4-methyl-m-phenylene diisocyanate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

From 1977-06-16 to 1977-07-30

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment; Restrictions: The humidity was low (4%) instead of 30-70% but this is acceptable and necessary due to the physico-chemical properties of TDI.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

The duration of exposure was 1h instead of at least 4h. 4 animals per sex instead of 5.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

m-tolylidene diisocyanate

EC Number:

247-722-4

EC Name:

m-tolylidene diisocyanate

Cas Number:

26471-62-5

Molecular formula:

C9 H6 N2 O2

IUPAC Name:

m-tolylidene diisocyanate

Details on test material:

- Name of test material (as cited in study report): Toluene diisocyanate (80:20 mixture of the 2,4- and 2,6- isomers)
- Isomers composition: 79.6 % (2,4 isomer)
- Lot/batch No.: ABH2146

Test animals

Species:

rat

Strain:

other: Alderly Park

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: data not available
- Age at study initiation: 6-10 weeks
- Weight at study initiation: 150-300 g
- Fasting period before study: none
- Housing: 4 rats/cage
- Diet : Oakes Powder 'O' diet, ad libitum except during the exposure
- Water : ad libitum except during the exposure
- Acclimation period: data not available


ENVIRONMENTAL CONDITIONS
- Temperature (°C): data not available
- Humidity (%): data not available
- Air changes (per hr): data not available
- Photoperiod (hrs dark / hrs light): data not available


IN-LIFE DATES: data not available

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: heated tube
- Exposure chamber volume: a 17 litre glass dessicator was used as an exposure chamber (there were no divisions in order to minimise deposition).
- Method of holding animals in test chamber: no data
- Source and rate of air: no data
- Method of conditioning air: The TDI was dispended into a syringe atomizer by a palmer slow injection apparatus (CF palmer limited). The entrained vapour passed through a heated glass tube (about 120 °C), mixed with diluting air and led into the animal exposure chamber. All air was dried to less than 4 % relative humidity.
- Treatment of exhaust air: no data
- Temperature, humidity, pressure in air chamber: no data, 4 %, no data

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere is drawn throught a glass sintered bubbler containing absolute alcohol. The Isocyanate (Urethane derivative) is subsequently analysed by Liquid Chromatography.
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Remarks:

A sample of air from the breathing zone of the rats was drawn through two sintered glass absorbers containing 10 mls of absolute alcohol at a rate of 1.25l/min for 5 minutes mid-way through each exposure. The trapped isocyanates were then analysed HPLC.

Duration of exposure:

1 h

Concentrations:

0, 17.4, 25.16, 43.2, 83.9, 267.1 ppm

No. of animals per sex per dose:

4

Control animals:

yes

Details on study design:

- Duration of observation period following administration: at least 14 days
- Frequency of observations and weighing: The behaviour of the animals was recorded throughout the exposure. Then, examination and weighing during the following fourteen days were preformed at approximately 2 days intervals.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, lung weight

Statistics:

no statitics were performed.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

66 ppm

95% CL:

31 - 141

Exp. duration:

1 h

Remarks on result:

other: (LC50= 0.48 mg/l) There was no significant difference between the LC50 of male and female rats.

Mortality:

Yes, 11/18 deaths occurred on day 1 or 2. For more details see Table 1 in field "Remarks on results including tables and figures".

Clinical signs:

other: At 17.4 ppm: after exposure, all animals were subdued and wheezing; 2 females lost weight over 10 days, were hunched and blue; 1 female died on day 15 and 1 was sacrificed in extremis. At 25.16 ppm: after exposure, all animals were wheezing and gas

Body weight:

All of the animals exposed which survived the first 36 hours after exposure lost weight during the first 4 days of the observation period. Some continued to lose weight and either died or were sacrificed.

Gross pathology:

See remarks.

Other findings:

- Potential target organs: lung
- Organ weights: The lung weights were increased indicating oedema.
- Other observations: Necropsy findings:
(1) At 17.4 ppm, 1 female died on day 15 had dark patches on all lobes of lungs; the animal sacrificed on day 15 had pale inflated lungs with red 2 lobes of right lung; lung weight was high.
(2) At 25.16 ppm: 1 female dying on day 2 had multiple dark red foci on all lung lobes, 2 dark red lobes; others sacrificed at end of study had red foci on lungs and consolidated lobes; 3 males had pale inflated lungs; lung weights were increased.
(3) At 43.2 ppm: animals dying had inflated lungs with dark patches full of fluid; at necropsy, lung weights increased and all lungs were pale, inflated with 2 animals showing dark patches.
(4) At 83.9 ppm: animals dying on study had red foci in lungs and animals surviving had inflated and pale lungs except for red areas of consolidation, lung weights were increased.
(5) At 267.1 ppm: animals dying on day 1 had fluid in lung and thorax, animals dying after Day 1 had inflated, red lungs; single survivor had pale enlarged lungs with red spots on all lobes, enlarged adrenals and gray kidneys.

Any other information on results incl. tables

Table 1: Concentrations, time of death and mortality per animals treated

Conc. (ppm)	Isomer ratio 2,4:2,6	Mortality (# dead/total)			Time range of deaths (days)
		Male	Female	Combined
17.4	3.13:1	0/4	1/4	1/8	day 15
25.16	2.53:1	1/4	3/4	4/8	(2-19)
43.2	4.1:1	2/4	1/4	3/8	(2-11)
83.9	3.13:1	1/4	2/4	3/8	(2-4)
267.1	2.27:1	4/4	3/4	7/8	(1-2)
controls	-	0/4	0/4	0/8	-

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category I

Remarks:

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

Conclusions:

TDI is toxic via inhalation, although its relatively low volatility, tendency to deposit on cool surfaces, and reactivity with moisture limits the acute toxicity hazard to some degree.

Executive summary:

In an acute inhalation toxicity study (Doe and Horspool, 1980), groups of young adult albino rats (Alderly Park strain, 4/sex) were exposed by inhalation route to Toluene diisocyanate (80:20 mixture of the 2,4- and 2,6- isomers) for 1 hour to whole body at concentrations of 0, 17.4, 25.16, 43.2, 83.9 and 267.1 ppm. Animals then were observed for at least 14 days. LC50 Combined = 66 ppm (95 % CL: 31 -141 ppm). All death animals showed signs of lung damage, the lungs were haemorrhagic and inflated or fluid filled.