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Diss Factsheets

Administrative data

Description of key information

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:
before Oct 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
e.g. no data on purity of test substance, non-GLP, test material (classified as Skin Irrit. Cat. 2) was applied undiluted
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Study conducted according to "Appraisal of the safety of Chemicals in Foods, Drugs and Cosmetics", by the Staff of the Division of Pharmacology, FDA (1959). The study design is equivalent to OECD 401, version of 1987.
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
- Strain: SPF-Wistar rats
- Source: Winkelmann, Paderborn, Germany
- Age at study initiation: no data
- Weight at study initiation: males 120-140 g, females 120-145 g
- Fasting period before study: 16 hours before study start feed was withheld
- Housing: singly
- Diet and Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 45-55
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 25.2 mL/kg
Doses:
15.9, 17.9, 20.0, 22.4 and 25.2 mL/kg bw (eq. to approx. 17000, 19200, 21400, 24000, and 27000 mg/kg bw; density at 20 °C: 1.07 g/mL)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Doses were defined based on an initially performed range finding; no details reported.
- Duration of observation period following administration: 14 days
- Examinations performed: clinical signs, body weight.
- Necropsy of survivors performed: yes
Statistics:
LD50 according to Litchfield & Wilcoxon
Sex:
male/female
Dose descriptor:
LD50
Effect level:
17 mL/kg bw
95% CL:
>= 15.74 - <= 18.36
Remarks on result:
other: 17.0 mL/kg is eq. to approx. 18200 mg/kg (density at 20 °C: 1.07 g/mL)
Mortality:
Mortalities occurred within 24 hours and up to 11 days post administration.
Mortalities in dose group: 4/10 at 15.9 mL/kg, 6/10 at 17.9 mL/kg, 8/10 at 20 mL/kg, 8/10 at 22.4 mL/kg, 10/10 at 25.2 mL/kg.
Clinical signs:
other:
Body weight:
other body weight observations
Remarks:
At the end of the 14-day post-exposure period surviving animals showed normal body weight gain.
Gross pathology:
At necropsy acute mortalities showed severe hyperemia of the gastrointestinal mucosa. For late mortalities and animals sacrificed at study termination a slight hyperemia of the gastrointestinal mucosa was found. Additionally, a loss of fur could be observed at the perineum and posterior extremities.
Executive summary:

In an earlier acute oral toxicity study according to "Appraisal of the safety of Chemicals in Foods, Drugs and Cosmetics" (FDA, 1959; equivalent to OECD TG 401) 5 male and 5 female rats received doses of undiluted 4,4´-methylenedicyclohexyl diisocyanate (15.9, 17.9, 20.0, 22.4 and 25.2 mL/kg bw; no details on substance identity available). Animals were observed for clinical signs and effects on body weight gain for a 14 -day post-exposure period. All animals were subjected to a gross necropsy.

Mortality occurred in all dose groups within 24 hours and up to 11 days post administration. Approximately 20 min. after substance administration reduced activity, impaired coordination, tremor, anomaly of posture, diarrhoea and piloerection were observed. These symptoms partly persisted 48 hours. The surviving animals exhibited normal behaviour in the further course of the study. At necropsy acute mortalities showed strong hyperemia of the gastrointestinal mucosa; for late mortalities and animals sacrificed at study termination slight hyperemia of the gastrointestinal mucosa was reported. Additionally a loss of fur was observed at the perineum and posterior extremities.

The calculated LD50 was 17 mL/kg bw (equivalent to 18200 mg/kg bw; density at 20 °C: 1.07 g/mL).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
18 200 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July - Aug 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
traditional method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Hsd/Win: WU (SPF)
- Source: Harlan-Winkelmann, Borchen, Germany
- Age at study initiation: 2-3 months
- Weight at study initiation: mean 170-200 g
- Housing: singly in Makrolon Type II cages (according to Spiegel & Goennert, Zschr. Versuchstierkunde 1, 38, 1961 and Meister, Zschr. Versuchstierkunde 7, 144-153, 1965)
- Diet and Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): approx. 50 %
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
>= 1.31 - <= 1.53 µm
Geometric standard deviation (GSD):
>= 1.71 - <= 1.77
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Mode of exposure: Animals were head-nose exposed to the aerosolized test article in restrainers made of Plexiglas.
- Generation of aerosol: The test substance was nebulized neat under dynamic conditions in a cylindric inhalation chamber. In order to increase the efficiency of the generation of respirable particles and to prevent larger particles from entering the chamber a preseparator/ baffle system was used. The inhalation chamber had the following dimensions: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 50 cm (internal volume = about 7.6 L). Details of this modular chamber and its validation have been published previously (Pauluhn, Journal of Applied Toxicology, 14, 55-62, 1994).
- Generation of atmosphere: Atmospheres were generated under dynamic conditions using a Braun Infusion pump or a Hamilton Microlab pump and a binary nozzle.
- Conditioning the compressed air: Compressed air was supplied by Boge compressors and was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer. Adequate control devices were employed to control supply pressure.
- Inhalation chamber equilibrium concentration: The test atmosphere generation conditions provide an adequate number of air exchanges per hour (approx. 237). Under such test conditions used chamber equilibrium is attained in less than one minute of exposure (t95% = 3 x chamber volume/chamber airflow). The ratio between the air supplied and exhausted was chosen so that approximately 90% of the supplied air is removed via the exhaust system.
- Exhaust air treatment: The exhaust air was purified via filter systems.
- Temperature and humidity measurements were performed by the computerized Data Acquisition and Control System using FTF11-sensors (Fa. Elka Electronic, Lüdenscheid).

TEST ATMOSPHERE
- The integrity end stability of the aerosol generation and exposure system was measured by using a RAS-2 real-time aerosol photometer (MIE, Bedford, Massachusetts, USA).
- Samples taken from breathing zone: yes
- Brief description of analytical method used: HPLC and additionally gravimetric analysis of filter samples (filter: Glass-Fibre-Filter, Sartorius, Göttingen, Germany; digital balance).
HPLC-method: Nitro-reagent-treated glass fibres were exposed to the test atmosphere. The content of isocyanate was analytically detected via HPLC.
- Particle size distribution: The particle-size distribution was analyzed using a BERNER critical orifice cascade impactor. 90% of the particle mass had an aerodynamic diameter - MMAD (Mass median aerodynamic diameter): The respirability of the aerosol was adequate, i.e. the mass median aerodynamic diameter (MMAD) was ~ 1.4 µm; geometric standard deviation (GSD) ~ 1.8.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
151, 388, 418, 552, 730, 865, and 1352 mg/m³ (gravimetric conc.)

No. of animals per sex per dose:
5
Control animals:
yes
Remarks:
air control
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Several times on day of exposure, twice on postexposure days, also on weekends.
- Frequency of weighing: Before exposure, on day of exposure, and on days 3, 7 and 14 post-exposure
- Necropsy of survivors performed: yes
- Other examinations performed: rectal temperature, reflexes
Statistics:
Calculation of LC50 was according to A.P. Rosiello et al., J. Tox. and Environ. Health 3, 797-809 (1977) and modified by J. Pauluhn; Bayer Report No. 11845 (1983)
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
434 mg/m³ air
95% CL:
>= 355 - <= 533
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
456 mg/m³ air
95% CL:
>= 313 - <= 667
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
431 mg/m³ air
95% CL:
>= 363 - <= 513
Exp. duration:
4 h
Mortality:
Mortalities occurred from 388 mg/m³ onwards from exposure day through post exposure day 4.
Number of deaths at each dose (time of death):
male rats: 0/5 at 151 mg/m³, 2/5 at 388 mg/m³ (1d-2d), 2/5 at 418 mg/m³ (1d-2d), 5/5 at 552 mg/m³ (1d-4d), 4/5 at 730 mg/m³ (1d-3d), 2/5 at 865 mg/m³ (1d-2d), 5/5 at 1.352 mg/m³ (0d-1d)
female rats: 0/5 at 151 mg/m³, 2/5 at 388 mg/m³ (1d), 2/5 at 418 mg/m³ (1d), 4/5 at 552 mg/m³ (1d-2d), 5/5 at 730 mg/m³ (1d), 5/5 at 865 mg/m³ (1d-3d), 5/5 at 1.352 mg/m³ (0d-1d)
Clinical signs:
other: see section "Other findings"
Body weight:
A significant and concentration dependent effect on body weight was observed in the post exposure period at and above 151 mg/m³.
Gross pathology:
Rats that died during the observation period: Hydrothorax, lung oedematous, trachea filled with foamy content, lung does not collapse after opening of thorax, lung reddish up to hepatoid appearance, liver with lobular pattern and pale, duodenumcontent mucous-reddish, spleen and kidneys pale.
Rats that were sacrificed at termination of the study no indications for specific concentration dependent effects on organs were found.
Other findings:
- Other observations:
Rectal temperature: a significant and concentration dependent decrease was seen.
Reflex examination: no indications for specific neurological changes were found.

Clinical signs were observed for all test substance treated group. Signs occurred during exposure and up to 12 days thereafter for males and 9 days thereafter for females and consisted of bradypnea, dyspnea, laboured breathing, rales, irregular breathing pattern, ungroomed coat, piloerection, motility reduced, tremor, hunched posture, highlegged gait, staggered gait, sluggish, cyanosis, vocalization, emaciation, serous discharge from nose, reddish rhinarium, wheezing, nose with red encrustations, nose-muzzle/red encrustations, and prostration (lying on belly).
At the end of the observation period all surviving animals were without symptoms.

Data from IUCLID4

RS-Freetext:
VALUE:
LC50 (male): 456 mg/m3 (95% confidence interval of 313 to 667 mg/m3)
LC50 (female): 431 mg/m3 (95% confidence interval of 363 to 513 mg/m3)
LC50 (male/female): 434 mg/m3 (95% confidence interval of 355 to 533  mg/m3)
MORTALITY:
Number of deaths at each dose (time of death), male rats: 151 mg/m3: 0/5;  388 mg/m3: 2/5 (1d-2d); 418 mg/m3: 2/5 (1d-2d); 552 mg/m3: 5/5 (1d-4d);  730 mg/m3: 4/5 (1d-3d); 865 mg/m3: 2/5 (1d-2d); 1,352 mg/m3: 5/5 (0d-1d)
Number of deaths at each dose (time of death), female rats: 151 mg/m3:  0/5; 388 mg/m3: 2/5 (1d); 418 mg/m3: 2/5 (1d); 552 mg/m3: 4/5 (1d-2d);  730 mg/m3: 5/5 (1d); 865 mg/m3: 5/5 (1d-3d); 1,352 mg/m3: 5/5 (0d-1d)
CLINICAL SIGNS:
Number of animals with clinical signs, male rats: >= 151 mg/m3: 5/5 (due  to early death at 1,352 mg/m3 clinical signs were only for 4/5 animals  recorded) showed during the exposure and up to 12d after the exposure  bradypnea, dyspnea, laboured breathing, rales, irregular breathing  pattern, ungroomed coat, piloerection, motility reduced, tremor, hunched  posture, highlegged gait, staggered gait, sluggish, cyanosis,  vocalization, emaciation, serous discharge from nose, reddish rhinarium,  wheezing, nose with red encrustations, nose-Muzzle/red encrustations,  prostration (lying on belly); at the end of the post observation period  all surviving animals were without symptoms
Number of animals with clinical signs, female rats: >= 151 mg/m3: 5/5  (due to early death at 1,352 mg/m3 clinical signs were only for 4/5  animals recorded) showed during the exposure and up to 9d after the  exposure bradypnea, dyspnea, laboured breathing, rales, irregular  breathing pattern, ungroomed coat, piloerection, motiltiy reduced,  tremor, hunched posture, highlegged gait, staggered gait, sluggish,  cyanosis, vocalization, emaciation, serous discharge from nose, reddish  rhinarium, wheezing, nose with red encrustations, nose-Muzzle/red  encrustations, prostration (lying on belly); at the end of the post  observation period all surviving animals were without symptoms
BODY WEIGHT:
>= 151 mg/m3: body weight retardation
RECTAL TEMPERATURE:
concentration dependent decrease
REFLEX EXAMINATION:
no substance induced effects
NECROPSY:
rats died during the post observation period:
pale liver, spleen and kidneys, lobular pattern of the liver, duodenum  was filled with a red mucous mass, trachea was filled with a mucous mass,  less collapsed lungs with red foci, pulmonary edema and hydrothorax;  lungs were red up to hepatoid changes, red secretions in the nose 
rats sacrificed at the end of the post observation period:
>= 151 mg/m3 no specific concentration dependent organ changes

Executive summary:

4,4´-Methylenedicyclohexyl diisocyanate has been assessed in the OECD HPV programme, 2005.

Partly cited from SIAR of SIAM 20 (Paris, April 19 -22, 2005):

An acute inhalation toxicity study of 4,4´-methylenedicyclohexyl diisocyanate (purity > 99.2 %) was performed "by exposing Wistar rats in seven groups, each containing 5 males and 5 females. The method used was essentially that of OECD TG 403. Each group was nose only exposed to concentrations of the aerosol of the test substance. After exposure (4 hours) the animals were observed for two weeks. The actual mean concentrations of 4,4´-methylenedicyclohexyl diisocyanate were 151, 388, 418, 552, 730, 865 and 1352 mg/m³. The test substance aerosol exhibited a particle-size indicating that this aerosol was of adequate respirability (90 % of the particle mass was ≤ 3 μm; mass median aerodynamic diameter (MMAD) ≈ 1.4 μm; geometric standard deviation (GSD) ≈ 1.8 μm). Rats exposed to ≥ 151 mg/m³ experienced signs of respiratory tract distress (i.e. salivation, bradypnea, stridor). Exposure to concentrations of ≥ 388 mg/m³ caused mortality, which occurred on the exposure day through post exposure day 4. Gross necropsy findings (less collapsed lungs including a hemorrhagic lung edema, red secretions in the nose, pale liver with lobular pattern, pale spleen and kidneys) were observed only in the rats which died during the observation period. The LC50 (4 h) stated in this study is 434 mg/m³ with confidence limits (95 %) of 355 - 533 mg/m³ both sexes combined."

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
434 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jan - Feb 1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
e.g. non-GLP, test material (classified as Skin Irrit. Cat. 2) was applied undiluted
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1981)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Bor: WISW (SPF TNO)
- Source: F. Winkelmann, Borchen, Germany
- Age at study initiation: no data
- Weight at study initiation (mean): males 240 g, females 211 g
- Housing: singly in Makrolon type III cages
- Diet and Water: ad libitum
- Acclimation period: 4-8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 60 +/- 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
other: covered with a mull patch, wrapped with an elastic bandage, fixed with Leukoflex
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: The application area was shorn 24 hours before administration.
- Type of wrap if used: The application area was covered with a mull patch (7x5 cm), wrapped with an elastic bandage and fixed with Leukoflex for 24 hours.
- Removal of test substance: Treated areas were washed with warm water after removal of the dressings.
Duration of exposure:
24 hours
Doses:
7000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
For dose finding a pretest was performed in advance. No details reported.

- Duration of observation period following administration: 14 days
- Frequency of observations: Animals were observed for effects during the first 6 hours after treatment and then daily in the further course of the study. Onset, type and duration of any clinical sign and onset of mortalities were recorded.
- Frequency of weighing: before application, and 1, 7, and 14 days thereafter
- Necropsy of survivors performed: yes
Statistics:
The statistical means of body weights were calculated. The LD50 was determined according to Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96, 1949, 99).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 7 000 mg/kg bw
Mortality:
Mortalities were not observed.
Clinical signs:
other:
Body weight:
other body weight observations
Remarks:
Body weight gain was transiently decreased.
Gross pathology:
At necropsy 7 animals showed partial hyperemia of the small intestine mucosa and 3 animals strong hyperemia of the forestomach mucosa. Additionally for one animal partly thickening of the forestomach mucosa was noted.
Executive summary:

An acute dermal toxicity study was conducted according to OECD TG 402 with 5 male and female rats per dose group. In that study the animals were once exposed for 24 hours to the undiluted test substance at a limit dose of 7000 mg/kg. The animals were observed for mortality, body weight gain and clinical signs for a period of 14 days. Gross necropsy was performed at termination of study.

Mortalities were not observed in the course of the study. Body weight gain was transiently decreased. The treated skin areas exhibited signs of irritation (erythema, oedema, scab formation). Gross necropsy findings, i.e. partial hyperemia of the small intestine mucosa, strong hyperemia of the forestomach mucosa and in one animal thickening of the forestomach mucosa also indicated irritant properties of the substance.

The LD50 was concluded to be > 7000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
7 000 mg/kg bw

Additional information

4,4´-Methylenedicyclohexyl diisocyanate has been assessed in the OECD HPV programme, 2005.

Cited from SIAR of SIAM 20 (Paris, April 19 -22, 2005): "4,4´-Methylenedicyclohexyl diisocyanate is of low oral and dermal acute toxicity with an oral LD50 (rat) of 9900 mg/kg bw and a dermal LD50 (rabbit) > 10000 mg/kg." Two additional studies that were not included in the OECD evaluation confirm the low oral and dermal acute toxicity with an oral LD50 (rat) of 18200 mg/kg bw and a dermal LD50 (rat) of > 7000 mg/kg. The effects were summarized in the OECD SIAR as follows: "Toxic symptoms after oral administration included severe diarrhea, loss of appetite and increasing weakness. Assessment of the acute inhalation toxicity data indicates that exposure to respirable aerosols of 4,4´-methylenedicyclohexyl diisocyanate confined predominantly to the respiratory tract. Clinical signs (salivation, bradypnea, stridor) indicated respiratory distress. A hemorrhagic lung edema was considered to be causative for mortality. An animal study according to OECD TG 403 gives a LC50 (4h, rat) of 434 mg/m³." A further acute inhalation toxicity study (OECD 403, rat), not included in the OECD evaluation, reveals a similar LC50 -value.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex VI, the substance is not legally classified for acute oral or dermal toxicity, but for acute inhalation toxicity with Cat. 3* (Minimum Classification).

Due to the LC50 of 434 mg/m³ and the criteria defined in Regulation (EC) No 1272/2008, Annex I, the required classification for acute inhalation toxicity is Cat. 2 (H330: Fatal if inhaled).