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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-09-20 to 2011-10-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Version / remarks:
adopted May 12, 1981
Deviations:
yes
Remarks:
Because the present study was a concentration range finding study not all aspects of the guideline were implemented.
Qualifier:
according to guideline
Guideline:
EU Method B.28 (Sub-Chronic Dermal Toxicity Test: 90-Day Repeated Dermal Dose Study Using Rodent Species)
Version / remarks:
published in the Official Journal of the European Union L142, dated May 31, 2008
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
(propan-2-ylidene)amino N-(3,3,5-trimethyl-5-{[2,4,6-trioxo-3,5-bis({1,3,3-trimethyl-5-[({[(propan-2-ylidene)amino]oxy}carbonyl)amino]cyclohexyl}methyl)-1,3,5-triazinan-1-yl]methyl}cyclohexyl)carbamate; (propan-2-ylidene)amino N-(3,3,5-trimethyl-5-{[2,4,6-trioxo-3-({1,3,3-trimethyl-5-[({[(propan-2-ylidene)amino]oxy}carbonyl)amino]cyclohexyl}methyl)-5-({1,3,3-trimethyl-5-[2,4,6-trioxo-3,5-bis(3,3,5-trimethyl-5-{[({[(propan-2-ylidene)amino]oxy}carbonyl)amino]methyl}cyclohexyl)-1,3,5-triazinan-1-yl]cyclohexyl}methyl)-1,3,5-triazinan-1-yl]methyl}cyclohexyl)carbamate
EC Number:
600-028-9
Cas Number:
1001254-87-0
Molecular formula:
Exact identification is not feasible
IUPAC Name:
(propan-2-ylidene)amino N-(3,3,5-trimethyl-5-{[2,4,6-trioxo-3,5-bis({1,3,3-trimethyl-5-[({[(propan-2-ylidene)amino]oxy}carbonyl)amino]cyclohexyl}methyl)-1,3,5-triazinan-1-yl]methyl}cyclohexyl)carbamate; (propan-2-ylidene)amino N-(3,3,5-trimethyl-5-{[2,4,6-trioxo-3-({1,3,3-trimethyl-5-[({[(propan-2-ylidene)amino]oxy}carbonyl)amino]cyclohexyl}methyl)-5-({1,3,3-trimethyl-5-[2,4,6-trioxo-3,5-bis(3,3,5-trimethyl-5-{[({[(propan-2-ylidene)amino]oxy}carbonyl)amino]methyl}cyclohexyl)-1,3,5-triazinan-1-yl]cyclohexyl}methyl)-1,3,5-triazinan-1-yl]methyl}cyclohexyl)carbamate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Cyclohexane, 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethyl-, homopolymer, acetone oxime-blocked of Evonik Degussa GmbH, batch 11-22-18 of 2011-06-28.
Purity: approx. 99.5 % blocked oligomers
Molecular weight distribution: Mn = 1000 g/mol, Mw = 1200 g/mol (GPC)

Test animals

Species:
rat
Strain:
other: Crl:CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS: 
- Strain: Crt:CD
-Source: Charles River Laboratories Germany GmbH, Sulzfeld
- Age: males: 71 days, females: 79 days
- Body weight: males: 353 - 442 g, females 218 - 286 g
- Number of animals: 20 male and 20 female rats
- Controls: Vehicle
- Diet: ad libitum, special diet for rats, SSniff R/M-H V 1534
- Water: ad libitum, tap water
- Adaption period: 27 days
ENVIRONMENTAL CONDITIONS
- Housing: single in MAKROLON cages
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55% +/- 20 %
- Photoperiod (hrs dark / hrs light): 12 hours artificial light, 12 hours dark

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Remarks:
Tap water
Details on exposure:
Area of exposure:
- Coverage: 10 % of body surface
- Type of wrap: non-occlusive sterile gauze dressing, held in place with non-irritating tape
- Time intervals for shaving: one day before 1st application and on test day 8

REMOVAL OF TEST SUBSTANCE
- Washing: After the 6-hour exposure period the dressing was removed. At the end of the exposure period, residual test item was removed where
practicable using water or some other appropriate method of cleansing the skin.
TEST MATERIAL
- Administration volume: 4 mL/kg b.w. day
- Concentration: 0, 30, 100, 1000 mg/kg b.w,/day
- Constant volume or concentration used: amount of the test item was adjusted to each animal's current body weight weekly
- The test item was suspended in the vehicle to the appropriate concentrations to allow the test item to be spread over the application site

VEHICLE
- Vehicle: tap water, control animals were handled in an identical manner, except for treatment with the test substance


Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
14 consecutive days, 6 hours per day
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
Low dose
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Mid dose
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High dose
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels for this preliminary study were selected based on available toxicity data.
Positive control:
not necessary

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:
- Cageside observations included skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour
patterns
CLINICAL OBSERVATIONS:
- Animals were observed individually before and after dosing at each time of dosing for any signs of behavioural changes, reaction to treatment or
illness. In addition, animals were checked regularly throughout the working day from 7.30 a.m. to 4.30 p.m. On Saturdays and Sundays, animals
were checked regularly from 8.00 a.m. to 12.00 noon with a final check performed at approximately 4.00 p.m.
DERMAL IRRITATION :
- Starting on test day 1 and daily thereafter, always at the end of the 6-hour exposure period, the administration sites were assessed based on
DRAIZE
BODY WEIGHT:
- starting on test day 1, day 8 and day 15
FOOD CONSUMPTION:
- quantity of food left by individual animals was recorded on a weekly basis throughout the experimental period. Food intake per rat (g/rat/week) was calculated using the total amount of food given to and left by each rat in each group on comple-tion of a treatment week
FOOD EFFICIENCY:
- The relative food consumption (in g/kg b.w./day) was determined
WATER CONSUMPTION:
- Drinking water consumption was monitored daily by visual appraisal throughout the study
MORTALITY
- Further checks were made early in the morning and again in the afternoon of each working day to look for dead or moribund animals. This would
have allowed post mortem examination to be carried out during the working period of that day. On Saturdays and Sundays a similar procedure was
followed except that the final check was carried out at approximately 4.00 p.m.
Sacrifice and pathology:
GROSS PATHOLOGY:
-On test day 15 (approx. 24 hours after the last administration) the animals were dissected following a randomisation scheme.
The animals were sacrificed under ether anaesthesia by cutting the aorta abdominalis, exsanguinated, weighed, dissected and inspected
macroscopically under the direction of a pathologist.
- All superficial tissues were examined visually and by palpation and the cranial roof was removed to allow observation of the brain, pituitary gland
and cranial nerves. After ventral midline incision and skin reflection all subcutaneous tissues were examined. The condition of the thoracic
viscera was noted with due attention to the thymus, lymph nodes and heart.
The abdominal viscera were examined before and after removal, the urinary bladder was examined externally and by palpation. The
gastrointestinal tract was examined as a whole and the stomach and caecum were incised and examined. The lungs were removed and all pleural
surfaces were examined under suitable illumination. The liver and the kidneys were examined. Any abnormalities in the appearance and size of the
gonads, adrenal glands, uterus, intraabdominal lymph nodes and accessory reproductive organs were recorded.

Other examinations:
no other examinations
Statistics:
The test item-treated groups 2 to 4 were compared with the control group 1. The following statistical method was used:
Multiple t-test based on DUNNETT, C. W., New tables for multiple comparisons with a control Biometrics, 482-491 (Sept 1964)
Body weight / Food consumption (p >/= 0.01)
This statistical procedure was used for all data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
None of the rats revealed any clinical signs.
Dermal irritation:
no effects observed
Description (incidence and severity):
No signs of local intolerance were noted.
Mortality:
no mortality observed
Description (incidence):
None of the rats died prematurely.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test item-related changes were noted.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test item-related influence was noted.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No test item-related influence was noted.

Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No changes were noted.
Details on results:
- Local tolerance
No local intolerance reactions were noted for the male and female animals treated dermally with 30, 100 or 1000 mg test item (solvent free)/kg b.w./day.
- Behaviour, external appearance, faeces, mortality
None of the male and female rats revealed any changes in behaviour or external appearance. The faeces of all animals were normally formed.
None of the animals died prematurely.
- Body weight
No test itemrelated changes in body weight and body weight gain were noted for the animals compared to the control group.
- Food and drinking water consumption
No test item related influence was observed on the relative food consumption. The visual appraisal of the drinking water consumption revealed no test item-related influence.
- Macroscopic post mortem systemic findings
No test item-related macroscopic systemic changes were noted for the male and female rats compared to the control group.


Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no signs of local or systemic intolerance.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

no other information

Applicant's summary and conclusion

Conclusions:
Dermal treatment with 30, 100 or 1000 mg test item (solvent free)/kg b.w./day for 14 days did not cause any signs of local or systemic intolerance.
Executive summary:

The aim of this 14-day dose-range-finding study was to select the dose levels for a possible later 90-day repeated dose toxicity study of test item by dermal administration to rats.

Dose levels of 30, 100 and 1000 mg test item /kg b.w. /day were administered in this study.

The appropriate dose of the test item was administered epicutaneously onto the shaved dorsum (approx. 10% of the body surface (semi-occlusive)) once daily for 14 consecutive days. The exposure time was 6 hours per day. The test item was suspended in the vehicle (tap water) to the appropriate concentrations to allow the test item to be spread over the application site.

The control animals were handled in an identical manner with concurrent vehicle. On test day 15 the animals were dissected following a randomisation sheme.

Conclusion:

Dermal treatment with test item for 14 days did not cause any signs of local or systemic intolerance.

None of the rats died prematurely.

No test item-related influence was noted on the body weight, food and drinking water consumption.

Macroscopic examination at necropsy revealed no test item-related changes at any of the tested groups.

Therefore, under the conditions of this study the highest concentration (1000 mg/kg bw /day) is considered to be the No Observed Adverse Effect Level (NOAEL).

 

After consideration of these data, the following dose levels were selected for the 90-day toxicity study by dermal administration to CD rats:

Group 1:       Control

Group 2:       30 mg test item (solvent free)/kg b.w./day

Group 3:     100 mg test item (solvent free))/kg b.w./day

Group 4:    1000 mg test item (solvent free)/kg b.w./day