Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21 December 2011 - 11 January 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):
Reaction products of 1,1’-methylenebis(4-isocyanatocyclohexane) and pentaerythritol triacrylate and pentaerythritol tetraacrylate

- Substance type: Clear colourless or slightly yellow, sticky resin
- Physical state: solid
- Purity: 98.5% (heating residue)
- Lot/batch No.: 90501
- Expiration date of the lot/batch: 24 April 2012
- Storage condition of test material: At room temperature protected from light

Study specific test substance information:
- General information: Avoid heat, direct sunlight, acid and base
- Hygroscopic No
- Volatile No
- Test substance handling Use amber-coloured glassware or wrap container in tin-foil.
- Specific Gravity / Density 1.10-1.20
- Stability at higher temperatures Yes, maximum temperature: 50°C, maximum duration: 1 month
- Stability in vehicle:
• Propylene glycol Unknown
• Ethyl acetate One month at room temperature
- Solubility in vehicle:
• Propylene glycol Not indicated
• Ethyl acetate Good

According to the test substance information, the test substance is stable to a maximum temperature of 50ºC for 1 month. However, the test substance formulations were heated at a maximum temperature of 50.9°C for a maximum of 23 minutes.
Evaluation: Taking into account that the test substance is stable at 50°C for 1 month, the test substance is considered to be stable at 50.9°C for 23 minutes.

Test animals

Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
female
Details on test animals and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 8 or 11 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean.
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.9 – 21.6
- Humidity (%): 42 - 62
- Air changes (per hr): approx 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 21-dec-2011 to 11-jan2012

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Ethyl acetate (specific gravity 0.902) and propylene glycol (specific gravity 1.036)
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes.

Frequency: single dosage, on Day 1.

VEHICLE Ethyl acetate (specific gravity 0.902, from VWR Prolabo, Leuven, Belgium) and propylene glycol (specific gravity 1.036, from Merck, Darmstadt, Germany).
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor. Trial formulations at a maximum temperature of 50°C showed that water, 1% aq. carboxymethyl cellulose, propylene glycol, polyethylene glycol 400 and corn oil were no suitable vehicles.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The test substance was weighed and stored protected from light using amber-coloured glassware. The test substance was mixed with ethyl acetate to reduce the viscosity of the test substance. Then, the mixture was further diluted with propylene glycol to the required dose concentration. The amount of ethyl acetate in total formulation was 20% (w/w). The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and of the test substance (which was set at 1.15 for calculations). No correction was made for purity of the test substance. In order to obtain homogeneity, the test substance formulations were heated in a water bath with a maximum temperature of 50.9ºC for a maximum of 23 minutes. The test substance formulations were allowed to cool down to a temperature of 20ºC prior to dosing.
Doses:
2000 mg/kg body weight


No. of animals per sex per dose:
6 (2 groups of three females in a stepwise manner)
Control animals:
no
Details on study design:
Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded
- Other examinations performed: none.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture was observed for the first group of animals on Day 1 only. Based on the short duration and on the absence of corroborative findings in any of the animals, the hunched posture observed for these animals was considered to be no significant clinical sign of toxicity.
No clinical signs were observed for the second group of animals.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 value of Reaction products of 1,1’-methylenebis(4-isocyanatocyclohexane) and pentaerythritol triacrylate and pentaerythritol tetraacrylate in Wistar rats was established to exceed 2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, Reaction products of 1,1’-methylenebis(4-isocyanatocyclohexane) and pentaerythritol triacrylate and pentaerythritol tetraacrylate does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011),
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.