Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion: 


Three studies are available for evlaution of skin irritation potential of the substance. The skin irritation potential of the substance was evalauted in a study conducted according to the patch test technique as described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959) of the US Association of Food and Drug Officials (AFDO). The substance was applied to each side of the shaved flank region of 6 Russian breed rabbits in quantities of 0.5 ml. The shaved skin area on the left side was slightly scarified just before treatment. A gauze patch of 2.5 x 2.5 cm laden with test substance was applied immediatly to the prepared skin. The patch was covered with an impermeable foil of 5x5 cm, which was fixed to the body of the animals with adhesive tape. The gauze patches were removed 24 hours after application. The reaction of the skin was appraised upon removal during an observation period of 9 days. A slight erythema without oedema was observed with the intact skin. Hence, the substance does not warrant classification as per the Regulation EC No. 1272/2008.


In another supporting study, the substance was observed to cause slight irritation, however, it does not warrant classification according to Regulation EC No 1272/2008 for skin irritation, as the scores were below the threshold values. A study with repetitive skin exposure with the the substance is available. In this study, the substance was found to cause increasing moderate to marked irritation when applied repeatedly to the rabbit skin. However, as the exposure was repeated for consecutive 5 days and the exposure duration was 24 hours for each application, this was considered to be a deviation from the guideline and hence the study was disregarded.


 


Eye irritation


Three studies are available for evlaution of eye irritation potential of the substance. A key study was performed to determine the eye irritation for the substance according to Hazardous Substances Regulations" under the USA. Federal Hazardous Substances Labelling Act Sect. 191.12 (February 1965), with slight modification. 100 mg of the test compound were instilled into the conjunctival sac of the left eye. The eyelids were then held closed for 1 second. The right eye served as a control. After 30 seconds the compound was, as far as possible, flushed out of the eyes of three of the rabbits with warm water for 1 minute. The rabbits were examined and the scored for the effects on eye 1, 24, 48 and 72 hours after application of the test compound and for any further period that was considered necessary. A mild to severe conjunctival reaction was seen in all treated eyes one hour after application of the compound. This had improved slightly by 24 hours. The unwashed eyes did not show very much change after this until day 10 when small areas of necrosis were seen in the nictitating membranes. These were still present at termination (day 14). The washed eyes however, had returned to normal by day 6 (2/3) and day 10 (1/3). A corneal reaction consisting of slight opacity and damage to the superficial epithelium was seen in all treated eyes at one hour. This was still present at 24 hours and thereafter, the eyes returned to normal by 48 hours (2/3 washed eyes), 72 hours (2/3 unwashed eyes) and 6 days (1/3 washed, 1/3 unwashed eyes). Increased folding of the iris was seen in all unwashed eyes at 24 hours. These had returned to normal by 48 hours (1/3) and 72 hours (2/3). The testing has been carried out with eyes of 3 rabbits washed after 30 seconds, while remaining 3 rabbits never received any washing. However, the modern guidelines correctly recommend "If the solid test substance has not been removed from the eye of the test animal by physiological mechanisms at the first observation time point of 1 hour after treatment, the eye may be rinsed with saline or distilled water." Further, the washing/flushing the eyes after exposure is a more realistic scenario for workers, as such an exposure will lead to an attempt to flush out the substance entered in the eye as soon as possible. Hence, not washing the eyes at all is considered to be an elevated testing condition, and the results obtained with such an exposure are not considered for hazard assessment. In line with the above argument, the findings of necrosis of the nictitating membranes of unwashed eyes seen in this study, is not considered for the hazard conclusion. The scoring for washed eyes is below the threshold of the classification, hence the substance is classified as not an eye irritant. In two other supporting studies though, the substance was shown to be a non-irritant to the eyes. However, taking the results from the available studies into account, the substance is considered to be not an eye irritant.

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:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
other: test technique as described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959) of the US Association of Food and Drug Officials (AFDO).
Deviations:
yes
Remarks:
occlusive and abraded testing represent elevated testing conditions according to today's standards. This has to be taken into account for the overall hazard and risk assessment.
Principles of method if other than guideline:
None
GLP compliance:
no
Species:
rabbit
Strain:
other: Russian breed
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Housing: single metal cages
- Diet (e.g. ad libitum): Nafag ad libitum
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18+/-1 °C
- Humidity (%): 55+/-5 %
- Photoperiod (hrs dark / hrs light): 14 hous light/day
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
not specified
Controls:
no
Amount / concentration applied:
The substance was applied to each side in quantities of 0.5 ml.
Duration of treatment / exposure:
24 h
Observation period:
The gauze patches were removed 24 hours after application. The reaction of the skin was appraised upon removal during an observation period of 9 days.
Number of animals:
6 (3 Males and 3 Females)
Details on study design:
6 rabbits (3 males; 3 females) of the Russian breed, weighing 1.4 to 1.7 kg, were shaved one day before treatment with an electric clipper on the flanks. The shaved skin area on the left side was slightly scarified just before treatment. A gauze patch of 2.5 x 2.5 cm laden with test substance was applied immediatly to the prepared skin. The patch was covered with an impermeable foil of 5x5 cm, which was fixed to the body of the animals with adhesive tape. The substance was applied to each side in quantities of 0.5 ml. The gauze patches were removed 24 hours after application. The reaction of the skin was appraised upon removal during an observation period of 9 days.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: with intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: with intact skin
Irritant / corrosive response data:
None
Other effects:
None

Scores for erythema

Erythema with intact skin
Animal Observation time
24 hours 48 hours 72 hours
1 0 0 0
2 0 0 0
3 0 0 0
4 1 0 0
5 0 0 0
6 1 0 0
Mean 0.33 0 0

Erythema with abraded skin
Animal Observation time
24 hours 48 hours 72 hours
1 1 1 0
2 1 1 0
3 1 0 0
4 1 0 0
5 1 1 1
6 1 0 0
Mean 1.00 0.50 0.17

Scores for oedema

Oedema with intact skin

Animal Observation time
24 hours 48 hours 72 hours
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
6 0 0 0
Mean 0 0 0

Oedema with abraded skin
Animal Observation time
24 hours 48 hours 72 hours
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
6 0 0 0
Mean 0 0 0
Interpretation of results:
other: Not classified as irritant according to the CLP Regulation (EC) No.1272/2008
Conclusions:
The substance was found to cause a slight erythema without oedema with the intact skin. Hence, it does not warrant classification as per the Regulation EC No. 1272/2008.
Executive summary:

The skin irritation potential of the test item was evalauted in a study conducted according to the patch test technique as described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959) of the US Association of Food and Drug Officials (AFDO). The test item was applied to each side of the shaved flank region of 6 Russian breed rabbits in quantities of 0.5 ml. The shaved skin area on the left side was slightly scarified just before treatment. A gauze patch of 2.5 x 2.5 cm laden with test substance was applied immediatly to the prepared skin. The patch was covered with an impermeable foil of 5x5 cm, which was fixed to the body of the animals with adhesive tape. The gauze patches were removed 24 hours after application. The reaction of the skin was appraised upon removal during an observation period of 9 days. A slight erythema without oedema was observed with the intact skin. Hence, the test item does not warrant classification as per the Regulation EC No. 1272/2008.

Endpoint:
skin corrosion: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
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
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
other: Hazardous Substances Regulations" under the U.S.A. Federal Hazardous Substances Labelling Act Sect. 191.12 (February 1965), with slight modification.
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
no
Species:
rabbit
Strain:
other: Porton strain
Details on test animals or tissues and environmental conditions:
Animals:
Healthy Neu Zealand White rabbits (Porton strain) aged 11-12 weeks with average body weights of 2.43 kgs. (M) and 2.20 kgs. (F), bred on the premises and maintained under a semi-barrier system. Six rabbits (3 M and 3 F) were acclimatised in the test area for one week prior to the start of the trial.

Husbandry:
The rabbits were caged singly in an experimental room maintained at a temperature of 20 °C. (+/- 1 °C) and a relative humidity of 50-70 % Animals were exposed to artificial light for 10 hours daily from 08.00 -10 .00 hours. A commercial irradiated diet (Styles-Oxoid) was fed ad lib. Sterile filtered water was available at all times.
Vehicle:
not specified
Amount / concentration applied:
100 mg
Duration of treatment / exposure:
None
Observation period (in vivo):
The rabbits were examined 1, 24, 48 and 72 hours after application of the test compound and for any further period that was considered necessary.
Number of animals or in vitro replicates:
6 animals
Details on study design:
The test was carried out in accordance with the procedure set out in the "Hazardous Substances Regulations" under the U.S.A. Federal Hazardous Substances Labelling Act Sect. 191.12 (February 1965), with slight modification. The eyes of the experimental animals were examined and found normal prior to the test. 100mg. of the test compound were instilled into the conjunctival sac of the left eye. The eyelids were then held closed for 1 second. The right eye served as a control. After 30 seconds the compound was, as far as possible, flushed out of the eyes of three of the rabbits with warm water for 1 minute. The rabbits were examined 1, 24, 48 and 72 hours after application of the test compound and for any further period that was considered necessary. The ocular reactions were scored by the method described in "Appraisal of the Safety of Chemicals in Food Drugs and Cosmetics" page 51, published by the Association of Food and Drug Officials of the U.S.A.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.55
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.66
Max. score:
2
Reversibility:
not fully reversible within: 10 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.3
Max. score:
3
Reversibility:
fully reversible within: 10 days
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritant / corrosive response data:
A mild to severe conjunctival reaction was seen in all treated eyes one hour after application of the compound. This had improved slightly by 24 hours. The unwashed eyes did not show very much change after this until day 10 when small areas of necrosis were seen in the nictitating membranes. These were still present at termination (day 14). The washed eyes however, had returned to normal by day 6 (2/3) and day 10 (1/3). A corneal reaction consisting of slight opacity and damage to the superficial epithelium was seen in all treated eyes at one hour. This was still present at 24 hours and thereafter, the eyes returned to normal by 48 hours (2/3 washed eyes), 72 hours (2/3 unwashed eyes) and 6 days (1/3 washed, 1/3 unwashed eyes). Increased folding of the iris was seen in all unwashed eyes at 24 hours. These had returned to normal by 48 hours (1/3 and 72 hours (2/3)).
Other effects:
None
Interpretation of results:
other: Not classified as irritant according to the CLP Regulation (EC) No.1272/2008
Conclusions:
The substance is classified as not an eye irritant.
Executive summary:

A key study was performed to determine the eye irritation for the substance according to Hazardous Substances Regulations" under the U.S.A. Federal Hazardous Substances Labelling Act Sect. 191.12 (February 1965), with slight modification. 100 mg of the test compound were instilled into the conjunctival sac of the left eye. The eyelids were then held closed for 1 second. The right eye served as a control. After 30 seconds the compound was, as far as possible, flushed out of the eyes of three of the rabbits with warm water for 1 minute. The rabbits were examined and the scored for the effects on eye 1, 24, 48 and 72 hours after application of the test compound and for any further period that was considered necessary. A mild to severe conjunctival reaction was seen in all treated eyes one hour after application of the compound. This had improved slightly by 24 hours. The unwashed eyes did not show very much change after this until day 10 when small areas of necrosis were seen in the nictitating membranes. These were still present at termination (day 14). The washed eyes however, had returned to normal by day 6 (2/3) and day 10 (1/3). A corneal reaction consisting of slight opacity and damage to the superficial epithelium was seen in all treated eyes at one hour. This was still present at 24 hours and thereafter, the eyes returned to normal by 48 hours (2/3 washed eyes), 72 hours (2/3 unwashed eyes) and 6 days (1/3 washed, 1/3 unwashed eyes). Increased folding of the iris was seen in all unwashed eyes at 24 hours. These had returned to normal by 48 hours (1/3) and 72 hours (2/3). The testing has been carried out with eyes of 3 rabbits washed after 30 seconds, while remaining 3 rabbits never received any washing. However, the modern guidelines correctly recommend "If the solid test substance has not been removed from the eye of the test animal by physiological mechanisms at the first observation time point of 1 hour after treatment, the eye may be rinsed with saline or distilled water." Further the washing/flushing the eyes after exposure is a more realistic scenario for workers, as such an exposure will lead to an attempt to flush out the substance entered in the eye as soon as possible. Hence, not washing the eyes at all is considered to be an elevated testing condition, and the results obtained with such an exposure are not considered for hazard assessment. In line with the above argument, the findings of necrosis of the nictitating membranes of unwashed eyes seen in this study, is not considered for the hazard conclusion. The scoring for washed eyes is below the threshold of the classification, hence substance is classified as not an eye irritant.

 

Comment:

Since the study compared also a cohort that was instilled with the solid test material remaining in the eye and a cohort that was instilled with the test material for about 1 minute followed by a flush out procedure (as recommended by OECD guideline 405) results form animals of the first cohort have not been taken into account for hazard assessment since this test regimen represent an elevated testing condition while noone is able to judge if the scorings and effects observed are due to the intrinic properties of the test item or due to a mechanical effect of the crystals remaining in the conjunctival sac of the eye. In addition the wash-out procedure represents a more realistic scenario to assess risk of eye damage to workers, professionals and consumers (in case applicable at all).

 

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
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

The substance did not cause irritation to the skin or eyes, hence, it does not warrant the classification according to the CLP (Regulation EC No 1272/2008) criteria.