Registration Dossier

Administrative data

Description of key information

1. Acute oral toxicity (2009B), GLP, OECD 423, rats, 300 or 2000 mg/kg bw, substance solved in corn oil, LD50 > 300 mg/kg bw < 2000 mg/kg bw
2. Acute dermal toxicity (2001), GLP, OECD 402, rat, 2000 mg/kg bw, substance only moistened with distilled water, application to the skin semiocclusive for 24 hours, LD50 = 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-07-23 - 2009-10-09
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Wistar (strain: HsdCpb:Wu)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 8 -12 weeks
- Weight at study initiation: 165 g-197 g.
- Fasting period before study: food was withheld from the animals for approximately 16 - 24 h before administration of the test item, and they were fed again approximately 2 - 4 h after administration.
- Housing: group caged conventionally in polycarbonate cages on low dust wood granulate bedding (Lignocel BK 8-15, Firma Rettenmaier, Germany). (The cages of the animals were placed on racks. The wood granulate was randomly checked for contaminants at regular intervals. The analyses yielded no evidence of any adverse effects on the aim of the study. Wooden blocks for environmental enrichment were added to each cage. As soon as necessary, they were replaced by new ones. The cages were changed at least once a week. Feed racks and water bottles were not changed. All cage material was washed with hot water. In the first stage of the washing programs an alkaline cleaning agent (Neodisher Alka 300; Chemische Fabrik Dr. Weigert GmbH & Co. KG, concentration: 2.2 g/L) was used.)
- Diet (e.g. ad libitum): standard diet "Provimi Kliba 3883 PM SI5 Maus/Ratte Haltung, Kaiseraugst Switzerland" ad libitum, The food was available from racks in the lid of the cage. (The nutritive composition and the contaminant content of the standard diet were checked and analysed routinely in random samples. Nothing untoward was found.)
- 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). The available data yielded no evidence of any adverse effects on the aim of the study.)
- Acclimation period: at least 5 days
- Other a): At start of the study the animals were nulliparous and non-pregnant and free of all clinical symptoms or diseases.
- Other b): The animals were assigned to their groups by randomization. The random list was based on evenly distributed chance numbers by a software application. The animals were identified by labels on the cages stating study number, test item, animal number, group number, etc. and by individual animal identification using permanent skin marking.
- Other c): Occasional deviations from these standards occurred, e.g. during cleaning of the animal room. They did not have any apparent influence on the outcome of the study. The animal room was provided with sound from a radio program..
- Other d): The animal room was cleaned and disinfected weekly. A continuous pest control was performed using a cockroach trap without pesticides (e.g. Killgerm Roach Trap, Killgerm GmbH, Neuss, Germany). The contact of the animals with the traps was avoided in any case.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±2°C
- Humidity (%): 55 ±5%
- Air changes (per hr): approx. 10 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours/ 12 hours
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE: corn oil (dried with molecular sieve)
- Purity: The content of active ingredient(s) is not considered.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg body weight (The individual administration volumes were calculated on the base of the body weight at time of administration and were administered in a single oral administration by gavage.)

DOSAGE PREPARATION (if unusual): the test item was ground formulated in corn oil (dried with molecular sieve) to yield a solution. The applied formulations were well mixed before administration. The formulations for administration were prepared at room temperature. The administration volume was 10 mL/kg body weight.
Doses:
2000 mg/kg bw and 300 mg/kg bw
No. of animals per sex per dose:
3 females/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: at least 14 days
- Frequency of observations and weighing: Clinical signs and mortality rates were determined several times on the day of administration and subsequently at least once daily. Mortality and in the event of symptoms occurring, nature, duration and intensity (possible grading: no intensity specified; 1 = slight; 2 = distinct) were recorded individually. The day of administration is defined as day 1. The duration of the symptoms and the times of death are given relative to the time of administration to the individual animal. The real time points can be taken from the raw data. In general, death will be taken as a symptom. The weight gain of the animals was checked weekly until the end of the study (calculated based on rounded individual values). The weights are given in grams (g).
- Necropsy of animals which died or were killed in moribund state: yes (animals were weighed (except on day of administration) and dissected as soon as possible, and examined macroscopically.)
- Necropsy of survivors performed: yes (animals were sacrificed by carbon dioxide at the end of the study, dissected and examined macroscopically.)
- Other examinations performed: clinical signs, body weight
Statistics:
The LD50 value was estimated according to OECD - Guideline for Testing of Chemicals No. 423 -"Acute Oral Toxicity - Acute Toxic Class Method"; adopted: December 17, 2001.
Sex:
female
Dose descriptor:
LD100
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: death on days 2 to 5
Sex:
female
Dose descriptor:
other: 33 % mortality
Effect level:
300 mg/kg bw
Based on:
test mat.
Remarks on result:
other: one of three animals died on day 3
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
other: derived from the mortalities observed at 300 mg/kg bw and 2000 mg/kg bw
Mortality:
All animals dosed with 2000 mg/kg body weight died during the observation period.
One animal of 3 dosed with 300 mg/kg bw died in group one, one animal of 3 dosed with 300 mg/kg bw died in group two.
Clinical signs:
- at 2000 mg/kg bw: piloerection, blood-crusted snout, poor general condition, decreased motility, hunched posture, laboured breathing and narrowed palpebral fissure
- at 300 mg/kg bw: piloerection, decreased motility, uncoordinated gait, laboured breathing, narrowed palpebral fissure, blood-crusted snout and high legged gait.
Body weight:
- at 2000 mg/kg bw: not applicable as all animals died on day 2- 5
- at 300 mg/kg bw: the body weight gain was not affected in the surviving animals.
Gross pathology:
- at 2000 mg/kg bw: bright-red fluid in the body cavity thorax; extremities, skin and bones yellow discoloured.
- at 300 mg/kg bw: In the animals that died during the observation period the following changes were detected: autolysis and partial cannibalism. The necropsy performed at the end of the post-treatment observation period of the surviving animals did not reveal any treatment-related findings.
Other findings:
No other findings reported
Table 1: Dose-Responses
dose mg/kg toxicological bw. result  occurrence of signs time of death mortality (%)
female *
2000 3 / 3 / 3 2d  - 5d 2d     - 5d  100
(1st) 300   1 / 1 / 3 2d  - 3d 3d 33
(2nd) 300 1 / 2 / 3 2d  - 5d 3d 33
  *  number of animals which died spontaneously and/or were sacrificed in moribund state / number of animals with signs of toxicity / total number of animals used per group
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information harmful if swallowed Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The study was performed according to the OECD TG423 without deviations and therefore considered to be of the highest quality (reliability Klimisch 1). The validity criteria of the test system are fulfilled. The test material did induce mortality and treatment-related clinical signs in the dose group of 2000 mg/kg bw (100 % mortality) and in dose group 300 mg/kg bw (33 % mortality). According to OECD guideline 423 the LD50 cut-off of the test item is 500 mg/kg bw. The test material was considered to be harmful if swallowed after oral application under the conditions of the test and as the LD50 of the test item is >300-2000 is has to classified as GHS Category 4.
Executive summary:
The acute oral toxicity of bis(2,6-diisopropylphenyl)-carbodiimide was investigated in rats (Gillissen, 2009, according to OECD 423). The test item was administered in corn oil in concentrations of 300 and 2000 mg/kg bw via oral gavage to Wistar rats. Observations were made for 14 days. Mortality occurred with all animals in the group dosed with 2000 mg/kg bw. The symptoms were piloerection, blood-crusted snout, poor general condition, decreased motility, hunched posture, laboured breathing and narrowed palpebral fissure. In the gross pathology bright-red fluid in the body cavity thorax, yellow discoloured extremities, skin and bones were noted. One animal in each of the two groups dosed with 300 mg/kg bw died. The main symptoms after gavage were piloerection, decreased motility, uncoordinated gait, laboured breathing, narrowed palpebral fissure, blood-crusted snout and high legged gait. The gross pathology performed after sacrifice did not reveal treatment related findings. Additionally the body weight gain was not affected by oral gavage of 300 mg per kg bw. An oral LD50 of 300 < LD50 < 2000 was identified.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
The study is GLP compliant and has Klimisch score 1.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001-02-23 - 2001-10-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CD (Crl: CD® (SD) IGS BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS: Five male and five female Sprague-Dawley CD (Crl: CD® (SD) IGS BR)
- Source: Charles River (UK) Ltd, Margate, Kent, UK.
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: at least 200g
- Fasting period before study:
- Housing: On receipt the animals were randomly allocated to cages: individually (during the 24-hour exposure) or in groups of five (by sex) for the remainder of the study in suspended polypropylene cages furnished with wood flakes.
- Diet (e.g. ad libitum): Rat and Mouse SQC Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK, ad libitum
(The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.)
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period: at least five days.
- Other a): The females were nulliparous and non-pregnant. Animal selection at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°C.
- Humidity (%): 30 - 70%.
- Air changes (per hr): at least fifteen changes per hour.
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
- Other : Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study.


The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Vehicle:
other: moistened with distilled water
Details on dermal exposure:
TEST SITE
- Area of exposure: an area of shorn skin (approximately 10% of the total body surface area, area used: back and flanks of each animal)
- % coverage:
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: yes (For the purpose of the study the test material was weighed out according to each animals individual bodyweight and moistened with distilled water prior to application.)

The appropriate amount of test material, moistened with distilled water, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area, area used: back and flanks of each animal). A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24-hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place. After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.
Duration of exposure:
single application for 24 hours exposure
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. The clinical observations for females were not recorded on Day 9. This deviation was considered not to affect the purpose or integrity of the study.

After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests".

Any other skin reactions, if present were also recorded. Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
No specific information given
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths were recorded.
Clinical signs:
No signs of systemic toxicity.
Signs of dermal irritation noted were very slight to well-defined erythema, very slight oedema, crust formation, desquamation and small superficial scattered scabs.
Very slight to well-defined erythema was noted at the treatment sites of all animals two to four days after dosing and in two males and all females five days after dosing. Very slight erythema was noted at the treatment sites of three females six days after dosing and persisted in one female seven days after dosing. Very slight oedema was noted at the treatment sites of four males and three females two and three days after dosing. Small superficial scattered scabs were noted at the treatment site of one male six and seven days after dosing with desquamation noted eight days after dosing. Crust formation was noted at the treatment sites of all females five to eight days after dosing.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No other findings recorded
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The study was performed according to the OECD Guideline 402 without deviations and therefore considered to be of the highest quality (reliability Klimisch 1).The validity criteria of the test system was fulfilled. The test material did not induce any signs of acute dermal toxicity. The test material was considered to be not toxic via the dermal exposure route under the conditions of the test, which is based on the LD50 values derived from this study (LD50 > 2000 mg/kg bw).The test material does not meet the criteria for classification and will not require labelling for dermal toxicity in accordance with EU labelling regulations Commission Directive 93/21/EEC.
Executive summary:

The acute dermal toxicity of bis(2.6-diisopropylphenyl)carbodiimide was investigated in rats (Driscoll, 2001, according to OECD 402). The test item was moistened with distilled water and applied in a dose of 2000 mg/kg bw under semiocclusive conditions for 24 h. No death occurred and all animals showed expected gains in bodyweight over the study period. Additionally no abnormalities were recorded in the gross pathology performed after sacrifice. So the dermal LD50 was identified as LD50>2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study is GLP compliant and has Klimisch score 1.

Additional information

Acute oral toxicity:

Gillisson and colleagues investigated firstly the acute oral toxicity of bis(2,6-diisopropylphenyl)carbodiimide in rats in the beginning of 2009 (Gillissen, 2009c, according to OECD 423). However, as the substance was administered in corn oil with the aid of 10 % acetone in the concentrations of 5, 50, 300 or 2000 mg/kg bw by oral gavage, the results of this study have been considered not representative for the toxicity of bis(2,6 -diisopropylphenyl)carbodiimide. Therefore the study is classified as disregarded.

The methods and results are only given for the sake of completeness the clinical signs and mortality rates were determined several times on the day of administration and subsequently at least once daily for an observation period of at least fourteen days. Mortality and in the event of symptoms occurring, nature, duration and intensity (possible grading: no intensity specified /1 = slight / 2 = distinct) were recorded individually. The weight gain of the animals was checked weekly until the end of the study. Animals which died or were killed in moribund state were weighed (except on day of administration) and dissected as soon as possible, and examined macroscopically. The surviving animals were sacrificed by carbon dioxide at the end of the study, dissected and examined macroscopically. Mortality occurred with all animals in the groups dosed with 300 or 2000 mg/kg bw. No other clinical sign than death was observed. At 2000mg/kg bw, the gross pathology investigations revealed: partly haemorrhagic, watery intestine, black liver, haemorrhagic lung, gas-filled stomach with firm mass inside, black spleen, black kidneys, aqueous and clear fluid (approximately 2 ml) in the body and chest cavity. At 300 mg/kg bw the intestine was partly haemorrhagic and watery, a black liver, a haemorrhagic lung, a gas-filled stomach with a firm mass inside, a black spleen and kidneys were recorded. The necropsies performed at the end of the study revealed no particular findings in animals treated with 50 mg/kg bw. As mentionned above, these findings have to be judged carefully because the solvent chosen is influencing the outcome of the study considerably. Therefore the study is considered as disregarded and the results obtained by the later study in 2009, where only corn oil was used as a solvent, are considered reliable (see below).

The acute oral toxicity of bis(2,6-diisopropylphenyl)carbodiimide was investigated in rats again in 2009 (Gillissen, 2009a and b, according to OECD 423). The substance was administered in corn oil in the concentrations of 300 or 2000 mg/kg bw by oral gavage. Clinical signs and mortality rates were determined several times on the day of administration and subsequently at least once daily for an observation period of at least fourteen days. Mortality and in the event of symptoms occurring, nature, duration and intensity (possible grading: no intensity specified / 1 = slight / 2 = distinct) were recorded individually. Animals which died or were killed in moribund state were weighed (except on day of administration) and dissected as soon as possible, and examined macroscopically. The surviving animals were sacrificed by carbon dioxide at the end of the study, dissected and examined macroscopically. Mortality occurred with all animals in the group dosed with 2000 mg/kg bw. The symptoms in this group were piloerection, blood-crusted snout, poor general condition, decreased motility, hunched posture, laboured breathing and narrowed palpebral fissure. In the gross pathology bright-red fluid in the body cavity thorax, yellow discoloured extremities, skin and bones were noted. In the group dosed with 300 mg/kg bw only one of three animals died. The main symptoms after gavage of 300 mg/kg bw were piloerection, decreased motility, uncoordinated gait, laboured breathing, narrowed palpebral fissure, blood-crusted snout and high legged gait. The gross pathology performed after sacrifice did not reveal treatment related findings. Additionally the body weight gain was not affected by oral gavage of 300 mg bis(2,6-diisopropylphenyl)-carbodiimide per kg bw. An oral LD50 was identified as 300<LD50<2000 mg/kg bw.

The acute oral toxicity of bis(2,6-diisopropylphenyl)carbodiimide was investigated in rats (Kimmerle, 1962). The test item was administered in oil in concentrations of 50, 100, 200, 250 and 500 mg/kg bw via oral gavage to male albino rats (groups of 5). Observations were made for at least 5 days. Mortality occurred with all animals in the group dosed with 500 mg/kg bw. The symptoms were poor general condition, hunched posture and expanded abdomen. 4animals in the group dosed with 250 mg/kg bw and 2 animals in the group dosed with 200 mg/kg bw died. No mortality was found in the dose groups of 50 and 100 mg/kg bw. An oral LD50 of 200 < LD50 < 250 was identified.

The acute oral toxicity of bis(2,6-diisopropylphenyl)carbodiimide was investigated in Sprague Dawley rats (Birch, 1974). The test item was administered via stomach tube, after being warmed to liquefy in concentrations of 3160, 3980, 5010 and 6310 mg/kg bw. Observations were made for toxic signs for fourteen days and after sacrifice the viscera of the test animals were examined macroscopically.

No mortality occurred in the lowest dose group (3160 mg/kg bw), 3 of 5 animals died in the dose group 3980 mg/kg 4 of 5 animals died in the dose group 5010 mg/kg bw and all animals died in the group dosed with 6310 mg/kg bw. Survival time was two to nine days with most deaths occurring within four days. Toxic signs included reduced appetite and activity (three to five days in survivors increasing weakness, collapse, and death.

In the gross pathology there was lung and liver hyperaemia and gastrointestinal inflammation. In the animals sacrificed fourteen days after dosing the viscera appear normal by macroscopic examination. The Single Oral Dose LD50 for male and female rats was placed at 3360 mg/kg bw with lower and upper limits of 3470 to 4250 mg/kg. The compound was classed as slightly toxic by oral ingestion in male and female rats.

Conclusion:

According to the GLP-guideline study in 2009 (Gillissen, 2009a and b), the test item carbodiimide is toxic via the oral route (300 < LD50 < 2000). These results are similar with the old data obtained from the study Kimmerle (1962). The results of the GLP-guideline study (Gillissen, 2009C) are not suitable and therefore disregarded, due to the inadequate solvent (corn-oil with 10 % acetone) used. Moreover, the minimal data available for the studies of the Younger Laboratories (1974) and Steinhoff (1973) and the highly deviating results do not allow their consideration for the evaluation of the acute toxicity potential of bis(2,6 -diisopropylphenyl)carbodiimide.

Acute dermal toxicity:

The acute dermal toxicity of bis(2,6-diisopropylphenyl)carbodiimide was investigated in rats in 2001 (Driscoll, 2001, according to OECD 402). The substance was moistened with distilled water and applied in a dose of 2000 mg/kg bw under semiocclusive conditions for 24 h. The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. The clinical observations for females were not recorded on Day 9. This deviation was considered not to affect the purpose or integrity of the study. After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize (1977) "Dermal and Eye Toxicity Tests". Any other skin reactions, if present were also recorded. Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14. At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained. No signs of toxicity were noted and the slight signs of dermal irritation were very a slight to well-defined erythema, a very slight oedema, a crust formation, a desquamation and small superficial scattered scabs. All animals showed expected gains in bodyweight over the study period. Additionally no abnormalities were recorded in the gross pathology performed after sacrifice. A dermal LD50 was identified as LD50>2000 mg/kg bw.

 

The acute dermal toxicity of bis(2,6-diisopropylphenyl)carbodiimide was investigated in rabbits (Birch, 1974). The test item was applied in doses of 794, 1260, 2000, 3160, 5010 or 7940 mg/kg bw for 24 h. The compound was applied to the closely clipped, intact skin of New Zealand White albino male and female rabbits. The treated areas were covered with plastic strips and the animals held in wood stocks for periods up to twenty-four hours, after which time they were assigned to individual cages. Observations were made for toxic signs and the viscera of the test animals were examined microscopically. Toxic signs included reduced appetite and activity (four to eight days in survivors: increasing weakness, collapse, and death. At autopsy there were haemorrhagic areas of the lungs and liver, enlarged gall bladder and gastrointestinal inflammation. Surviving animals were sacrificed fourteen days after dosing. The viscera appeared normal by macroscopic examination. The Acute Skin Absorption Minimal Lethal Dose for male and female rabbits was found to be greater than 3160 mg/kg bw and less than 5010 mg/kg bw.

Conclusion:

The two available studies confirm that carbodiimide is not toxic via the dermal exposure route. Therefore no classification is necessary

Acute toxicity, other routes:

The acute intraperitoneal toxicity of bis(2,6-diisopropylphenyl)carbodiimide was investigated in rats (Kimmerle, 1962). The test item was administered in oil in concentrations of 10, 25, 50, 100, 250 and 500 mg/kg bw via intraperitoneal injection to male albino rats (groups of 5). Mortality occurred with all animals in the group dosed with 500 mg/kg bw. The symptoms were poor general condition, hunched posture and expanded abdomen. 4animals in the group dosed with 250 mg/kg bw. No mortality was found in the dose groups of 10, 25, 50 and 100 mg/kg bw. An LD50 of ca. 200 mg/kg bw was identified.

Prediction using TOXTREE (v2.5.0)

The chemical structure of bis(2,6-diisopropylphenyl)carbodiimide was assessed by Toxtree (v.2.5.0) modelling tool for its toxicity class according to the rules of Cramer (with extensions). Bis(2,6-diisopropylphenyl)carbodiimide is of unknown level of toxicity because it is not a normal constituent of the body and contains more than one aromatic ring with substituents. So, no prediction was possible, as it was classified as a Class III substance and those do not permit a strong initial presumption of safety, or may even suggest significant toxicity or have reactive functional groups.


Justification for selection of acute toxicity – oral endpoint
A vehicle without concern was used in this study.

Justification for selection of acute toxicity – inhalation endpoint
The endpoint is not relevant due to the very low vapour pressure.

Justification for selection of acute toxicity – dermal endpoint
The most reliable study available.

Justification for classification or non-classification

Acute oral Toxicity:

According to OECD guideline 423 the LD50 cut-off of the test substance is 500 mg/kg bw. The test material does meet the criteria for classification and will require labelling for oral toxicity in accordance with Regulation (EC) No. 1272/2008.

The LD50 of the test item is >300-2000, therefore it has to be classified as GHS Category 4. So it is regarded as harmful if swallowed after oral application (H302 - Harmful if swallowed).

Acute inhalation Toxicity:

The test material does not need to be subject to an acute inhalation toxicity test, since this exposure route is not relevant for this chemical. Even though some experimental data for carbodiimide is available, their minimal details and their old age do not allow classification or labelling for inhalatory toxicity in accordance with Regulation (EC) No. 1272/2008.

 

Acute dermal Toxicity:

The test material does not meet the criteria for classification and will not require labelling for dermal toxicity in accordance with Regulation (EC) No. 1272/2008.