on result:
other: Minimal congestion at 1 hour, slight at 2 days (possibly due to animal having rubbed the eye)
Irritation parameter:
conjunctivae score
Remarks:
derived from verbal description of findings
Basis:
animal #2
Remarks:
not washed
Time point:
other: 1 hour
Score:
ca. 2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Moderate swelling and discharge, mild redness
Irritation parameter:
conjunctivae score
Remarks:
derived from verbal description of findings
Basis:
animal #2
Remarks:
not washed
Time point:
other: day 4
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Mild irritation

Instilllation of trimethy orthoformate produced moderate corneal injury, slight transient iritic congestion, and mild conjunctivitis; only minimal microscopic corneal effects were noted at 7 -14 days.

Prompt washing was ineffective in reducing injury.

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992-11-16 to 1992-12-16
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
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: Kleine Weisse Russen, strain Chbb:HM, SPF
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Kleine Weisse Russen, strain Chbb:HM, SPF
- Age at study initiation: adult
- Weight at study initiation: 2 - 3 kg
- Housing: conventional, individual animals in stainless steel cages
- Diet: ad libitum, Ssniff K 4 Alleindiaet fuer Kaninchen
- Water: communal drinking water ad libitum
- Acclimation period: > 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: From: 1992-11-16 To: 1992-12-07
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 cm3 liquid test substance placed into the conjunctival sac of one eye
- Untreated eye serves as control

VEHICLE
- none
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
1, 24, 48, 72 hours, 6, 8, 10, 13, 17, 20 days after application

Number of animals or in vitro replicates:
3 males
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: with warm physiological saline
- Time after start of exposure: 24 hours after application (after fluorescein test)

FLUORESCEIN TEST
- 24, 48, 72 hours and 6 days after application

SCORING SYSTEM: OECD Guideline 405: Table 1: Grading of ocular lesions

TOOL USED TO ASSESS SCORE: hand-slit lamp / fluorescein
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
fully reversible within: 20 d
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 17 d
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 17 d
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 20 d
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 17 d
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 17 d
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 d
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 17 d
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.45
Max. score:
2
Reversibility:
fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible
Remarks:
no changes at any time point
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.78
Max. score:
4
Reversibility:
fully reversible within: 6 d
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 h
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 d
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 6 d

Time post application

 

1 h

 

 

24 h

 

 

48 h

 

 

72 h

 

 

6 d

 

8,

10,

13 d

 

17 d

 

 

20 d

 

Animal

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

Conjunctivae: erythema

2

2

2

2

3

3

2

3

3

2

3

3

2

2

2

1

1

1

0

0

1

0

Conjunctivae: chemosis

1

2

2

1

2

2

1

2

2

1

2

2

1

1

1

1

0

1

0

0

0

0

Iris

0

0

0

0

1

1

0

1

1

0

0

0

0

0

0

0

0

0

0

0

0

 

 

0

Cornea

1

1

1

0

1

1

0

1

2

0

1

1

0

0

0

0

0

0

0

0

0

 

 

0

Examination w. fluorescein

 

 

0

3

4

0

3

1

0

1

1

0

0

0

 

 

 

Exudation

x

x

x

 

x

x

 

x

x

 

 

 

 

 

 

Exudation (white, slimy)

x

 

 

 

x

x

 

x

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conjunctivae incl. nictitating membrane: bleeding

 

 

 

slight

severe

severe

x

x

x

x

x

x

 

 

 

 

 

 

 

 

 

 

 

 

Iris: reddened

 

 

 

 

x

x

 

x

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

From the numerical scores of the individual animals at 24, 48, and 72 hours, the following averages were calculated:

 

Animal 1

Animal 2

Animal 3

Average

Conjunctivae: erythema

2.00

3.00

3.00

2.67

Conjunctivae: chemosis

1.00

2.00

2.00

1.67

Iris

0

0.67

0.67

0.45

Cornea

0

1.00

1.33

0.78

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin:

A key study conducted 1992 according to guideline OECD 404 and under GLP is available. The study is considered to be relevant, reliable (Klimisch 1) and adequate for the purposes of risk assessment, classification and labelling. No irritating effect was observed in any of the three rabbits tested.

A supporting study (non-GLP, 1962) with much higher doses and 6-hour exposure essentially confirms these findings; the author concludes that trimethyl orthoformate is non-irritating, although slight transient erythema was observed in one animal.

No skin irritation was found during the dermal induction phase in two guinea pig sensitisation studies (cf. section 7.4.1).

Eye:

A key study conducted 1992 according to guideline OECD 405 and under GLP is available. The study is considered to be relevant, reliable (Klimisch 1) and adequate for the purposes of risk assessment, classification and labelling. Corneal opacity (3-day average score 0.78) and iritis (average score 0.45) were reversible in 6 days. Erythema (average score 2.67) and chemosis (average score 1.67) of the conjunctivae were reversible within 17-20 days.

A supporting study (non-GLP, 1962) essentially confirms the findings; corneal effects subsided to trace microscopic changes after 14 days. Immediate washing with tap water did not reduce the effects.

Respiratory:

Clear signs of respiratory irritation were observed in a rat inhalation toxicity study (cf. section 7.2.2).


Effects on eye irritation: moderately irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on the eye irritation effects observed in eye irritation studies and respiratory irritation effects observed in rat acute inhaltion toxicity studies, the substance meets GHS classification criteria for serious eye damage/irritation category 2 (H319) and STOT-respiratory tract irritation - single exposure category 3 (H335)