Registration Dossier

Administrative data

Description of key information

Skin irritation:
- not irritating in rabbits and rats:
- one study according to OECD Guideline 404; GLP; RL1; undiluted test material applied to the intact skin of 3 animals for 4 hours; very slight to moderate cutaneous reactions (erythema grade 1 and 2) were observed for up to 72 hours (2/3 animals) or 4 d (1/3 animals); fully reversible within 4 - 5 days
- one study according to US FHSA Federal regulation 16 CFR 1500.41; pre-GLP; RL2; undiluted test material applied to intact and abraded skin sites for 24 h under occlusive dressing; very slight edema and/or erythema (grade 1) were observed in 5/6 animals; reversibility cannot be judged due to short recovery period
- non-guideline study in rat, pre-GLP; RL3 (Documentation insufficient for assessment)
Eye irritation:
- not irritating in rabbits:
- one study according to OECD Guideline 405; GLP; undiluted test material applied to left eye of 3 animals without washing; slight redness (grade 1) of the conjunctiva in 2/3 animals after 1 hour, no ocular reactions 24, 48 and 72 hours after treatment
- one study similar to OECD Guideline 405; pre-GLP; undiluted test material applied to the eye of 3 animals, not indicated if washing was done; slight redness in 2/3 animals was fully reversible within 3 days; no cornea or iridial effects

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:
1993-07-20 to 1993-07-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted 12th May 1981
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.3 ± 0.1 kg
- Housing: individually in polystyrene cages
- Diet (e.g. ad libitum): pelleted diet, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18±3
- Humidity (%): 50±20
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated left flank served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
7 d
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 6 cm²
- Type of wrap if used: gauze patches were held in contact with the skin by means of adhesive hypoallergic aerated semi-occlusive dressing and restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no (after removal of the patches, no residual test substance was observed)

SCORING SYSTEM: according to OECD guideline 404
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 4 d
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 4 d
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 5 d
Irritation parameter:
edema score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Very slight to moderate cutaneous reactions (erythema grade 1 and 2) were observed for up to 72 h (2/3 animals) or 4 d (1/3 animals) after the removal of the dressing. From day 3 to 6, a dryness of the skin was observed at the treatment site in 1/3 animals. During the whole observation period, the animals were free of edema.
All effects were fully reversible within 4 or 5 days.
Other effects:
no other effects reported

 

Rabbit number

reaction

score after 1h/24h/48h/72h/4d/5d/6d/7d

1

erythema (max score 4)

0/1/1/1/0/-/-

edema (max score 4)

0/0/0/0/0/-/-

2

erythema (max score 4)

1/2/2/1/0/-/-

edema (max score 4)

0/0/0/0/0/-/-

3

erythema (max score 4)

1/2/2/2/1/0/0

edema (max score 4)

0/0/0/0S/0S/0S/0

- = no cutaneous examination performed; S = dryness of skin

Interpretation of results:
GHS criteria not met
Conclusions:
ETMA is not irritating to rabbit skin
Executive summary:

In a primary dermal irritation study according to OECD guideline 404, adopted 12 May 1981, 3 male New Zealand white rabbits were dermally exposed to 0.5 mL of ETMA (99.94 % a.i.) for 4 h to ca. 6 cm² body surface area. Animals then were observed for 6 days. Irritation was scored by the method of Draize.

Very slight to moderate cutaneous reactions (erythema grade 1 and 2) were observed for up to 72 hours (2/3 animals) or 4 d (1/3 animals) after the removal of the dressing. From day 3 to 6, a dryness of the skin was observed at the treatment site in 1/3 animals. During the whole observation period, the animals were free of edema. All effects were fully reversible within 4 or 5 days.

In this study, ETMA is not a dermal irritant.

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:
1993-07-27 to 1993-07-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted 24th February 1987
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.6 ± 0.1 kg
- Housing: individually in polystyrene cages
- Diet (e.g. ad libitum): pelleted diet, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18±3
- Humidity (%): 50±20
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated right eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
The eyes were not rinsed after administration of the test substance.
Observation period (in vivo):
72 h
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: according to OECD guideline 405


TOOL USED TO ASSESS SCORE: fluorescein (only for 24 h observation)
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
chemosis score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
A slight redness (grade 1) of the conjunctiva was noted in 2/3 animals after 1 hour. No ocular reactions were observed 24, 48 and 72 hours after treatment.

 

Rabbit number

reaction

Scores after

1/24/48/72 h

1

Conjunctivae, chemosis

0/0/0/0

Conjunctivae, redness

0/0/0/0

Conjunctivae, discharge

E/0/0/0

Iris

0/0/0/0

Cornea, opacity

0/0/0/0

2

Conjunctivae, chemosis

0/0/0/0

Conjunctivae, redness

1/0/0/0

Conjunctivae, discharge

E/0/0/0

Iris

0/0/0/0

Cornea, opacity

0/0/0/0

3

Conjunctivae, chemosis

0/0/0/0

Conjunctivae, redness

1/0/0/0

Conjunctivae, discharge

E/0/0/0

Iris

0/0/0/0

Cornea, opacity

0/0/0/0

E =Scoring obscured by residual test substance

max scores: conjunctival chemosis: 4, conjunctival redness: 3, conjunctival discharge: 3, iris lesions: 2, corneal lesions: 4

Interpretation of results:
GHS criteria not met
Conclusions:
ETMA is not irritating to the rabbit eye.
Executive summary:

In a primary eye irritation study according to OECD guideline 405, adopted 24 February 1987, 0.1 mL of ETMA (99.94% a.i.) was instilled into the conjunctival sac of 3 young adult New Zealand White rabbits without washing. The untreated right eye served as control. Animals then were observed for 3 days.  Irritation was scored by the method of Draize.

Slight redness (grade 1) of the conjunctiva was noted in 2/3 animals after 1 hour. No ocular reactions were observed 24, 48 and 72 hours after treatment. 

In this study, ETMA is 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

Skin irritation

In a primary dermal irritation study according to OECD guideline 404, adopted 12 May 1981, 3 male New Zealand white rabbits were dermally exposed to 0.5 mL of ETMA (99.94 % a.i.) for 4 h to ca. 6 cm² body surface area. Animals then were observed for 6 days. Irritation was scored by the method of Draize.

Very slight to moderate cutaneous reactions (erythema grade 1 and 2) were observed for up to 72 hours (2/3 animals) or 4 d (1/3 animals) after the removal of the dressing. From day 3 to 6, a dryness of the skin was observed at the treatment site in 1/3 animals. All effects were fully reversible within 4 or 5 days.

In this study, ETMA is not a dermal irritant.

Supporting studies:

In a primary dermal irritation study according to US FHSA Federal regulation: 16 CFR 1500.41, 6 rabbits were dermally exposed to 0.5 mL of ETMA (purity not given in the study report, but according to sponsor >98% typical purity) to approximately 6.25 cm² body surface area. Two application sites per animal were treated, one site was left intact, the other was abraded. Test sites were covered with an occlusive dressing for 24 hours. Animals were observed for 72 hours. Irritation was scored according to FHSA Federal guideline 16 CFR 1500.41. This scoring system is similar to OECD guideline 404.

Very slight edema (grade 1) and very slight erythema (grade 1) was observed in 1/6 animal after 24 h, very slight edema alone was observed in 4/6 animals at the 24 h reading. 4/6 animals had very slight edema (grade 1) and very slight erythema (grade 1) after 72 h, 1/6 animals edema alone was observed in 1/6 animals after 72 h. 1/6 animals did not show any irritant response at any time point. The treated abraded skin sites showed identical effects as the intact sites.

The observation time did not extend beyond 72 hours, even though a slight skin response was still present at that time in 5 animals. Therefore, the full reversibility of the effects can not be proved.

The treated abraded skin sites showed identical effects as the intact sites.

In this test, the test substance showed only a slight irritating activity.

Study performance does not comply with requirements of the relevant recent EU and OECD guidelines, were semi-occlusive dressing, an exposure period of 4 hours, treatment of only intact skin and a recovery period of up to 14 days is stipulated. Study is therefore of limited adequacy for C&L purposes due to intensity of the exposure regime and too short recovery period.

In a primary dermal irritation study, rats were exposed to undiluted ETMA (98.8% a.i.).

No gross abnormalities were observed except for slight desquamation after the fourth application of the material. According to the study authors, the material is practically non-irritatant to rat skin.

No details on the applied method are available. Thus, the study is considered not reliable and not appropriate for C&L purposes.

Eye irritation

In a primary eye irritation study according to OECD guideline 405, adopted 24 February 1987, 0.1 mL of ETMA (99.94% a.i.) was instilled into the conjunctival sac of 3 young adult New Zealand White rabbits without washing. The untreated right eye served as control. Animals then were observed for 3 days.  Irritation was scored by the method of Draize.

Slight redness (grade 1) of the conjunctiva was noted in 2/3 animals after 1 hour. No ocular reactions were observed 24, 48 and 72 hours after treatment. 

In this study, ETMA is not irritating to the rabbit eye.

 

This finding is supported by the following study:

In a primary eye irritation study, one drop of ETMA (98.8% a.i.) was instilled into the eye of 3 New Zealand White rabbits (sex not given). Animals then were observed for 7 days. It was not indicated in the study report, if the eyes were washed after treatment.  Irritation was scored by the method of Draize.  

Instillation of one drop of the test substance into the rabbit eye resulted in moderate initial pain in 2 animals and severe initial pain in one animal. Only transient irritation of the conjunctivae was observed: grade 1 redness (some blood vessels hyperaemic (injected)) was present after 1-2 h in two animals. In one of these, the effect has resolved at the 1 d observation. In the second animal, grade 1 redness was fully reversible within 3 days. The same two animals showed grade 1-2 conjunctival discharge at the 1-2 h observation, which has resolved at the 1 day observation. No effects to the cornea or iris were observed.  

In this study, ETMA is not irritating to the rabbit eye.

Respiratory irritation

No data on the respiratory irritation of ETMA are available.

 

There are no data gaps for the endpoint irritation/corrosion. No human information is available for this endpoint. However, there is no reason to believe that these results would not be applicable to humans.


Justification for classification or non-classification

Based on the available data, ETMA does not need to be classified for eye irritation or skin irritation according to regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.