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Administrative data

acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-05-20 to 2009-07-02
1 (reliable without restriction)

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
GLP compliance:
Test type:
up-and-down procedure

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-Methylenediphenyl diisocyanate, oligomers
EC Number:
EC Name:
4,4'-Methylenediphenyl diisocyanate, oligomers
Cas Number:
Molecular formula:
C14 H10 N O [C29 H20 N4 O2]n NCO, n= 0-2
1,1'-methylenebis(4-isocyanatobenzene) homopolymer

Test animals


Administration / exposure

Route of administration:
oral: gavage
other: propylene carbonate - NF
Details on oral exposure:
The 175 mg/kg dose level was prepared at 35 mg/ml and dosed at 5 ml/kg
(dose volume). The 550, 2000 and 5000 mg/kg levels were dosed as received at 0.45, 1.6 or 4.1 ml/kg, respectively. The 175 mg of test article
was brought to a volume of 5 ml with the vehicle. Each preparation was
made daily on the day of dosing. The stock bottle was inverted several
times prior to dispensing. The 175 mg/kg formulation was described as a
clear liquid. The test article stock bottle was purged with nitrogen after use.
The test article/dosing suspensions were
administered on Day 1 to each rat as a single
dose via oral gavage. Animals were fasted
overnight prior to dose administration. Each
animal received its designated dose based on
fasted body weight determined just prior to dosing.
The dose volumes were between 0.45 and 5 ml/kg
and were based on the specific density of
1.22 g/ml as per the MSDS.
Details on study design:
The first animal was dosed at an initial dose level of 175 mg/kg. Since this
animal survived, the second animal received a higher dose (550 mg/kg) and the
third received the test article at 2000 mg/kg. One animal followed by two
additional animals were dosed at 5000 mg/kg. The dose for each successive
animal was adjusted up or down, depending on the previous result. The test
continued based on the fixed time interval outcomes of all the animals up to that
point and until one of the stopping criteria was first met. There were three
possible stopping criteria.
• 3 consecutive animals survive at the limit dose;
• 5 reversals occur in any 6 consecutive animals test;
• or at least 4 animals have followed the first reversal and the specific likelihood-ratios exceed the critical value.

Results and discussion

Effect levels
Key result
Dose descriptor:
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality was not observed in any of the animals dosed at 175, 550, 2000 or
5000 mg/kg of the test article.
Clinical signs:
other: All animals appeared normal throughout the study at 550, 2000, 5000 mg/kg. Clinical signs of soft stool and piloerection were observed in one animal at 175 mg/kg on Day 2.
Gross pathology:
Terminal necropsy revealed no visible lesions in any of the animals at 175, 550
2000 or 5000 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Based on the results of this study, the oral LDso for the test material in rats was estimated to be greater than 5000 mg/kg.
Executive summary:

The available data indicate that all substances of the MDI category are of low toxicity by the oral route. Following acute oral exposure, the NCO groups present on the substances of the MDI category react with acids within the stomach leading to formation of an insoluble polymerized mass that is excreted in the feces without being absorbed. Acute oral toxicity studies performed on a sufficient representation of category substances define a lack of acute oral toxicity across the category.

This low toxicity is consistent with the overall hypothesis:  a) the bioaccessible reactive NCO group drives chemical and biological activity, and b) MDI substances are not systemically absorbed because the NCO groups present on them react with acids within the stomach leading to the formation of an insoluble polymerized mass that is excreted in the feces without being absorbed. 

All substances of the MDI category share similar chemical features namely that they a) all contain a significant amount of mMDI, and b) contain at least two NCO functional groups per molecule which is bound to an aromatic ring and this ring is connected to a second aromatic ring by a methylene group. It is the NCO value (driven by the bioaccessible groups on monomeric MDI and low molecular weight constituents (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As reactive NCO groups are a common feature of all substances of the MDI category, it is predicted that these have a similar reactivity profile and a read across within the category is warranted (detailed information on the Mode of Action is available in Category Justification Document).