m-tolyl isocyanate

Endpoint summary

Description of key information

Acute Tox. Oral:

K2, Oral, OECD TG 425, Rats; LD50 = 2926 mg/kg bw for rat (male+female), Loeser (1980)

S2 Oral, , LD50 = 3191 mg/kg bw (male rats), Loeser (1979)

 

Acute Tox. Inhalation:

K1, OECD TG 403, Rat 4-hr inhalation aerosol, LC50 = 33 mg/m³ air and for female rats a LC50 = 30 mg/m³ air (analytical vapour concentration), Pauluhn (1988)

S2, Inhalation Hazard Test, Thyssen (1980)

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:

other information

Study period:

From 12 November 1979 to 20 October 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Rationale for alternative/additional species to rat n/a
- Source: Winkelmann, Borchen)
- Females (if applicable) nulliparous and non-pregnant: [yes, 5]
- Rationale for use of males (if applicable) n/a
- Age at study initiation:
- Weight at study initiation: 179 g
- Fasting period before study: n/a
- Housing: Mkrolonkafugen Type III cage.
- Historical data: n/a
- Diet (e.g. ad libitum): n/a
- Water (e.g. ad libitum):n/a
- Acclimation period: n/a
- Microbiological status when known n/a
- Method of randomisation in assigning animals to test and control groups :n/a

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1.5
- Humidity (%): 60 ± 5
- Air changes (per hr): 12 hours , from 7 am to 7 pm
- Photoperiod (hrs dark / hrs light): n/a

IN-LIFE DATES: From: To: n/a

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

1000, 1500, 2000, 2500, 3100, 4000 or 5000 µl/kg bw (= ca. 1060, 1590, 2120, 2650, 3286, 4240, 5300 mg/kg bw)

No. of animals per sex per dose:

5 male and 5 female rats/group

Control animals:

no

Details on study design:

Five male and 5 female young adult male Wistar rats (160 -180 g) per group reveived per gavage a single dose of 1000, 1500, 2000, 2500, 3100, 4000 or 5000 µl/kg bw m-tolylisocyanate. The animals were observed for mortality body weights and clinical signs through day 14.

Statistics:

calculation of LD50 according Fink and Hund, Arzneim Forsch 15, 624 (1965)

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 926 mg/kg bw

Based on:

test mat.

95% CL:

2 380 - 3 210

Mortality:

Males:
none for male rats at 1000 µl/kg bw, 1500 µg/kg bw doses.
20% at 2000 µl/kg bw dose
40% 2500 µg/kg bw dose
40 % 3100 µl/kg bw dose
100% 4000 µl/kg bw dose
100% 5000 µl/kg bw dose.

Females:
0% 1000 µl/kg bw dose
20% 1500 µg/kg bw dose
20% 2000 µl/kg bw dose
20% 2500 µg/kg bw dose
60 % at 3100 µl/kg bw dose
80% 4000 µl/kg bw dose
100% 5000 µl/kg bw dose respectively.

Body weight:

lower than 10% body weight loss

Remarks:

body weight reduction at 1500 µl/kg bw and above.

Other findings:

Signs of intoxication: Sedation, reduction of gerneral condition. Female rats showed a body weight reduction at 1500 µl/kg bw and above. A dose of 1000 µl/kg bw was tolerated by male and female rats without symptoms.

 

Dose mg/kg	Sex	Symptoms
1.0	M	-
1.5	M	Worsening General well-being; Sedation.
2.0	M	Worsening General well-being; Sedation.
2.5	M	Worsening General well-being; Sedation.
3.1	M	Worsening General well-being; Sedation.
4.0	M	Worsening General well-being; Sedation.
5.0	M	Worsening General well-being; Sedation.
1.0	F	-
1.5	F	Worsening General well-being; Sedation; Weight lost.
2.0	F	Worsening General well-being; Sedation.
2.5	F	Worsening General well-being; Sedation.
3.1	F	Worsening General well-being; Sedation; Weight lost.
4.0	F	Worsening General well-being; Sedation; Weight lost.
5.0	F	Worsening General well-being; Sedation.

 

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

Moderately Toxic. No symptoms at 1000 µl/kg bw was tolerated by male and female rats without symptoms.

Executive summary:

Five male and 5 female young adult male Wistar rats (160 -180 g) per group were dosed undiluted at 1000, 1500, 2000, 2500, 3100, 4000 or 5000 µl/kg bw m-tolylisocyanate. The animals were observed for mortality body weights and clinical signs through day 14.

Signs of intoxication: Sedation, reduction of gerneral condition. Fermale rats showed a body weight reduction at 1500 µl/kg bw and above. A dose of 1000 µl/kg bw was tolerated by male and female rats without symptoms.

The symptoms appeared 1 hour after application low to moderately pronounced and partially held until the last test day. The deaths were recorded from the 4th hour to the 4th day of the experiment. There were none between males and females significant differences in the nature and intensity of the symptoms and the number of deaths. The acute oral LD50 for male rats is 2760 µl/kg bw (= ca. 2926 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 926 mg/kg bw

Quality of whole database:

The materials/methods and results are described in detail and are sufficient for evaluation.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

Study period:

From 27 July 1987 To 27 July 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study - well documented

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Thirteen groups of 5 to 10 male and female rats each were exposed nose/head-only to 0, 25, 62, 74, 99, 111, 159, 169, 173, 176, 274, 331, or 492 mg/m³ m-tolylisocyanate (vapour) for 4 hours.

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Rationale for alternative/additional species to rat (if applicable) n/a
- Source: Bayer AG.
- Females (if applicable) nulliparous and non-pregnant: [yes
- Rationale for use of males (if applicable) n/a
- Age at study initiation: 7 weeks
- Weight at study initiation: 160 gr 220 gr
- Fasting period before study: n/a
- Housing: Makrolon-Kafigen Type III cage
- Historical data: n/a
- Diet (e.g. ad libitum): n/a
- Water (e.g. ad libitum):n/a
- Acclimation period:n/a
- Microbiological status when known n/a
- Method of randomisation in assigning animals to test and control groups n/a

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 50
- Air changes (per hr): 12, from 6 am to 6 pm.
- Photoperiod (hrs dark / hrs light): n/a

IN-LIFE DATES: From: To:n/a

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

air

Details on inhalation exposure:

Chamber:
8 to 10 bars.
110 volumes automatically conditioned.
70% test atmosphere.

Environmental conditions without test animals:
Temperature: 24 °C
Humidity: 14 %

Environmental conditions with test animals:
Temperature: 25 °C
Humidity: 34%

Environmental conditions with test item:
Temperature: 21- 23°C (supply air)
Humidity: 10 to 40 % (supply air) 40 to 50 % (exhaust air)

Duration of exposure:

4 h

Concentrations:

0, 25, 62, 74, 99, 111, 159, 169, 173, 176, 274, 331, or 492 mg/m³

No. of animals per sex per dose:

5 to 10 male and 5 to 10 female rats/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 4 hours
- Frequency of observations and weighing:n/a
- Necropsy of survivors performed: no
- Clinical signs including body weight:serous and blood nasal discharge, breathing difficulties, cyanosis, dyspnea, reduced motility.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:n/a

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

33 mg/m³ air

Based on:

test mat.

95% CL:

26 - 44

Exp. duration:

4 h

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

30 mg/m³ air

Based on:

test mat.

95% CL:

24 - 39

Exp. duration:

4 h

Mortality:

during the post-exposure period which had no symtoms immediately after the exposition to m-tolylisocyanate.

Clinical signs:

irregular respiration

Remarks:

aggravated and slowed down breathing; Pulmonary edema and hydrothorax, hyperinflated lungs

Body weight:

Body-weight gain was noted from group 3 onwards.

Gross pathology:

Registered chages in the following organs:
Liver,
spleen,
and
kidneys.

Other findings:

Group 1 and Group 2::
All rats tolerated exposition symptomless.
Group 3: breathing difficulties, minor cyanosis and ruffled fur.
Group 4:breathing, tachypnea, Piloerection, cyanosis, emaciation, Motility issues, prostration (prefinal)
and flabbiness (lethargy).
Group 5:aggravated breathing, reduced motility ruffled fur, serous nasal discharge.
From 1st follow-up day also slowed breathing. End the follow-up week cyanosis and Emaciation,
slackness (lethargy).
From the middle of the 2nd week of follow-up, tachypnea.
Group 6: serous nasal discharge, sniffles, reduced breathing, Lethargy, reduced motility, tremors, scruffy and balked fur.
1st follow-up week= cyanosis, emaciation and wheezing.
Group 7:serous nasal discharge, reduced breathing, Lethargy, reduced motility, cyanosis, emaciation, scruffy fur, at the end of follow-up 1 rat was still presenting these symptoms.
Group 8:serous nasal discharge, reduced breathing, Lethargy, reduced motility, cyanosis, emaciation, scruffy fur, Motility issues, prostration.
Group 9:serous nasal discharge, reduced breathing, Lethargy, reduced motility, cyanosis, emaciation, scruffy fur, Motility issues, prostration. Symptoms more severe depending on the concentration of the test item.

A concentration of 6.6 mg/m³ m-tolylisocyanate for 4 hours was tolerated by the rats without clinical symptoms. A concentration of 13 mg/m³ influenced the body weight and was the beginning of the mortality range.

m-tolylisocyanate has a strong irritation potential on the respiratory tract. The duration of the symptoms are determined by the breathing discomfort, which have a low tendency to reversibility. In the lower concentration range the breathing discomfort was evident after 1 week. Therefore rats died during the post-exposure period which had no symtoms immediately after the exposition to m-tolylisocyanate.

 

 

N. animal	Nominal Concentration (mg/m^3)	SV Substance consumption (mg)	Primary Air (ml/min)	Diluted Air (l/min)	Mean S (l/min)
1	-	-	10000	-	10.00
2	25	60	33	10.0	10.03
3	62	150	123	10.0	10.12
4	74	180	148	10.0	10.15
5	99	240	100	10.0	10.10
6	111	270	150	10.0	10.15
7	159	390	200	10.0	10.20
8	169	420	360	10.0	10.36
9	173	430	350	10.0	10.35
10	176	430	200	10.0	10.20
11	274	690	500	10.0	10.50
12	331	850	700	10.0	10.70
13	492	1180	1000	9.0	10.00

 

 

Males:

N. animal	Nominal Concentration (mg/m^3)	Symptom duration	Time of death	Mortality (%)
1	-	-	-	0
2	25	-	-	0
3	62	14d-28d	-	0
4	74	7d-28d	8d-9d	30
5	99	4h-28d	8d-10d	30
6	111	4h-14d	2d-12d	100
7	159	4h-28d	8d-18d	70
8	169	4h-12d	2d-12d	100
9	173	4h-12d	7d-12d	100
10	176	4h-22d	8d-22d	100
11	274	4h-10d	7d-10d	100
12	331	4h-8d	1d-8d	100
13	492	4h-24h	<24h	100

 

Females:

N. animal	Nominal Concentration (mg/m^3)	Symptom duration	Time of death	Mortality (%)
1	-	-	-	0
2	25	8d-20d	-	0
3	62	7d-28d	13d	10
4	74	4h-28d	9d-15d	30
5	99	4h-28d	11d-16d	20
6	111	4h-28d	7d-12d	80
7	159	4h-16d	8d-17d	90
8	169	4h-12d	2d-16d	100
9	173	4h-12d	2d-12d	100
10	176	4h-19d	2d-19d	100
11	274	4h-12d	8d-12d	100
12	331	4h-14d	3d-14d	100
13	492	4h-3d	1d-3d	100

 

Interpretation of results:

Category 1 based on GHS criteria

Conclusions:

According to the United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS), Fifth revised edition 2013, is classified under Category 1.
T+ = Very Toxic; Potential high acute hazard.

Executive summary:

Thirteen groups of 5 to 10 male and female rats each were exposed nose/head-only to 0, 25, 62, 74, 99, 111, 159, 169, 173, 176, 274, 331, or 492 mg/m³ m-tolylisocyanate (vapour) for 4 hours.

A concentration of 6.6 mg/m³ m-tolylisocyanate for 4 hours was tolerated by the rats without clinical symptoms. A concentration of 13 mg/m³ influenced the body weight and was the beginning of the mortality range.

m-tolylisocyanate has a strong irritation potential on the respiratory tract. The duration of the symptoms are determined by the breathing discomfort, which have a low tendency to reversibility. In the lower concentration range the breathing discomfort was evident after 1 week. Therefore rats died during the post-exposure period which had no symtoms immediately after the exposition to m-tolylisocyanate.

The NOEL for male and female rats is 6.6 mg/m³ m-tolylisocyanate in air.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

30 mg/m³ air

Quality of whole database:

The materials/methods and results are described in detail and are sufficient for evaluation.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral route: 

In an acute oral toxicity study conducted in accordance with OECD 401 (Loeser, 1980), an LD50 of 2926 mg/kg bw on female rats was determined.  Five male and 5 female young adult male Wistar rats (160 -180 g) per group were dosed undiluted at 1000, 1500, 2000, 2500, 3100, 4000 or 5000 µl/kg bw m-tolylisocyanate. The animals were observed for mortality body weights and clinical signs through day 14.  Signs of intoxication: Sedation, reduction of gerneral condition. Fermale rats showed a body weight reduction at 1500 µl/kg bw and above. A dose of 1000 µl/kg bw was tolerated by male and female rats without symptoms.  The symptoms appeared 1 hour after application low to moderately pronounced and partially held until the last test day. The deaths were recorded from the 4th hour to the 4th day of the experiment. There were none between males and females significant differences in the nature and intensity of the symptoms and the number of deaths. The acute oral LD50 for male rats is 2760 µl/kg bw (= ca. 2926 mg/kg bw).

In a second acute oral toxicity study conducted in accordance with OECD 401 (Loeser, 1980), an LD50 of 3191 mg/kg bw fwas determined for males.  Five groups of 10 young adult male Wistar rats (160 -180 g) were dosed undiluted at 1000, 2000, 3100, 4000 or 5000 µl/kg bw m-tolylisocyanate. The animals were observed for mortality, body weights and clinical signs through day 14.  The corresponding mortality was 0% (1000 µl/kg bw), 10% (2000 µl/kg bw), 50 (3100 µl/kg bw), 80% (4000 µl/kg bw) and 100% (5000 µl/kg bw) respectively.  Signs of intoxication: Sedation, scrubby fur, cyanosis. The acute oral LD50 for male rats is 3010 µl/kg bw (=ca. 3191 mg/kg bw).

 

Inhalation route: 

In an acute inhalation study conducted according OECD 403 (Pauluhn, 1988) for male rats a LC50 = 33 mg/m³ air and for female rats a LC50 = 30 mg/m³ air (analytical vapour concentration) was determined. In an inhalation-hazard test rats were placed in a 10 l glass chamber and were exposed whole body for 3 or 10 min to the vapour of m-tolylisocyanate and were observed for 14 d after the exposure to the test substance. 3 min. exposure: 1/5 males died after 8d; 3/5 females died after 9d, signs of irritation were found;  10 min.exposure: all rats died within 3d, signs of irritation were found.

In a second acute inhalation study (Thyssen, 1980), five male and five female Wistar rats/exposure-period were exposed to saturated vapor atmosphere (whole body exposure) for 3 min or 10 min, respectively. Generation of the test atmosphere was carried out at room temperature (20 °C) by a stream of air being bubbled through the testsubstance. Animals were carefully observed during exposure and up to 14 days post exposure. A necropsy was performed on animals onto an exposure time of 10 minutes and which died during the observation period or were killed after termination of the study.  After an exposure time of 3 minutes to m-tolylisocyanate 1 out of 5 male rats died after 8 days, and 3 out of 5 female rats died after 9 days.  Immediately after the beginning of the exposure all animals revealed abnormal behaviour, breathing discomfort, a temprary excitement or sedation, increased lacrimation and salivation and a strong irritation on the visible mucuous membranes of the eyes and nose (redness).  The surviving rats showed these symptoms immediately after exposure and during the whole observation period.  After an exposure time of 10 minutes all animals died within 3 days. Until dead the animals revealed the same symtoms as after an exposure of 3 minutes.  The animals which died had dark red coloured lugs filled with fluid.. The lungs were partly inlated. In the chest cavity a clear, yellowish fluid was presented. the surviving animals were killed 14 days after exposure. At necropsy changes in the lungs were observed (lungs were pale, laced with red dots, partly dark colored and inflated).

Justification for classification or non-classification

Harmonised classification:

The substance does not have a harmonised classification according to the Regulation (EC) No. 1272/2008 (CLP). 

 

Self-classification:

Based on the available information on the registered substance, self-classification is proposed according to GHS and CLP:

GHS not classified as a result of the LD50 = ca. 3000 mg/kg bw for the Oral route.

GHS classified for T+ R26 or Category 1, justified as a result of the LC50 = 30 mg/m³ air the Inhalation Route.

No study available for dermal route.