Registration Dossier

Administrative data

Description of key information

Skin irritation (OECD 404): irritating
Eye irritation (non-guideline study): corrosive
Respiratory irriation (similar to OECD 403): irritating

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:
15 August 2005 to 24 October 2005
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
GLP compliance:
yes
Species:
rabbit
Strain:
other: Japanese White
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Japan Laboratory Animals Inc.- Age at study initiation: 18 weeks (16 weeks upon receipt)- Weight at study initiation: 2.97-3.13 kg- Housing: individually in aluminium cages (W 360 x D 550 x H 350 mm; Nippon Cage Co., Ltd.) with wire mesh bottoms- Diet: RC4 pelleted diet (Oriental Yeast Co., Ltd., Lot Nos. 050620 and 050727) provided in stainless steel feeders, ad libitum- Water: tap water (Fulimi Water Union), provided via automatic water supply system, ad libitum- Acclimation period: 12 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 23±5- Humidity (%): 55±25- Air changes (per hr): 11-14- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: not required, untreated sites of the same animals served as control
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied: 0.5 mL
Duration of treatment / exposure:
3 min, 1 h, and 4 h
Observation period:
14 days
Number of animals:
3
Details on study design:
TEST SITE- Area of exposure: 2.5 x 2.5 cm²- Type of wrap if used: lint sheet covered and fixed with Kinesio tex tape (Kinesio Co., LTD.)REMOVAL OF TEST SUBSTANCE- Washing (if done): with absorbant cotton soaked with water for injection- Time after start of exposure: 3 min, 1 h, and 4 hSCORING SYSTEM: Draize scoring system
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48, and 72 h
Score:
2.7
Max. score:
4
Reversibility:
fully reversible within: 9 days
Remarks on result:
other: 4 h exposure duration; scaling on days 5-9
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48, and 72 h
Score:
3.7
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: 4 h exposure duration; eschar from 72 h post exposure until study termination
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48, and 72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: 4 h exposure duration; scaling from day 6 until study termination
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48, and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: 4 h exposure duration
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48, and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 13 days
Remarks on result:
other: 4 h exposure duration
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48, and 72 h
Score:
2.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: 4 h exposure duration
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48, and 72 h
Score:
2.7
Max. score:
4
Reversibility:
fully reversible within: 9 days
Remarks on result:
other: 1 h exposure duration; scaling on days 5-10
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48, and 72 h
Score:
2.7
Max. score:
4
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: 1 h exposure duration; scaling on days 8-12
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48, and 72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: 1 h exposure duration; scaling on days 7-12
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48, and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: 1 h exposure duration
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48, and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 9 days
Remarks on result:
other: 1 h exposure duration
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48, and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: 1 h exposure duration
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48, and 72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: 3 min exposure duration
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48, and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: 3 min exposure duration; scaling on days 6-8
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48, and 72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: 3 min exposure duration; scaling on days 6-12
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48, and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: 3 min exposure duration
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48, and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: 3 min exposure duration
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48, and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
other: 3 min exposure duration
Other effects:
After 4 h of exposure, the mean erythema score for all animals over 24, 48, and 72 h was 3.1, with one animal showing the max. score of 4. The effect was fully reversible in two animals within 7 and 9 days, respectively, whereas in the third animal the erythema score of 4 persisted until study termination. The mean oedema score after 4 h of treatment was 2.2, with a max. score of 4 in one animal after 24 h. Oedema were fully reversible within 7, 8, and 13 days, respectively. After 1 h of exposure, the mean erythema and oedema scores of all three animals over 24, 48, and 72 h were 2.7 and 2.0, respectively, with erythema scores never exceeding a score of 3 and oedema never exceeding a score of 2 in any of the animals. On day 10 following exposure none of the animals showed any skin reactions on this test site. Exposure to the test item for 3 min revealed mean erythema and oedema scores of 1.4 and 0.4, respectively, whereas erythema never exceeded a score of 2 and oedema never exceeded a score of 1. On day 8 of the observation period neither erythema nor oedema were observed in any of the animals at this test site. As other skin reactions scaling was observed in 2/3, 3/3, and 2/3 animals after 4 h, 1 h, and 3 min of exposure, respectively. Echar formation was observed only in 1/3 animals after 4 h of treatment, but in none animal after 1 h and 3 min of exposure. There were no findings in any of the animals at any test site suggesting corrosiveness of the test item. No skin reactions were observed in any animal on the control site. There were no abnormalities in the general condition and the body weight development of any animal during the observation period.
Interpretation of results:
other: CLP/EU GHS Category 2 (H315) according to Regulation (EC) No 1272/2008
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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The study predates the appropriate OECD test guideline and GLP. Although not in accordance with recent guideline (only 2 animals tested, of which one reveived an eye wash) the study is sufficient for assessment as the observations were severe enough for a classification as severe eye irritant (worst case outcome).
Qualifier:
no guideline followed
Principles of method if other than guideline:
0.1 mL of undiluted test material was instilled into the conjunctival sac of each of two albino rabbits. After 20 s, the treated eye of one animal was washed for 1 min. Following treatment for 4 h, the eye damage was examined.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
No details are given in the study report.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL- Amount applied: 0.1 mL
Duration of treatment / exposure:
4 h
Observation period (in vivo):
21 d
Number of animals or in vitro replicates:
21
Details on study design:
REMOVAL OF TEST SUBSTANCE- Washing: the eye of one animal was washed with tap water for 1 min- Time after start of exposure: 20 s after test material instillation SCORING SYSTEM: No scores were given in the study report.TOOL USED TO ASSESS SCORE: hand-slit lamp / fluorescein
Remarks on result:
other: No scores were given in the study report.
Irritant / corrosive response data:
Animal 12101 (without washing): - Cornea: slight opacity, where seen, 1-4 h; slight generalised opacity with severe swelling 1-2 days; generalised opacity increasing from mild to moderate 3-14 days, swelling of cornea severe; extensive, very fine, dense superficial vascularisation penetrating into cornea by 14 days with an ulcer in the centre. At 21 days, pannus with some areas staining yellow (still active ulcer)- Iris: could not see 1-4 h; slight injection (no flare) 1 day; swelling and deepened folds (no redness) 2-3 days; could not see 7 days; moderate congestion 9 days; could not see 14 or 21 days- Conjunctivae (redness): severe blanching, mild redness 1-4 h; moderate with necrotic area and haemorrhage 1-3 days; severe to moderate 7, 9, and 14 days; moderate 21 days- Conjunctivae (swelling): severe 1 h-14 days; by 7 days there were adhesions of tissues and eye could not be opened. At 9 days using a local anesthetic and "Q-tips" these adhesions were separated, somewhat. Swelling remained severe but eye could be partly opened. Mild to moderate 21 days.Conjunctivae (discharge): copious 1-4 h; copious purulent, Hemastix positive 1 day; moderate purulent 3-7 days; moderate purulent (becoming bloody) 9 days; moderate purulent 14 days; mild purulent 21 daysAnimal 12102 (with washing): - Cornea: mild opacity. where seen 1-4 h; generalalised mild to moderate opacity with moderate to severe swelling 1-14 days; vascularisation began penetrating (shallow type) into cornea by 7 days with an area in central cornea staining yellow (an ulcer). By 14 and 21 days pannus over > 3/4 of cornea with active ulcer in center.- Iris: could not see 1-4 h; moderate congestion (no flare) 1 day; moderate congestion with flare 2-3 days; moderate congestion 7 days but too opaque to see a flare- Conjunctivae (redness): severe blanching with mild redness 1-4 h; moderate to severe 2-7 days; mild 14 and 21 days- Conjunctivae (swelling): severe 1 h-1 day; moderate 2-7 days; slight 14 and 21 days- Conjunctivae (discharge): copious 1-4 h; copious purulent 1-3 days; mild purulent 7 days; none 14 days; mild purulent 21 days
Interpretation of results:
other: CLP/EU GHS Category 1 (H318) according to Regulation (EC) No 1272/2008
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

In the available key study (Bozo Research Center, Inc., 2005) the test item was investigated for skin irritating/corrosive properties according to the OECD test guideline 404, and in compliance with GLP. Each of three Japanese White rabbits was semiocclusively administered the undiluted test material for 3 min, 1 h, and 4 h. Untreated skin was covered in the same manner and served as control site. After 4 h of exposure, the mean erythema score for all animals over 24, 48, and 72 h was 3.1, with one animal showing the max. score of 4. The effect was fully reversible in two animals within 7 and 9 days, respectively, whereas in the third animal the erythema score of 4 persisted until study termination. The mean oedema score after 4 h of treatment was 2.2, with a max. score of 4 in one animal after 24 h. Oedema were fully reversible within 7, 8, and 13 days, respectively. After 1 h of exposure, the mean erythema and oedema scores of all three animals over 24, 48, and 72 h were 2.7 and 2.0, respectively, with erythema scores never exceeding a score of 3 and oedema never exceeding a score of 2 in any of the animals. On day 10 following exposure none of the animals showed any skin reactions on this test site. Exposure to the test item for 3 min revealed mean erythema and oedema scores of 1.4 and 0.4, respectively, whereas erythema never exceeded a score of 2 and oedema never exceeded a score of 1. On day 8 of the observation period neither erythema nor oedema were observed in any of the animals at this test site. As other skin reactions scaling was observed in 2/3, 3/3, and 2/3 animals after 4 h, 1 h, and 3 min of exposure, respectively. Eschar formation was observed only in 1/3 animals after 4 h of treatment, but in none animal after 1 h and 3 min of exposure. There were no findings in any of the animals at any test site suggesting corrosiveness of the test item. There were no abnormalities in the general condition and the body weight development of any animal during the observation period. Based on the outcome of the study the test item meets the criteria to be classified for skin irritancy (Xi, R38) according to 67/584/EEC and (Cat 2, H315) according to EC/1272/2008.

 

Eye irritation

In the available key study (DuPont, 1976) the test item was investigated for eye irritating properties. Two albino rabbits received 0.1 mL of the undiluted test material into the conjunctival sac of one eye, whereas the other eye remained untreated and served as control. The eye of one animal was washed for 1 minute with tap water 20 seconds after test material instillation, whereas the treated eye of the second animal remained unwashed. The test item produced severe corneal opacity, mild to moderate iritis, and severe conjunctival irritation in an unwashed rabbit eye. At 21 days the eye was left with a corneal ulcer, almost total corneal pannus, and mild conjunctival irritation; whereas the iris was not visible. The eye treated with the test item and promptly washed had moderate to severe corneal opacity, moderate irritis, and severe conjunctival irritation. At 21 days there remained a corneal ulcer, > 3/4 corneal pannus, and mild conjunctival irritation; the iris was normal. In conclusion, the test item is a severe eye irritant, which produces irreversible ocular effects. Hence, the test substance meets the criteria to be classified for risk of serious damage to eyes (Xi, R41) according to 67/584/EEC and irreversible effects on the eye (Cat 1, H318) according to EC/1272/2008.

 

Respiratory irritation

No study is available investigating the respiratory properties of the submission substance. However, data obtained from an acute inhalation toxicity study (Dow Chemical U.S.A., 1978) revealed strong irritating effects on the respiratory tract after inhalation exposure. 10 Fischer 344 rats per sex per dose were exposed to vaporised test material in a whole-body inhalation system for 1 and 6 h, respectively. The doses applied into the inhalation chamber were 40, 20, and 10 ppm (equal to 0.2533, 0.1267, and 0.0633 mg/L) for 1 h and 7, 4, and 2 ppm (equal to 0.0443, 0.0253, and 0.0127 mg/L) for the 6 h exposure duration. The LC50 determined was 4.4 ppm (equal to 0.0281 mg/L). In the 6 h exposure experiment rats exposed to the test material showed progressively increased signs of eye and nasal irritation and respiratory difficulties during treatment. Just after exposure there were signs of eye irritation, and dried dark red-brown exudate on the noses; respiratory difficulties appeared to have diminished, only slight rales being observable in a few rats. 16 h later there was evidence of severe respiratory distress in all animals exposed. Clinical signs in the animals treated for 1 h developed much more quickly than in the 6 hour exposure experiment. During exposures, all rats showed signs of eye and nasal irritation and respiratory difficulties. After exposure and a 30 min venting period, both male and female rats, showed diminished signs of respiratory difficulties, but did show laboured breathing, stains on their noses, and appeared lethargic.

The incidence of the effects observed showed a clear dose-relationship. Gross pathology revealed generally effects on the respiratory tract, as well as irritating effects to the eyes.

Data obtained from the repeated dose toxicity study via the inhalation route (The Dow Chemical Company, 1980) also indicate irritating effects to the respiratory system. 20 Fischer 344 rats per sex per dose were treated with vapour of the test item in a whole-body inhalation system for 6 h/day and 5 days/week for 13 consecutive weeks at doses of 25, 80, and 250 ppb (equivalent to 1.583, 0.507, and 0.158 mg/m³), whereas control animals were treated with the vehicle only (air). At the end of the exposure period 10 animals per sex per dose were sacrificed. In order to assess the reversibility of treatment-related effects and to identify potential latent effects of exposure, the remaining 10 animals per sex per dose were maintained for further 30 and 90 days of observation, respectively. Although no clinical signs were observed, histopathological examination revealed hyperplasia of the respiratory epithelium lining the nasal turbinates was observed in 4/10 males and 5/10 females of the high dose group and 3/10 males of the mid dose group. However, the effect was reversible, since it was not observed in any of the recovery groups.

In conclusion, the registered substance exhibits transient respiratory irritating properties in a dose-dependent manner. According to the Guidance on the Application of Regulation (EC) No 1272/2008, Section 3.8.5.2, the registered substance would meet the criteria for classification with STOT SE Cat 3 (H335, May cause respiratory irritation), since “Category 3 effects should be confined to changes, whether functional or morphological, occurring in the upper respiratory tract (…). Localised irritation with associated adaptive responses (…) may occur and are consistent with Category 3 responses.” However, due to the fact that rats are obligatory nasal breathing, the effects observed are considered to be less severe in humans. In addition, the substance meets the criteria to be classified as very toxic after inhalation (T+, R26 according to 67/584/EEC and Cat 1, H330 according to EC/1272/2008) and safety precautions conducted for acute inhalation toxicity will also cover the risk of respiratory irritation. This is in accordance with Annex I: 3.8.2.2.1 of the Guidance on the Application of Regulation (EC) No 1272/2008: “(e) this special classification would occur only when more severe organ effects including in the respiratory system are not observed”. In the acute inhalation toxicity study strong irritating effects on the respiratory tract were observed, which caused mortality and lead to the classification of acute toxicity via inhalation. In accordance with Section 3.8.5.2: “… a double classification for the same effect has to be avoided”, classification for respiratory irritation is considered superfluous and therefore not warranted.


Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on this data, the registered substance meets the criteria to be classified for risk of serious damage to eyes (Xi, R41) and skin irritancy (Xi, R38) according to 67/584/EEC and irreversible effects on the eye (Cat 1, H318) and skin irritancy (Cat 2, H315) according to EC/1272/2008.