1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Full report, methods are in accordance with test guidelines.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Reference 2

Reference Type:

publication

Title:

Absorption, distribution, metabolism and excretion of an inhalation dose of (14C) 4,4'-methylenediphenyl diisocyanate in the male rat.

Author:

Gledhill A, Wake A, Hext P, Leibold E and Shiotsuka R.

Year:

2005

Bibliographic source:

Xenobiotica 35(3): 273-92

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:

Investigation of the routes and rates of excretion and the tissue distribution of radioactivity in the male rat following a 6 hour inhalation exposure to [14C]-MDI/kg.

GLP compliance:

yes

Test material

Test material information

Constituent 1

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)

Constituent 2

Reference substance name:

benzene, 1,1'- methylenebis[4-isocyanato-

IUPAC Name:

benzene, 1,1'- methylenebis[4-isocyanato-

Details on test material:

Unlabeled test substance:
- Name of test material (as cited in study report): diphenylmethane 4,4'-diisocyanate, casnr. 101-68-8, monomeric MDI.
- Physical state: solid
- Analytical purity: 98% (Sigma-Aldrich)
- storage conditions: 0-4°C in the dark, under nitrogen

Radiolabelled test substance:
- Name of test material (as cited in study report): 14C-diphenylmethane 4,4'-diisocyanate (Amersham)
- Lot/batch No.: CTL ref no. Y00122/026
- Radiochemical purity (if radiolabelling): >97% following repurification (as determined by HPLC)
- Specific activity (if radiolabelling): 4.48GBq/mMole
- Locations of the label (if radiolabelling): ring labelled
- Storage condition of test material: desiccated, at -20°C

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Biological Services Section
- Weight at study initiation: 291-348g
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: >4 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3°C
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: Inhalation; condensation aerosol, head-only

Details on exposure:

TYPE OF INHALATION EXPOSURE: head only
The routes and rates of excretion and the tissue distribution of radioactivity in the male rat (6 groups of four Wistar-derived rats) following a 6 hour inhalation exposure (condensation aerosol, head-only) to 14C-MDI at a nominal concentration of 2 mg/m³ was investigated.

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Each test atmosphere was generated using a condensation aerosol. A saturated vapor was generated and delivered into the 46 liter exposure chamber at nominal flow rates of 10 l/min. The test subsance concentration and the minimum of 12 air changes was regulated with diluting air at 2 l/min.
- Method of holding animals in test chamber: poIycarbonate tubes , with latex collar fitted around each animal's neck

TEST ATMOSPHERE
- MDI concentration (Particulate mass concentration was measured gravimetrically): 3.67mg/l +/-0.76
The received mean total dose of radioactivety was 33.72 kBq per animal, being equivalent to 0.078 mg MDI equivalents per rat.
- no MDA was detected in the test atmosphere (atmospheric concentrations of MDI were determined by analysis of a filter sample)
- Particle size distribution (aerodynamic particle size distribution was measured using a Marple Cascade Impactor) :
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.39µm/ 2.01
Analysis of the radioactiv dose preparation by liquid scintillation counting.

Duration and frequency of treatment / exposure:

6 hour(s)

Doses / concentrations

Remarks:

Doses / Concentrations:
Males: 3.67 mg/m³ (non toxic dose level)

No. of animals per sex per dose / concentration:

Males: 4 Females: 0

Details on study design:

Immediately after the exposure, one group was killed by a lethal injection to determine the received dose. These rats were decapitated and the skin was separately removed from the head and the body. The head, skin from the head, carcass and pelt were analysed separately. The radioactivity in each of these tissues was summed for each animal to determine the received dose.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, various tissues, cage washes, bile
- Time and frequency of sampling: Four groups were killed at intervals up to 168 hours after exposure and selected tissues taken for analysis in order to investigate tissue distribution of absorbed material. Urine and faeces were also collected from these rats. Rats in the fifth group were surgically fitted with a bile duct cannula prior to exposure and urine, bile and faeces were collected until 48 hours after dosing, when these rats were terminated.
The radioactivity in excreta, bile and tissues was measured.
In a separate exposure experiment, 4 male rats were exposed to a similar 14C-MDI atmosphere for 6 hours before urine, faeces and exhaled CO2 were collected for up to 36 hours.

ANALYSIS OF RADIOACTIVITY: Liquid scintillation counting (Packard Tricarb instrument)

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

In conclusion, most of the systemically available dose was excreted via bile with a slightly smaller proportion excreted in urine. There was no radioactivity present in exhaled CO2.

Main ADME results 2

Type:

distribution

Results:

Radioactivity was widely distributed, with the respiratory and excretory organs containing the highest concentrations of radioactivity. These declined to low levels of residues in all tissues analysed after 168 hours.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Particle size analyses (MMAD 1.39 µm, GSD 2.01) and the amounts of radioactivity found in the lungs (approximately 13% of the dose) demonstrated that the 14C-MDI atmospheres were highly respirable to the rats. Inhalation exposure of rats to 14C-MDI resulted in the rats receiving a combined inhalation/oral dose as radioactivity deposited on the head and pelt during the exposure was ingested during grooming.

During the 168 hour post-exposure period approximately 5% and 79% of the dose were excreted in urine and faeces, respectively (see table2). Over a 48 hour interval after exposure, bile duct cannulated rats excreted approximately 12% of the dose in urine, 14% in bile and 34% in faeces. In conclusion, most of the systemically available dose was excreted via bile with a slightly smaller proportion excreted in urine. There was no radioactivity present in exhaled CO2.

Details on distribution in tissues:

Radioactivity was widely distributed, with the respiratory and excretory organs containing the highest concentrations of radioactivity. These declined to low levels of residues in all tissues analysed after 168 hours.
More in detail, immediately after the exposure period the highest proportions of radioactivity were found in the residual carcass and gastrointestinal content (accounting for 37% and 32% of the dose respectively). The lungs, gastrointestinal tract, liver and respiratory nasal tissue accounted for 13%, 4%, 3% and 1% of the dose respectively. All other tissues measured contained less than 1% of the received dose. The highest concentration of radioactivity (67 µg equiv./g) was present in the respiratory nasal tissue.
The lungs and trachea contained 7 and 3 µg equiv./g respectively, and the olfactory nasal tissue and thyroid each contained approximately 1.0 µg equiv./g respectively. The concentration of radioactivity in each of the other tissues analysed was 0.5 µg equiv./g or less. At 8 hours after the end of exposure the gastrointestinal contents contained the highest proportion of radioactivity, accounting for 48% of the dose. The residual carcass contained 34% of the dose and the lungs 10%. Respiratory nasal tissue and the liver contained 4% and 3% of the dose respectively, and the gastrointestinal tract and stomachcontents each contained 2% of the dose. Again, the respiratory nasal tissue contained the highest concentration of radioactivity, 394 µg equiv./g. The lung, trachea and olfactory nasal tissue contained the next greatest concentrations: 5 µg equiv./g in the lungs and 1 µg equiv./g in each of the trachea and olfactory nasal tissue. Other tissues contained radioactivityat 0.5 µg equiv./g or less.
By 24 hours after the end of exposure the highest proportion of radioactivity was present in the residual carcass and the gastrointestinal contents (19% and 13% of the dose respectively). Lungs and liver were the only other tissues containing appreciable amounts of radioactivity, 6% and 2% of the dose respectively.

All other tissues contained radioactivity at or below 1% of the dose. Respiratory nasal tissue, lungs and trachea contained radioactivity at concentrations of 17.3 and 1 µg equiv./g respectively. The concentration of radioactivity in the olfactory nasal tissue was 0.3 µg equiv./g and in the adrenals 0.2 µg equiv./g. All other tissues contained radioactivity concentrations of 0.2 µg equiv./g or less. At 168 hours after exposure, the lungs contained 4% of the administered dose and the gastrointestinal contents contained 1% of the dose. The residual carcass contained 5% of the dose. All other tissues contained less than 1% of the dose. Respiratory nasal tissue, thyroid and the lungs contained the highest concentrations of radioactivity, 3 µg equiv./g, 3 µg equiv./g, and 2 µg equiv./g respectively. The concentration of radioactivity in the adrenals was 0.3µg equiv./g. All other tissues contained less than 0.2 µg equiv./g.

Details on excretion:

Total excetion in rats 168h after dosing: 86.4% (total recovery: 99.5%),
approximaterly 79% in faeces, 5% in urine and 3% in terminal cage wash. 1% of the dose was present in the GI-tract content.

Total excetion in bile cannulated rats 48h after dosing: 62.16%, approximaterly 34% in faeces, 12% in urine, and 14% in the bile. At the temination of
this experiment the mean percentage of dose present in the gastrointestinal tract contents was 23%.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

According to the author, the tissue distribution of radioactivity at different time points after exposure, when considered with the excretion data, imply that the systemic doses were mainly due to absorption of radioactive material present in the gastrointestinal tract after ingestion, with pulmonary absorption of radioactivity deposited in the lungs accounting for only a minor, hardly quantifiable portion of the systemic dose.

Immediately at the end of the exposure period 32% of the received dose was present in the gastrointestinal tract, which could be explained by ingestion of radioactivity deposited on the head and the respiratory tract during exposure. The residual carcass analysed immediately at the end of the exposure period contained 37% of the received dose, with 36% of this present on the skin and 1% present in the true residual carcass (without skin). At 168 hours after dosing, the radioactivity in the residual carcass had decreased to 5% of the received dose. This decrease in radioactivity was accompanied by a concomitant increase in the cumulative excretion of radioactivity in the faeces. It was found reasonable by the author, to conclude therefore, that radioactivity present on the skin was ingested during grooming. This conclusion was supported by the excretion, from the bile duct cannuled rats, of 34% of the received dose in faeces. If the exposure to radioactivity was exclusively via the inhalation route, the radioactivity in faeces from these animals would have been negligible.

Table 1: Distribution of radioactivity (%) in rats terminated immediately after cessation of exposure.

^skin from head	^28
^pelt	^8
^head	^15
^carcass	^49

Table 2: Mean excretion of radioactivity in urine, faeces and bile (expressed as % of received radioactivity +/-SD)

^time after dosing [h]	^urine	^faeces	^urine (bile cannulated rats)	^faeces (bile cannulated rats)	^bile
^0-6	^0.39 +/-0.12	^-	^7.57 +/-0.12		^6.25 +/-1.77
^6-12	^1.35 +/-0.29	^36.82 +/-9.61	^1.41 +/-0.12	^17.08 +/-13.4	^2.3 +/-0.43
^12-24	^0.94 +/-0.24	^6.01 +/-4.03	^1.31 +/-0.12	^4.01 +/-4.01	^2.36 +/-0.73
^24-36	^0.68 +/-0.33	^17.03 +/-4.76	^1.51 +/-0.12	^7.47 +/-4.55	^1.98 +/-0.86
^36-48	^0.26 +/-0.02	^2.84 +/-3.05	^0.73 +/-0.12	^5.87 +/-4.213	^0.93 +/-0.74
^48-72	^0.46 +/-0.17	^6.91 +/-1.91
^72-96	^0.38 +/-0.09	^3.65 +/-0.74
^96-120	^0.3 +/-0.11	^2.55 +/-0.51
^120-144	^0.18 +/-0.03	^1.61 +/-0.29
^144-168	^0.151 +/-0.04	^1.34 +/-0.68
^0-48	^-	^-	^12.36 +/-6.89	^34.44 +/-14.83	^13.83 +/-8.5
^0-168	^5.09 +/-1.09	^78.75 +/-17.49

Table 3: Tissue and carcass residues of radioacticity. Values expressed as % of received radioactivity (+/-SD) of n=4 rats. Only tissues with >1% are listed.

	^0h	^8h	^24h	^168h
^GI-tract	^4.173 +/-0.801	^2.391 +/-0.769	^0.992 +/-0.406	^0.141 +/-0.007
^liver	^3.379 +/-0.756	^2.876 +/-0.42	^2.004 +/-0.408	^0.424 +/-0.058
^lungs	^12.771 +/-2.521	^10.15 +/-1.897	^5.558 +/-0.944	^3.558 +/-0.503
^nasal tissue (respiratory)	^1.44 +/-1.873	^4.069 +/-2.603	^0.182 +/-0.247	^0.058 +/-0.01
^residual carcass	^37.106 +/-9.752	^33.56 +/-8.637	^18.539 +/-4.058	^5.001 +/-1.187
^total	^61.063	^54.901	^28.544	^5.159
^GI-content	^31.787 +/-5.133	^47.543 +/-19.356	^13.177 +/-5.487	^0.617 +/-0.13

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results

Executive summary:

Following a 6 hour inhalation exposure to [14C]-MDI, radioactivity was widely distributed. Initially, tissues associated with the respiratory tract contained the highest concentration of radioactivity, but over the 168 hour time course after the exposure period, these declined markedly to leave low residues in all tissues analysed.

Radioactivity deposited on the head and pelt during the exposure was ingested during grooming resulting in a combined oral/inhaled dose, with the ingestion derived dose predominating. Most of the systemically available dose was excreted via bile (14%) with a slightly smaller (12%) proportion excreted in urine.

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