Registration Dossier

Administrative data

Description of key information

An acute oral study on rats was performed according to OECD 425 guideline and GLP. The oral LD50 value was established to exceed 2000 mg/kg body weight. Based on these results, the substance does not have to be classified for acute toxicity according to the CLP Regulation.

Trimethyl hexamethylene Diisocyanate, a reactant, remains present at a concentration of 8% after the substance is manufactured. Trimethyl hexamethylene Diisocyanate has a health hazard classification, acute (inhalation) toxicity (H330), that has not been investigated because there is no requirement to do so in accordance with Annex VII of the REACH Regulation.

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:
The experimental start date was 02 May 2018 and the experimental completion date was 22 May 2018.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
December 2002
Deviations:
no
GLP compliance:
yes
Remarks:
Analyses conducted to support the information in the Certificate of Analysis were not conducted in compliance with the GLP or GMP regulations. The characterization of the test item was conducted under a sponsor or sponsor subcontractor quality system.
Test type:
up-and-down procedure
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: BZA13264
- Expiration date of the lot/batch: 23 June 2018
- Manufacturing date: 23 April 2018

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature under nitrogen

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was administered as received. Adjustment was made for specific gravity of the test item. No correction was made for the purity/composition of the test item.
Species:
rat
Strain:
other: Crl: WI(Han)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 9-10 weeks old
- Weight at study initiation: 178 to 191 g
- Fasting period before study: overnight for a maximum of 20 hours
- Housing: On arrival and following assignment to the study, animals were individually housed (pilot and full study) or group housed (limit study, up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. The room in which the animals were kept was documented in the study records.
Animals were separated during designated procedures/activities. Each cage was clearly
labeled.
- Diet (ad libitum): Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures. The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility. It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
- Water (ad libitum): Municipal tap-water was freely available to each animal via water bottles. Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility. It is considered that there were no known contaminants in the water that would interfere with the objectives of the study.
- Acclimation period: animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24ºC (actual daily mean of 21ºC)
- Humidity (%): 40 to 70% (actual daily mean of 41 to 53%)
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms
- Photoperiod (hrs dark / hrs light): A 12-hour light/12-hour dark cycle was maintained

IN-LIFE DATES: Completion of in-life: 24 July 2018 (week 25, last date of necropsy).
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg

DOSAGE PREPARATION: The dose volume for each animal was based on the body weight measurement prior to dosing. Dose volume (mL/kg body weight) was calculated as follows:
Dose level (g/kg) / spec.gravity or density (g/mL). MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg

DOSAGE PREPARATION: The dose volume for each animal was based on the body weight measurement prior to dosing. Dose volume (mL/kg body weight) was calculated as follows:
Dose level (g/kg) / spec.gravity or density (g/mL).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The dose levels were based on the OECD test guidelines and were selected from the series 5 (lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight. The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test item.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At periodic intervals on the day of dosing (at least three times) and once daily therafter.
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, clinical signs (skin/fur piloerection), body weight, macroscopic findings.
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.
All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate). Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.
Preliminary study:
No mortality was observed after treatment of the first animal at a dose level of 2000 mg/kg.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No mortality occured
Clinical signs:
Piloerection was noted for four out of five animals on day 1.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
Not applicable

Body weights (gram):

Animal

Day 1

Day 8

Day 15

1

178

209

216

2

181

201

211

3

191

206

219

4

191

213

219

5

180

202

216

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of Thio Isocyanate Adduct in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, Thio Isocyanate Adduct 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Executive summary:

The objective of the study was to determine the potential toxicity of Thio Isocyanate Adduct, when given by oral gavage at a single dose to rats of a single sex at one or more defined doses to evaluate the potential reversibility of any findings. The study was carried out in compliance with OECD guidelines 425. Initially, Thio Isocyanate Adduct was administered by oral gavage to one female Wistar rat at 2000 mg/kg body weight. Based on the absence of mortality, four additional female Wistar rats were dosed at 2000 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Piloerection was noted for four out of five animals on Day 1. The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

The oral LD50 value of Thio Isocyanate Adduct in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, Thio Isocyanate Adduct 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The oral LD50 value was established to exceed 2000 mg/kg body weight. Based on these results, the substance does not have to be classified for acute toxicity according to the CLP Regulation No 1272/2008.

While there is no requirement to provide information on acute toxicity, via the inhalation route, an acute toxicity estimate can be calculated.

The acute toxicity estimation of the reactant, Trimethyl hexamethylene Diisocyanate (EC 915 -277-1), is 0.05 mg/l.

The acute toxicity (inhalation) estimation of the registered substance is 0.625 mg/l. For this reason, the substance has been classified as "Acute Tox. 3" with the hazard statement for a "H331: Toxic if inhaled", according to the CLP Regulation No 1272/2008.