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EC number: 701-276-1 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study meets generally accepted scientific principles
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
- Objective of study:
- distribution
- excretion
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Principles of method if other than guideline:
- Distribution and excretion of [14C]MDI after topical application for 24 and 48h.
- GLP compliance:
- no
Test material
- Reference substance name:
- 4,4'-methylenediphenyl diisocyanate
- EC Number:
- 202-966-0
- EC Name:
- 4,4'-methylenediphenyl diisocyanate
- Cas Number:
- 101-68-8
- Molecular formula:
- C15H10N2O2
- IUPAC Name:
- 1,1'-methylenebis(4-isocyanatobenzene)
- Reference substance name:
- benzene, 1,1'- methylenebis[4-isocyanato-
- IUPAC Name:
- benzene, 1,1'- methylenebis[4-isocyanato-
- Details on test material:
- [Ring-U-14C]methylenediphenyl-4,4'-diiso-cyanate, [14C]MDI (Amersham)
specific activity 28 mCi/mmol
Acetone was dried 1 day before use by distillation over sodium sulphate and was added to the screwcapped vials containing [14C]MDI.
Quantitative analysis of isocyanate group content as ethylcarbamate by HPLC analysis.
Constituent 1
Constituent 2
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Ivanovas, Kisslegg, FRG or from BRL, Basel, Switzerland
- Weight at study initiation: approx. 220 g.
- Housing: Macrolone cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): NAFAG 890, Nafag AG, Gossau SG, Switzerland
- Water (e.g. ad libitum): yes
- Acclimation period: 7 days
Administration / exposure
- Route of administration:
- dermal
- Vehicle:
- acetone
- Details on exposure:
- TEST SITE
- Area of exposure: 3 x 3 cm
- Type of wrap if used: non, without occlusion
- Time intervals for shavings or clipplings: clipped 1 or 3 days prior to dosing.
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): approximately 100 µl, 2.5-3.6 mg MDI (experiment 1) or 6.9 mg MDI (experiment 2)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
15.1 and 10.9 mg/kg bw (experiment 1) or 29.8 and 29.1 mg/kg bw MDI (experiment 2).
- No. of animals per sex per dose / concentration:
- 4 in total
- Control animals:
- yes, concurrent vehicle
- Details on dosing and sampling:
- Animals were killed after 24h or 48h.
Blood was drawn by open heart puncture.
Epidermis (including hair remnants) of the treated area was scraped off with a scalpel blade.
The remainder of the skin, after removal of the subcutaneous fat, was analyzed as dermis.
Tissues and body fluids sampled: urine, faeces, blood, plasma, serum and organs.
In an additional experiment DNA and nuclear protein were isolated and the amount of [14C]MDI binding was determined. DNA binding was additionally assayed by the 32P-postlabeling method.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- 24h (48h) after topical administration of radiolabeled MDI, about 10% (12%) of the radioactivity was still found in the treated epidermis.
- Details on distribution in tissues:
- Total recovery: 50%
Systemic distribution of radioactivity was more or less uniform (1 nmol MDI equivalent per g tissue).
Only in the tongue the radioactivity was higher (due to low amount of oral exposure).
Dermal concentration was about 50 times higher than in blood. Concentrations in the muscle were 10 times lower than in blood.
Plasma concentration of radioactivity was 1.8-fold higher than the concentration in whole blood.
- Details on excretion:
- In feces after 24h: 22 and 16%
In feces after 48h: 6 and 15%.
In urine after 24h: 0.6 and 0.8%
In urine after 48h: 0.2 and 0.3%
(for 2 rats each)
Metabolite characterisation studies
- Details on metabolites:
- In the same study protein and DNA associated radioactivity in the epididermis, dermis , lung, liver, and kidney was assayed.
Nuclear protein exhibited extremely high specific activities (up to 10exp6 dpm/mg) in the epidermis. Specific activities of nuclear protein from liver, lung and kidney were about 10000-fold lower.
In experiment 1 (24h, 350µCi [14C]MDI administered per rat) none of the DNA samples contained detectable radioactivity.
In experiment 2 (48h, double amount of MDI-radioactivity) some hardly detectable radioactivity was associated with the DNA of both epidermis and liver (3-4 adducts per 10exp7 DNA-nucleotides.) But this includes the metabolites and conjugates which were systemically available.
In view of the extremely high radioactivity associated with epidermal protein, a substantial fraction of the DNA radioactivity is expected to be due to contamination by protein.
Conversion to the units of the Covalent Binding Index, CBI = (μmol adduct/mol DNA nucleotide per mmol chemical administered/kg bw) resulted in a value of <0.1 (maximum binding).
32P-postlabeling analysis did not reveal isocyanate-DNA adducts.
Any other information on results incl. tables
Table 1: Distribution of radioactivity after topical application of [14C]MDI, 24 and 48 h postdosage.
experiment 1 (24h) |
experiment 2 (48h) |
|||
body weight |
242 |
235 |
232 |
238 |
dose (mg/kg) |
15.1 |
10.9 |
29.8 |
29.1 |
dose (nmol/g) |
60 |
43 |
117 |
114 |
epidermis (nmol/g) |
2200 (9) |
1700 (12) |
9300 (12.6) |
13000 (12) |
dermis (nmol/g) |
n.d. |
n.d. |
74 (0.2) |
127 (0.4) |
blood (nmol/ml) |
1.4 (0.16) |
0.6 (0.1) |
1.3 (0.08) |
2.2 (0.14) |
plasma (nmol/ml) |
n.d. |
n.d. |
2.4 |
4.2 |
tongue (nmol/g) |
5.1 (0.017) |
1.2 (0.007) |
n.d. |
n.d. |
lung (nmol/g) |
0.6 (0.004) |
0.4 (0.005) |
0.6 (0.002) |
1.1 (0.005) |
liver (nmol/g) |
1.7 (0.09) |
1.4 (0.09) |
1.8 (0.05) |
3 (0.09) |
kidney (nmol/g) |
1 (0.019) |
0.8 (0.012) |
1.8 (0.011) |
2.9 (0.017) |
muscle (nmol/g) |
n.d. |
n.d. |
0.2 (0.064) |
0.3 (0.067) |
feces 24h (nmol/g) |
n.d. |
n.d. |
1985 (22.5) |
1470 (16.3) |
feces 48h (nmol/g) |
n.d. |
n.d. |
1211 (6) |
1777 (14.6) |
urine 24h (nmol/ml) |
n.d. |
n.d. |
27 (0.56) |
26 (0.81) |
urine 48h (nmol/ml) |
n.d. |
n.d. |
10 (0.2) |
6 (0.34) |
In brackets: percentage of radioactivity in whole organ in relation to the total administered
n.d., not determined.
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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