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Acute Toxicity: oral

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Administrative data

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

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Test guidelineopen allclose all
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(2,6-diisopropylphenyl)carbodiimide
EC Number:
218-487-5
EC Name:
Bis(2,6-diisopropylphenyl)carbodiimide
Cas Number:
2162-74-5
Molecular formula:
C25H34N2
IUPAC Name:
N,N'-bis(2,6-diisopropylphenyl)carbodiimide
Details on test material:
- Name of test material: bis(2,6-diisopropylphenyl)-carbodiimide
- Substance type: organic technical product
- Physical state: solid
- Appearance: white solid
- Lot/batch No.: 08120024
- Expiration date of the lot/batch: 2009-11-15
- Stability under test conditions: No analysis was performed on stability of the test item in dried corn oil. Test item characteristics were not suggestive of a rapid reaction with the vehicle. Therefore, formulations should be were prepared freshly prior to start of treatment (non-GLP).
- Storage condition of test material: room temperature (product information given by the sponsor)
- Other: 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.

Test animals

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

Administration / exposure

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.

Results and discussion

Effect levelsopen allclose all
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

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.