4,4'-methylenedicyclohexyl diisocyanate

Acute Toxicity: oral

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1976

Report date:

1976

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-methylenedicyclohexyl diisocyanate

EC Number:

225-863-2

EC Name:

4,4'-methylenedicyclohexyl diisocyanate

Cas Number:

5124-30-1

Molecular formula:

C15H22N2O2

IUPAC Name:

1,1'-methylenebis(4-isocyanatocyclohexane)

Details on test material:

- Purity: no data

Test animals

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

Administration / exposure

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

Results and discussion

Effect levels

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.

Applicant's summary and conclusion

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).