Registration Dossier

Administrative data

Description of key information

Skin irritation: not irritating [Kurth 2007]

Eye irritation: not irritating [Amir 2007]

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:
Feb 2006 - Mar 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
A combined study on acute dermal toxicity and on local tolerance was used to assess skin irritation/corrosion. The study design and reporting deviates from the current OECD TG 404, however, the study is considered sufficient for assessment of this endpoint.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
exposure time 24 hrs instead of 4 hrs, 6 animals instead of 3, rats instead of rabbits, few details in test description and reporting
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Remarks:
Han:WIST
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: no data
- Weight at study initiation: males (238 - 250 g); females (201 - 208 g)
- Fasting period before study: no data
- Housing: one per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: ≥ 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23
- Humidity (%): 54 - 58
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
physiological saline
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 477-499 mg (male animals), 402-421 mg (female animals)

VEHICLE
- Amount(s) applied: 0.7 mL
- Concentration: 0.9%
- Lot/batch no. : 4342A191
- Purity: no data

Duration of treatment / exposure:
24 h
Observation period:
The application sites were evaluated 1, 24, 48 and 72 h after removal of the patches.
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 4 x 9 cm
- % coverage: approximately 10% of the body surface area of a rat
- Type of wrap: gauze

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 h

OBSERVATION TIME POINTS: 1, 24, 48, 72/74 hours (The evaluation of the application sites of the male animals was performed 2 hours later on day 5 (i.e. 72 hours after removal of the patches). This deviation is not considered to have a relevant influence to the study result because all animals were without local findings also on the earlier time points.

SCORING SYSTEM:
- Method of calculation: The scoring system recommended by the EU (Amendment of the Directive 67/548/EEC, Annex V, B.4. Acute toxicity (Skin irritation) in the version of the Directive 92/69/EEC, dated 31 Jul 1992.)


Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
The mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after administration were 0 for swelling, reddening and scab formation after administration of 2000 mg/kg test substance.
Other effects:
A single dermal administration of the test substance to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, compound-related clinical findings and gross pathological findings. After administration of the test substance a slight decrease in body weight was observed in all male animals and one female animal on day 7 of the study. This effect was reversible on day 14.
Interpretation of results:
other: not irritating
Remarks:
in opinion of study director
Executive summary:

A combined study on acute dermal toxicity and on local tolerance was conducted . The study design and reporting deviates from the current OECD TG 404, however, the study was considered sufficient for assessment of skin irritation/corrosion. A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg did not show irritating potential.

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:
May 2016
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
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kisslegg, Germany
- Age at study initiation: no data
- Weight at study initiation: males 3.3 – 3.6 kg, females 4.0 - 4.6 kg
- Housing: 1 animal per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1-20.9
- Humidity (%): 61.0-65.0
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the left eye remained untreated and served as control
Amount / concentration applied:
0.1 mL of the test substance were applied, which corresponded to a mass of 40.6 to 48.2 mg of the test substance.
Duration of treatment / exposure:
test substance remained in the eye
Observation period (in vivo):
4-5 days
Duration of post- treatment incubation (in vitro):
not applicable
Number of animals or in vitro replicates:
2 males and 2 females
Details on study design:
Four rabbits (2 male, 2 female) each received a volume of 0.1 mL test substance into the conjunctival sac of the right eye. This volume, measured in a specially prepared syringe, corresponded to 40.6– 48.2 mg test substance. The left eye remained untreated and served as control. At first, only one animal was treated, as in case of severe intolerance reactions the other animals would not have been exposed for humane reasons. The other animals were treated one day later. During administration and observation on the administration day (first day of the test) the animals were kept in restraining cages for approximately 2 hours. No food or water was available during this time.

Clinical observation:
Conjunctivae, eyelids, cornea and iris were evaluated before administration, 0.5, 1 and 2 hours thereafter, and then every 24 hours until termination of the study. Clinical observation was performed in each animal as long as findings occurred. Evaluation of the local tolerance on the conjunctiva of the rabbits was performed according to the score system recommended for the EU (Annex to EEC guideline 92/69/EWG, dated 31 Jul 1992, for the 17th adaptation of the EEC guideline 67/548/EWG, B 5. Acute Toxicity (Eye irritation). Off J EEC, L383A, Luxembourg, 29 Dec 1992.). In addition, all other local findings at the eyes as well as all other reactions to treatment were recorded.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Remarks:
reddening
Basis:
mean
Time point:
24/48/72 h
Score:
0.58
Max. score:
3
Reversibility:
fully reversible within: max. 5 days
Irritation parameter:
conjunctivae score
Remarks:
swelling
Basis:
mean
Time point:
24/48/72 h
Score:
0.25
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritant / corrosive response data:
According to the system of evaluation recommended for EU (Annex to EEC guideline 92/69/EWG, dated 31 Jul 1992, for the 17th adaptation of the EEC guideline 67/548/EWG, B 5. Acute Toxicity (Eye irritation). Off J EEC, L383A, Luxembourg, 29 Dec 1992.), the values of findings relevant for classification at the time-points 24, 48 and 72 hours after administration were 0 for cornea and iris for every single animal at each time point.
Conjunctivae (reddening): 24 h - 3 animals with the score 1 (slight) and 1 animal with the score 2 (moderate); 48/72 h - 3 animals with the score 0 (no reddening) and 1 animal with the score 1 (slight)
Conjunctivae (swelling): 24/48/72 h - 3 animals with the score 0 (no swelling) and 1 animal with the score 1 (slight)
Other effects:
The treatment did not cause any effects on body weight gain.

Details about frequency, intensity and duration of the findings are to be taken from Table 1.

Table 1: Summary of local findings after single administration of the test substance in the rabbit eye. A/B = summation of positive findings/number of animals concerned. x-y = first - last day of occurence of a finding.

            Right eye 0.1 ml test substance
      male     female
   A/B x-y   A/B  x-y
 Conjunctiva        
 Reddening (all conjunctiva incl. conjunctiva sklerae)        
 - clear injection of a few vessels  3/2 1 - 2  4/2  1 -4 
 -diffuse crimson, single vessels are difficult to notice 5/2  1 -1  6/2  1 -2 
Swelling (conjunctiva and third eyelid)         
 - slight (incl. membrana nicitans) 3/2  1 -1  6/1  1 -4 
 - clearly with partial ectropium 3/2  1 -1     
 - with half eyelid closure     3/1  1 -1 
Interpretation of results:
other: not irritating
Remarks:
in the opinion of the study director
Executive summary:

A single conjunctival administration of the test substance (technical quality including impurities) into the conjunctival sac of the rabbit eye provoked slight irritation on administration day which decreased in severity from day 2 onwards and were fully reversible on day 5 after administration. Based on these findings, no irreversible effect is to be expected after contact of the human eye with the substance.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A combined study on acute dermal toxicity and on local tolerance was conducted . The study design and reporting deviates from the current OECD TG 404, however, the study was considered sufficient for assessment of skin irritation/corrosion. A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg did not show irritating potential. [Kurth 2007]

A single conjunctival administration of the test substance (technical quality including impurities) into the conjunctival sac of the rabbit eye provoked slight irritation on administration day which decreased in severity from day 2 onwards and were fully reversible on day 5 after administration. Based on these findings, no irreversible effect is to be expected after contact of the human eye with the substance. [Amir 2007]

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No. 1272/2008 (CLP) is not required.