Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-12-15 to 2011-12-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
2009
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
chemical name: Homopolymer (isocyanurate type) of 3-isocyanatomethyl 3, 5, 5-trimethyl cyclohexyl isocyanate, caprolactam blocked
To reduce the particle size, the test material was milled at the test facilty using a ball mill.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS:  RccHan: (WIST)
- Source: Harlan Laboratories, Horst, The Netherlands
- Age:  8 weeks old
- Weight at study initiation: males: 201 - 209 g, females: 169 - 185 g
- Number of animals:3 males and 3 females
- Fasting period before study: 16 hours
- Housing: in groups of three, when not exposed
- Diet: ad libitum, RM3, Rat & Mouse No. 3, Breeding Diet
- Water: ad libitum, tab water
- Acclimatisation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 2 °C
- Humidity (%): 45% - 65 %
- Photoperiod (hrs dark / hrs light): 12 hours darkness, 12 hours artifical light
- Air changes: 10 air changes per hour

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: compressed filtered air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Type of exposure: animals were exposed to the test atmosphere in a nose-only exposure unit consisting of a cylindrical column, surrounded by a
transparent cylinder. The column has a volume of ca. 40 litres and consists of a top assembly with the entrance of the unit, a homogenization
section, a rodent tube section and at the bottom the base assembly with the exhaust por
- Method of holding animals in test chamber (volume 40 l): separatley in tubes
- Source of air: compressed filtered air
- Type or preparation of particles: With the test material as delivered by the sponsor the aerodynamic particle size of the particles in the generated
test atmosphere was too large, the mass median aerodynamic diameter (MMAD) was 5.2 µm. Therefore, the test material was milled in a Ball Mill
fitted with a zirconium beaker and 100 zirkonium balls with a diameter of 10 mm. A four-fold repetition of milling during 40 seconds at a speed of 350 revolutions per minute followed by a pause of 20 seconds with reversal of the direction of rotation after each pause resulted in a powder that could be aerolised with a MMAD below 3 pm.
- Method of particle size distribution: using a cascade impactor acording to MAY, analysis is carried out twice during inhaltion period.
Measurement of the distribution of particle sizes in the test atmosphere during exposure yielded that the mass median aerodynamic diameter
(MMAD) was 1.6 pm and that the geometric standard deviation (gsd) was 2.9. A second measurement during exposure showed the same
values. lt was estimated from these measurements that79% and 74% of the mass of the aerosol present at the animals' breathing zone was
contained in particles with an aerodynamic diameter smaller than 4 pm in the first and second measurement, respectively
- Temperature, humidity: T: 20.9 +/- 0.1°C, H: 45.0 % +/- 1.0 %, measured twice per hour
TEST ATMOSPHERE
- Concentrations: 5.3 mg/l 
- Air flow exit (L/h): 97
- Oxygen concentration: 20.7%
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Actual concentration of the test material in the test atmosphere was measured 7 times during exposure by gravimetric filter analysis. Particle size distribution measurements were carried out, using a cascade impactor.
Duration of exposure:
4 h
Concentrations:
5.3 mg/l gravimetric concentration
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
EXAMINATIONS: 
- Post dose observation period: 14 days
- body weights: before,  7 and 14 days after treatment   
- mortality: once per hour during, and once after treatment on day of  exposure; 
thereafter twice daily
- clinical signs: during and following exposure, observations were made and recorded systematicallye,  at least twice daily until all symptoms
subsided, thereafter each working day
- Necropsy: all animals (macroscopic) when found dead or at terminal  sacrifice. In addition, the weight of the lungs was determined.
Statistics:
not necessary

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.3 mg/L air
Exp. duration:
4 h
Mortality:
No animal died prematurely.
Clinical signs:
all animals showed shallow respiration and a decreased respiration rate. Approximately an hour after exposure clinical signs were restricted to
piloerection in one female animal and lethargy in another female animal. Lethargy and muscle weakness were seen in 2 male and 2 female animals,
blepharaspasm in 1 male and all female animals, piloerection and hunched posture in 2 male and all female animals and irregular respiration and
encrustation of the eyes in one male animal. The next day the latter signs were still present in that particular male animal and piloerection and
hunched posture were present in all animals. ln the remainder of the observation period these or other abnormalities were not seen.
Body weight:
Body weight was decreased up to 18 and 19 grams for female and male animals, respectively, one day after exposure, but on day 3 body weights
were on the preexposure level again. Animals resumed growing from day 3 onwards at a rate considered within normal limits for this strain
and age.
Gross pathology:
Abnormalities at necropsy were restricted to the lungs. ln male animals abnormalities consisted of pale and in one animal also red areas
on all lobes. ln female animals petechia were seen on one lobe in one animal and diffuse on the lungs on another. ln two animals the lungs were grey discoloured and white areas were seen on the lobes.
Other findings:
no other findings

Any other information on results incl. tables

no further remarks


Applicant's summary and conclusion

Conclusions:
Because none of the animals died during this study, the 4-hour LC50 value of Cyclohexane, 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethyl-, homopolymer, caprolactam-blocked (IPDI homopolymer, caprolactam-blocked) in rats is higher than 5.3 g/m3.
Executive summary:

The aim of the present study was to examine the acute (4-hour) inhalation toxicity of cyclohexane, 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethyl-, homopolymer, caprolactam-blocked (IPDI homopolymer, caprolactam-blocked) in rats. A group of 3 male and 3 female rats were exposed during a single 4 -hour period to a test atmosphere containing 5.3 g/m3 of the test substance. The mass median aerodynamic diameter of the particles in the aerosol was 1.6 µm and the distribution of particle sizes had a geometric standard deviation (gsd) of 2.9 (measured in duplicate). After exposure, the animals were kept for a 14 -day observation period and sacrificed for necropsy.

Shallow respiration and decreased respiration rate, both graded as very slight, developed during exposure. After exposure, lethargy, muscle weakness, blepharospasm, piloerection and hunched posture were seen in most animals. The next day, the latter two abnormalities were still present in all animals. ln the remainder of the observation period these or other abnormatlities were no longer seen.

One day after exposure, body weight was decreased. Animals resumed growing from day 3 onwards at a rate considered within the normal range for this strain and age.

Abnormalities at necropsy consisted in male animals of pale and, in one male, also red areas on all lobes of the lungs. Petechia were seen on the lungs in one female animal and on one lung lobe in another female animal. ln two female animals the lungs were grey discoloured and white areas were seen on the lobes. Gross abnormalities were not seen in other organs or tissues.

Because none of the animals died during the study, the 4-hour LC50 in rats is higher than 5.3 g/m3.