2,4,6-triisopropyl-m-phenylene diisocyanate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989-05-23 - 1989-06-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Limit test

Deviations:

yes

Remarks:

acclimatisation period only 4 days

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Richtlinie 84/449/EWG (Amtsblatt der Europäischen Gemeinschaften Nr. L 251 vom 19.09.1984, S.96)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2,4,6-triisopropyl-m-phenylene diisocyanate

EC Number:

218-485-4

EC Name:

2,4,6-triisopropyl-m-phenylene diisocyanate

Cas Number:

2162-73-4

Molecular formula:

C17H22N2O2

IUPAC Name:

2,4-diisocyanato-1,3,5-tris(propan-2-yl)benzene

Test material form:

liquid

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Strain Bor: WISW (SPF Cpb)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen,
- Age at study initiation: 7 weeks (male), 10 weeks (female),
- Weight at study initiation: ca. 171 g (male), ca. 166 g (females, which were nulliparous and not pregnant),
- Fasting period before study: 16 hours before and up to 4 hours post application the animals did not receive any food (before and after this period the standard diet was given ad libitum).
- Housing: conventionally in cages equipped on low dust wood granules.
- Other: all animals in this study were housed in one room. In cases animals from other toxicological studies were housed in the same room. However appropriate organisational measures were taken to exclude confusion or any interference. The animal room was disinfected once weekly and 1 to 3 times a year a pest control was undertaken. On these occasions a contamination of the diet or any contact to the animals was excluded. The cage racks were cleaned in regular intervals and drinking bottles, lid of cages and feeding dishes were exchanged regularly. The complete cage was cleaned with hot water.
- Diet (e.g. ad libitum): "Fixed-formula"-standard diet (Altromin® 1324 Pellets (producer: Altromin GmbH und Co KG, Lage)). For feeding mangers the lids in the cage were used. The standard diet was regularly controlled and analysed for its nutritive composition and degree of contaminant with spot samples.
- Water (e.g. ad libitum): Drinking water ad libitum, the drinking bottles comprised a volume of 700 ml and were out of polycarbonate.
- Acclimation period: 4 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C,
- Humidity: ca. 50 ± 10 %,
- Air changes: ca. 10-times air change per hour,
- Photoperiod: 12-hour light dark cycle (artificial illumination from 6 to 18 o'clock MEZ).

All animals were marked with pricrinic acid (fur, chronologically numbered), the cages were marked with: substance name, type of animal, dosing, study number, application type, sex and number of animals.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

peanut oil

Remarks:

DAB0 - (Oleum Arachidis) Henry Lamotte, Charge 5917

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw

Doses:

2000 mg/kg bw.
According to the OECD - Guideline 401 (1987), it is sufficient to characterise the acute oral toxicity with doses up to 2000 mg/kg bw.

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were made twice daily (on day 0 of application observations were made several times, only daily on weekends and official holidays), the bodyweights were determined weekly
- Necropsy of survivors performed: yes (All remaining animals were sacrificed at the end of the observation period after inhalation of diethylether. Every animal was submitted to a gross pathology and the findings were recorded individually.)
- Other examinations performed: clinical signs, body weight, histopathology

Statistics:

If a calculation of the mean (median) lethal dose (LD50) was possible, it was conducted via a computer assisted maximum-likelihood-method. Where the results would show 0 and 100 % mortality, the geometric mean will be used as an approximate LD50 value.
If values of 0 % and 100 % mortality appeared, the geometric mean was taken as approximate LD50.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Only one female died

Mortality:

Within the 14 day observation period, only one female animal died.

Clinical signs:

other: Day 0: After application of 2000 mg/kg bw all animals showed piloerection. Day 1: the surviving animals showed collectively increased urine production. Day 2: all surviving animals were symptom free. In the female rat which died 3 hours after applicati

Gross pathology:

The gross pathology investigation of the female rat (died on the day of application) revealed: hyperaemic lung and stomach.
All animals sacrificed at the end of the observation period were pathologically and anatomically normal.

Other findings:

No other findings were reported

Any other information on results incl. tables

Table 1: summary of clinical symptoms and death

Intensity and occurrence of symptoms and death
males
Doses (mg/kg)	2000
Application volume (mL/kg)	10
Way of application	PON
Number-dead animals	0
Number- animals with symptoms	5
Number- used animals	5
Starting time of symptoms	15'
Free of symptoms from... On	2d
Occurrence of death from	---
Occurrence of death till	---
	Number of animals / highest intensity
piloerection	5/2
polyuria	5/*
females
Doses (mg/kg)	2000
Application volume (ml/kg)	10
Way of application	PON
Number-dead animals	1
Number- animals with symptoms	5
Number- used animals	5
Starting time of symptoms	15'
Free of symptoms from... On	2d
Occurrence of death from	3h
Occurrence of death till	---
	Number of animals / highest intensity
piloerection	5/2
hypersalivation	1/2
laboured breathing	1/1
polyuria	4/*
* observation without specifying intensity

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: other: EU-GHS

Conclusions:

The study was performed according to the OECD TG401 with only minor 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 not induce treatment-related mortality. The clinical signs were piloerection and increased urine production. The test material was considered to be relatively non-toxic under the conditions of the test. The LD50 was identified to be >2000 mg/kg body weight.

Executive summary:

A study on the acute oral toxicity of 2,4-Triisopropylbenzoldiisocyanat for male and female Wistar rats (Bomhard, 1990) was conducted according to the OECD Guideline 401 - standard acute method with the only deviation that the acclimatisation period was only 4 days. This deviation is not judged to influence the results of the study significantly. A dose of 2000 mg/kg bw of the test substance was administered via gavage to the rats. Observations were made for a period of 14 days. No treatment-related mortalities or signs of systemic toxicity, beside piloerection during the first 24 hours following administration and an increased urine production on the following day, were observed.

One female rat died 3 hours after application, as clinical signs hypersalivation and laboured breathing were noted.

No treatment-related body weight changes were reported.

In the one female rat pathological abnormalities (hyperaemic lung and stomach) were found, in all other animals sacrificed at the end of the observation period no pathological findings were noted. The acute oral median lethal dose (LD50) of the test material in rats of both sexes observed over a period of 14 days was estimated to be greater than 2000 mg/kg bw.