Registration Dossier

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Administrative data

Description of key information

1. Skin irritation (1993), GLP, OECD 404, rabbit, 0.5 g, undiluted, 4 hours semiocclusive conditions, non-irritant
2. Skin irritation (2010), GLP, OECD 404, rabbits, undiluted, 0.5 mL, 4 hours, occlusive, irritant
3. Skin irritation / corrosion (2010), GLP, OECD 431, reconstructed human epidermis, 30 mg in sodium chloride solution, 20 min, non-irritant
4. Skin corrosion (2009), GLP, OECD 431, reconstructed human skin model, 3 and 60 min, not corrosive
5. Skin irritation/corrosion - QSAR using TOXTREE (v2.5.0) - Prediction (2011) - skin: class unknown
6. Skin irritation (1974), no guideline followed, rabbit, 0.5 g, undiluted, 24 h occlusive conditions, non-irritant
7. Skin irritation (1961), no guideline followed, rabbit, unchanged or moistened with oil or with water , 24 h semiocclusive conditions, non-irritant
8. Skin irritation (1973), no guideline followed, rabbit, 1, 2 4 or 8 hours exposure, slight reddening after 8 hours of exposure
9. Eye irritation (2010), GLP, OECD 405, rabbit, 0.1 g, 1 h, non-irritant
10. Eye irritation (1993), GLP, OECD 405, rabbit, 0.1 g, non-irritant
11. Eye irritation /corrosion - QSAR using TOXTREE (v.2.5.0) - Prediction (2011) - eye: NOT lesions R34, R35, R36 or R41
12. Eye irritation (1974), rabbits, 01. ml, undiluted, washed after 24 hours with sodium chloride solution, not irritating
13. Eye irritation (1961), rabbit and dog, undiluted, not irritating
14. Eye irritation (1973), rabbit, not irritating, unreliable report

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
in-vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993-02-04 - 1993-04-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EEC directive 84/449/EEC
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harald Schriever; Kaninchenfarm, Bremervörde, Neuendamm
- Animal selection: random
- Animal identification: with individual ear tags; cage labelled with ear tag no., sex, date of study initiation, project no.
- Housing: individual housing (50 x 45 x 40 cm, L x B x H) in a battery of cages, each equipped with a paper roll disposal system
- Diet (e.g. ad libitum): Ssniff K-Haltung (Ssniff Spezialdiäten GmbH, Soest/Westfalen, Germany)
- Water (e.g. ad libitum): ad libitum (half-yearly analyses and bacteriological tests)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3°C
- Humidity (%): 30 - 70 % (Measurement: with thermo hygrometer twice daily)
- Photoperiod (hrs dark / hrs light): artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.
Type of coverage:
semiocclusive
Preparation of test site:
other: fur was removed with electric clippers
Vehicle:
water
Remarks:
moistened sufficiently with aqua ad injectabilia to ensure good contact with the skin
Controls:
other: an adjacent area of untreated skin served as control
Amount / concentration applied:
0.5 g on about 6 cm² in size
Duration of treatment / exposure:
4 h
Observation period:
30-60 min, 24, 48 and 72 h after patch removal.
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: roughly 8 x 15 cm on the back of each animal
- % coverage:
- Type of wrap if used: each test area was covered with a semi-occlusive dressing consisting of Ypsiplast® (Holthaus Medical, Remscheid-Lüttringhausen), which was held in place by non-irritating tape Elastoplast® (Beiersdorf AG, Hamburg), and Stülpa® (P. Hartmann AG, Heidenheim-Brenz), which enveloped the whole of the animal's trunk.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the 4-h exposure period, the dressing was removed and any residual sample was carefully washed off with water or an appropriate solvent.
- Time after start of exposure: 4 hours

24 h before treatment, fur was removed with electric clippers from an area of roughly 8 x 15 cm on the back of each animal. The skin was examined for abrasions and only animals with healthy, intact skin were used in the test.
The solid test article was moistened sufficiently with Aqua ad injectabilia to ensure a good contact with the skin.
In each animal, 0.5 g of the test article were applied to the test site (ca. 6 cm² in size), an adjacent area of untreated skin serving as a control.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 30-60 minutes and 24; 48; 72 hours
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 30-60 min and 24; 48; 72 hours
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
No test article-dependent findings were observed. No toxic effects were observed.
Other effects:
No other effects reported

Table 1: individual detailed data

 

Time after patch removal

Animal number

30-60 min

24 h

48 h

72 h

 

Ery

Oed

Ery

Oed

Ery

Oed

Ery

Oed

 

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

T= test site,

C= control site,

Ery = erythema,

Oed = oedema.

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The study was performed according to the OECD Guideline 404 with no deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. The mean grades of skin reactions at 24, 48 and 72 h after patch removal were lower than the value classified as irritant by the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh). When applied to the skin, the test article may therefore be considered to be non-irritant. The test material did not induce irritation on the intact skin of rabbits. The product bis(2.6-diisopropylphenyl)carbodiimide is considered to be not irritating to the skin.
Executive summary:

The skin irritation potential of the test substance was investigated in rabbits (Kaufmann, 1993, according to TG OECD 404). Bis(2.6-diisopropylphenyl)carbodiimide was applied to the skin of rabbit (skin prepared with electric clippers, 0.5 mg pure substance moistened with water) for 4 hours under semiocclusive conditions. The study was performed according to the OECD Guideline 404 with no deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. After this period the skin was evaluated 30- 60 min, 24, 48 and 72 h after patch removal. No test article- dependent findings were observed. The mean grades of skin reactions were lower than the value classified as irritant by the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh). When applied to the skin, the test article may therefore be considered to be non- 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:
2009-02-19 - 2010-01-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline Study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: Crl:KBL(NZW)BR
Details on test animals or tissues and environmental conditions:
For reasons of animal welfare a sequential testing strategy was followed in accordance with the current version of the EEC Directive No. 440/2008 and the OECD Guideline No. 405, irrespective of the requirements of other guidelines for testing for eye irritation/corrosion in rabbits.
This testing strategy comprised a stepwise approach including the evaluation of existing human and/or animal data showing effects on the eye or the skin, the performance of a SAR evaluation for eye and skin corrosion/irritation, measurement of pH value, the evaluation of data on systemic toxicity via the oral route, the performance of a validated in vitro test for skin corrosion (Human 3D Epidermal Skin Model) and in vivo testing for skin irritation/corrosion in rabbits before in vivo testing for eye irritation/corrosion in rabbits.

TEST ANIMALS: Healthy adult albino rabbits free of clinical signs. The health of the animals was routinely examined for the main specific pathogens by the breeder. Before the study the rabbits had been vaccinated against pasteurellosis and all animals were medicated against coccidiosis. No treatment with antibiotics was performed prior to receipt of the animals, or during the acclimatisation phase or study period. In some cases the animals had already been used in earlier studies. This has no influence to the results of this study. Females were nulliparous and not pregnant.
- Age at study initiation: young adult animals
- Weight at study initiation: 3.5 kg-3.6 kg
- Housing: individually in cage units metal/noryl by EBECO. Excrement trays below the cages contained low dust wood granulate bedding (J. Rettenmaier & Sons, Rosenberg, Germany). The wood granulate was changed at least twice weekly. The animals were regularly transferred to clean cages.
- Diet (e.g. ad libitum): standard diet "Ssniff K-Z" 4mm (manufacturer: Ssniff Spezialdiäten GmbH, Soest, Germany), approximately 100 g per animal per day (To satisfy the needs of roughage, hay was offered additionally (hay, irradiated, delivered by Harlan Nederland, 5961 NM Horst, Netherlands or Harlan Winkelmann GmbH, Borchen, Germany, respectively hay pellets, manufacturer: Ssniff Spezialdiäten GmbH, 59494 Soest, Germany). The nutritive composition and the contaminant content of the standard diet were checked and analysed routinely in random samples. No unwanted ingredients were detected.)
- Water (e.g. ad libitum): tap water ad libitum from polycarbonate bottles (The tap water was of drinking water quality (according to the Drinking Water Decree in the current version) and analysed routinely. The wood granulate was randomly checked for contaminants at regular intervals.)
- Acclimation period: at least 5 days
- Other: The animals were identified by labels on the cages stating at least study number, test compound, animal number and by tattooed number assigned by the breeder.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ±3°C
- Humidity (%): 50 ±25%
- Photoperiod (hrs dark / hrs light): light/ dark cycle with a 12 hours rhythm.
- Other: The humidity and air temperature were continuously recorded. Occasionally deviations from the standards occurred, e.g. during cleaning of the animal room or effects of the weather. They did not have any apparent influence on the outcome of the study. The animal room was provided with sound from a radio program.

The animal room was cleaned at least once a week and disinfected at least once a month. It was ensured that the diet was not contaminated, and that there was no contact of the cleaning or disinfecting solution with the test animals.
Vehicle:
unchanged (no vehicle)
Remarks:
0.1 g of powder for each animal was placed into the conjunctival sac
Controls:
other: the untreated eye served as the control
Amount / concentration applied:
The solid test compound was heated in a drier to approximately 60°C (duration: approx. 2h). When the test substance was liquid, approx. 1 mL was taken and was given in a mortar. When the substance was crystallised again (duration approx. 1 min.), it was pulverised. From this powder 0.1 g was weighed for each animal.
Duration of treatment / exposure:
1 hour (eye was rinsed approximately 1 hour after instillation.)
Observation period (in vivo):
approximately at 1, 24, 48 and 72 hours post application.
If no irritation indices were observed after 72 h, the study was finished.
If eye irritations were observed, animals were monitored usually on day 7, 14 and 21 after application until the changes had completely subsided, however for not more than 21 days after application.
Number of animals or in vitro replicates:
3
Details on study design:
On the day before the test, both eyes of each animal were examined including fluorescein examination. Only animals with healthy intact eyes were used.
0.1 g of the pulverized test substance was placed into the conjunctival sac of one eye of the first animal after having gently pulled the lower lid away from the eyeball. The lids were gently held together for about one second in order to prevent loss of the test compound. The other eye, which remained untreated, served as control.
Because of the fact that one hour after treatment a severe irritation was not observed, a further two rabbits were treated as described.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The eye was rinsed approximately 1 hour following instillation.
- Time after start of exposure: 1 hour

SCORING SYSTEM:
The degree of ocular lesions was recorded as specified by DRAIZE and any serious lesions or toxic effects other than ocular lesions were also recorded and fully described.
As general criteria the body weight of each animal was recorded at the beginning of the study. If clinical findings other than eye irritations occur they were recorded daily.

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
48 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
48 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
48 h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
72 h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 2 days
Irritant / corrosive response data:
Only redness of the conjunctivae was noted (up to 48 hours after instillation). No effects on iris or cornea were observed.
Other effects:
No other effects reported
Table1: Irritant Effects on the Eye 
Animal 1,Body Weight3.6kg
Observation 1h 24 h 48 h 72 h day7 day14 day21
Degree of cornea opacity 0 0 0 0 - - -
Area of cornea opacity 0 0 0 0 - - -
Iris 0 0 0 0 - - -
Redness conjunctivae 2 2 1 0 - - -
Chemosis conjunctivae 0 1 0 0 - - -
Animal 2,Body Weight3.5kg            
Observation 1h 24 h 48 h 72 h day7 day14 day21
Degree of cornea opacity 0 0 0 0 - - -
Area of cornea opacity 0 0 0 0 - - -
Iris 0 0 0 0 - - -
Redness conjunctivae 2 2 1 0 - - -
Chemosis conjunctivae 0 1 0 0 - - -
Animal 3,Body Weight3.5kg            
Observation 1h 24 h 48 h 72h day7 day14 day21
Degree of cornea opacity 0 0 0 0 - - -
Area of cornea opacity 0 0 0 0 - - -
Iris 0 0 0 0 - - -
Redness conjunctivae 2 1 0 0 - - -
Chemosis conjunctivae 0 0 0 0 - - -
- :no further examination
Animal 1, 2 and 3, 1 h p.a.:   test compound adhered to cornea and conjunctiva 

Table 2: Summary of Irritant Effects (Score)  
          Mean Reversible
Animal   24h 48h 72h scores Response (days)
  Corneal opacity 0 0 0 0.0 na
1 Iritis 0 0 0 0.0 na
Redness conjunctivae 2 1 0 1.0 3
  Chemosis conjunctivae 1 0 0 0.3 2
  Corneal opacity 0 0 0 0.0 na
2 Iritis 0 0 0 0.0 na
Redness conjunctivae 2 1 0 1.0 3
  Chemosis conjunctivae 1 0 0 0.3 2
  Corneal opacity 0 0 0 0.0 na
Iritis 0 0 0 0.0 na
3 Redness conjunctivae 1 0 0 0.3 2
  Chemosis conjunctivae 0 0 0 0.0 na
response:
corneal opacity : mean scores < 2 = -,  > 2 < 3 = +, > 3 = ++
iritis : mean scores < 1 = -,  > 1 < 2  = +, =2=++
conjunctival redness : mean scores < 2,5 = -, > 2.5  = +,
conjunctival oedema : mean scores < 2 = -, > 2  = +,
na : not applicable 
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: Eu-GHS
Conclusions:
The study was performed according to the OECD TG405 without deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. The test material did induce only slight reversible irritation on rabbit eyes. The test material was considered to be not irritating under the conditions of the test.
Executive summary:

The test substance bis(2.6-diisopropylphenyl)carbodiimide was investigated for its potential to cause irritation in the rabbit eye according to OECD TG405 (Gmelin, 2010). 0.1 g of pure substance were instilled into the conjunctival sac, the untreated eye served as control. Under the conditions of this experiment bis(2.6-diisopropylphenyl)carbodiimide was found to cause no irritation when applied to the rabbit eye mucosa. No corrosion effect was observed at each of the measuring intervals. No discoloration of the cornea and conjunctivae which could be related to effects of the test material was observed. Additionally no corrosive or acute toxicological signs were observed in the animals during the test period. According to classification criteria in the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh) the test substance is not irritating to eyes and should be unclassified. There were no systemic intolerance reactions.

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

Additional information

Skin irritation

 

The skin irritation potential of the test substance was investigated in rabbits (Kaufmann, 1993). Bis(2,6-diisopropylphenyl)carbodiimide was applied to the skin of rabbit (skin prepared with electric clippers, 0.5 g pure substance moistened with water) for 4 hours under semiocclusive conditions. The study, which is considered to be the key study, was performed according to the OECD Guideline 404 with no deviations and according to the good laboratory practice principles and is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. After 4 hours, the patch was removed, any residual sample was carefully washed off with water or an appropriate solvent and the skin was evaluated after 30- 60 min, 24, 48 and 72 h. No test article- dependent findings were observed. The mean grades of skin reactions were lower than the value classified as irritant by the European regulation (EC) No. 1272/2008. When applied to the skin, the test article may therefore be considered to be non- irritant.

 

In another study bis(2,6-diisopropylphenyl)carbodiimide investigated for its skin irritation potential was applied to shorn rabbit skin (0.5 mL undiluted substance) for 4 hours under occlusive conditions (Gmelin, 2010). After this period the skin was washed carefully and observations were made after 1, 24, 48, 72 hours, 7 days and 14 days. Thereafter, the animals were observed up to 14th day post application. After 24 hours erythema was noticeable (grade1) which increased after 48 hours (grade 2) and was not reversible within 14 days. Additionally after 7 days a slight not reversible oedema was noticeable in all animals. The study was performed according to GLP and the OECD Guideline 404. However, as a result of the waxy structure of the compound, an occlusive contact occurred to the skin of animals. This is considered to be a deviation from the principles laid out in the OECD guideline 404 and therefore this result is disregarded and considered to be not reliable. The outcome of the study cannot be taken into account for the assessment of the skin irritating potential and for classification and labelling.

 

Bis(2,6-diisopropylphenyl)carbodiimide was applied to a reconstructed human epidermis EST-1000 in vitro test system for detection of skin irritation after topical application of the test item (Wingenroth, 2010, according to TG OECD 431). The test item was applied to the inserts (30 mg per insert (plus 30 µL 0.9 % sodium chloride to moisten and ensure good contact with the skin) for 20 minutes. After this period the inserts were washed carefully in PBS and observations were made after 43.5 hours. The MTT (Methylthiazoletetrazolium) method was used to determine the value of viability 101.23%. Thus the results showed no irritant property of the test item by the assay used.

 

Bis(2,6-diisopropylphenyl)carbodiimide was applied to a reconstructed human skin model in vitro test system for detection of skin corrosion after topical application of the test item (Wingenroth, 2009, according to TG OECD 431). The test item was applied to the inserts for 3 and 60 minutes. After this period the inserts were washed carefully in phosphate buffered saline and observations were made. The MTT (Methylthiazoletetrazolium) method has determined the following values of viability after 3 min or after 60 min of incubation: 103.16% and 102.45%, respectively. Thus, the results show that no corrosive property of the test item was determined by the assay used.

 

The skin irritating potential of bis(2,6-diisopropylphenyl)carbodiimide was investigated in rabbits (Birch, 1974). The test item (0.5 g substance per se, warmed to liquefy) was applied to the clipped, intact and abraded skin of six albino male and female rabbits under a one inch by one inch square patch, two single layers thick. The patches were held in place with adhesive tape. The trunk of each animal was wrapped with plastic strips, to retard evaporation and avoid contamination, for the twenty-four hour exposure period. Observations were made over a period of seven days. Based on the low reactions observed, which were fully reversible within 48 hours, the compound was not classed as a primary skin irritant (Primary Irritation Score: 1.0.).

 

The effect of the bis(2,6-diisopropylphenyl)carbodiimide on the intact skin was determined on the external ear of rabbits (1961), to which small cellulose pads containing the dry substance, the substance moistened with oil, or the substance moistened with water were attached with plaster, after which they were left for 24 hours. When the external ears of the rabbits were examined at the end of the 24-hour period the substance was found to have caused slight reddening, which lasted for only a short while. After a further 24 hours this symptom of irritation was no longer visible. In conclusion it is stated that the test item is considered not irritating to the skin.

In conclusion, it is stated that the test item is not a skin irritant as proven with studies according to or similar to OECD404 and 431. This is based on the study performed by Kaufmann (1993), which was chosen to be the key study, because it was performed according to the principles laid out in the OECD Guideline 404 (substance should have only semi-occlusive contact to the skin).

 

Eye irritation

In an eye irritation study (Gmelin, 2010, according to TG OECD 405), bis(2,6-diisopropylphenyl)carbodiimide was applied to rabbits eyes for 1 hour. 0.1 g of pure substance was instilled into the conjunctival sac, the untreated eye served as control. After this period the eye was rinsed and observations were made after 1, 24, 48 and 72 hours. Thereafter, the animals were observed up to 21th day. Only slight redness of the conjunctiva and slight chemosis occurred, which was all reversible within 3 or 2 days. Under the conditions of this experiment bis(2,6-diisopropylphenyl)carbodiimide was found to cause no irritation when applied to the rabbit eye mucosa. No corrosion effect was observed at each of the measuring intervals. No discoloration of the cornea and conjunctivae which could be related to effects of the test material was observed. Additionally no corrosive or acute toxicological signs were observed in the animals during the test period. According to classification criteria in the Regulation (EC) No. 1272/2008 the test substance is not irritating to eyes and should be unclassified. There were no systemic intolerance reactions.

 

The test substance bis(2,6-diisopropylphenyl)carbodiimide was investigated for its potential to cause irritation in the rabbit eye according to TG OECD 405 (Kaufmann, 1993). 0.1 g of pure substance was instilled into the conjunctival sac, the untreated eye served as control. Observations were made after 1, 24, 48 and 72 hours. Thereafter, the animals were observed up to 4th day. Slight to moderate redness and chemosis of the conjunctivae were apparent in all animals up to 24-72 h post applicationem. No other toxic effects were observed. Under the conditions of this experiment bis(2,6-diisopropylphenyl)carbodiimide was found to cause no irritation when applied to the rabbit eye mucosa. No corrosion effect was observed at each of the measuring intervals. No discoloration of the cornea and conjunctivae which could be related to effects of the test material was observed. Additionally no corrosive or acute toxicological signs were observed in the animals during the test period. According to classification criteria in the European regulation (EC) No. 1272/2008 the test substance is not irritating to eyes and should be unclassified. There were no systemic intolerance reactions.

 

The test item bis(2,6-diisopropylphenyl)carbodiimide was subject to an eye irritation study (Birch, 1974). 0.1 mL of undiluted sample was placed in the conjunctival sac of the right eye of each of six albino male and female rabbits and observations made over a period of seven days for inflammation. The treated eyes were washed with sodium chloride solution USP after the twenty-four hour reading. The left eye served as a control. The data were scored according to the method of Draize, et al. Immediately after instillation slight discomfort was noted. After 10 minutes slight erythema, copious discharge, but no oedema was seen. After 1 -hour the rabbits showed slight to moderate erythema, very slight oedema in one instance and copious discharge. After 24 -hours slight erythema, copious discharge, but no oedema was to be seen. After 48 -hours slight erythema, slight discharge in four instances and no oedema was noticeable. After 72 -hours slight erythema in four instances; no oedema or discharge was found in the rabbits. At 120 and 168 -hours the eyes appeared normal and zero readings were apparent. Therefore the compound was not classed as an eye irritant.

 

The test item bis(2,6-diisopropylphenyl)carbodiimide was subject to an eye irritation study (1961). The powder was placed in the conjunctival sac of rabbits and dogs and observations were made. The small amount of the compound which was introduced into the conjunctival sac of rabbits and dogs caused a merely temporary mechanical irritation of the conjunctiva. The cornea was not affected. Therefore the substance is not considered eye-irritating based on the results of this experiment.

In summary it is clear that the test item is not an eye irritant and will not require classification or labelling.

Prediction using TOXTREE

For the estimation of the eye and skin irritation/corrosion potential, the structure of bis(2,6 -diisopropylphenyl)carbodiimide was entered into the Toxtree modelling tool. The experimentally determined melting point of 50.97 °C and a water solubility of 1.4 g/L at 20°C was also taken for the assessment of irritation potential. Bis(2,6 -diisopropylphenyl)carbodiimide is assessed as not corrosive to skin(not R34 or R35).


Justification for selection of skin irritation / corrosion endpoint:
The most reliable study available.

Justification for selection of eye irritation endpoint:
The study is a GLP compliant and has Klimisch score 1.

Justification for classification or non-classification

Skin irritation

 

According to the Regulation (EC) No. 1272/2008, the test material does not meet the criteria for classification and will not require labelling as irritating to the skin.

 

Eye irritation

The mean grades of ocular reactions at 24, 48 and 72 h p.a. were lower than the value classified as irritating to the eyes by the Regulation (EC) No. 1272/2008, therefore the substance should not be classified.