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Basic toxicokinetics

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basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD 417 guideline study (GLP)
Reason / purpose for cross-reference:
reference to other study

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
equivalent or similar to guideline
OECD Guideline 417 (Toxicokinetics)
GLP compliance:

Test material

Constituent 1
Reference substance name:
m-tolylidene diisocyanate
EC Number:
EC Name:
m-tolylidene diisocyanate
Cas Number:
Details on test material:
- Name of test material (as cited in study report): Technical grade TDI (Mondur TD-80)
- Isomers composition: ca. 80% 2,4-TDI, ca. 20% 2,6-TDI
- Supplier: Mobay Chemical Corporation

- Isomers composition: 82% 2,4-TDI; 18% 2,6-TDI
- Lot/batch No.: 84-68-19
- Supplier: Midwest Research Institute
- Radiochemical purity: >=99%
- Specific activity: 23.5 mCi/mmol
- Storage condition of test material: frozen at -80°C

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratory
- Age at study initiation: 51-53 days
- Weight at study initiation: 128-143 g
- Housing: Polycarbonate cages on Ab-Sorb-Dri hardwood chip bedding
- Individual metabolism cages: yes
- Diet: Purina rodent chow ad libitum
- Water: tap water ad libitum

- Temperature (°C): 22 + / - 1.5
- Humidity (%): 50 + / - 15%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: glass chamber designed for head only exposure

The 14C-TDI atmosphere was generated by continuously bubbling dried air through a micro-generator containing 14C-TDI. The doses were prepared by transferring neat 14C-labeled TDI directly into the micro-generator. Volumes were determined by weight. In preparing the high dose, measured amounts of nonlabeled TDI were added to the micro-generator. The ideal volume of material in the micro-generator was ca. 0.175 mL and the maximum flow rate of air through the micro-generator was 200 cm3/min. During exposure, the micro-generator was kept in a constant temperature water bath (25-28°C). Airflow through the exposure chamber was controlled by the exhaust pump. The minimum exhaust rate was one air exchange per minute (1000 cm3/min). TDI was removed from the exhaust air by first bubbling the air through aliquots of ethylene glycol monoethyl ether and Marcali absorbing solutions in four serial impingers, and then adsorbance onto activated charcoal. The solvent solution was frozen at -20°C for later extraction.
Chamber atmospheres of TDI were monitored every 30 min during the 4-hr exposure with concentration analyzed by the Marcali method. The adjustion of the concentration was conducted by variation of the air flow through the chamber (exhaust rate) and/or the air flow through the generator (generation rate).
The Marcali method is resulting in a one value for both TDI-isoforms. No differentiation between 2,4-TDI and 2,6-TDI is possible.

Duration and frequency of treatment / exposure:
4 h
Doses / concentrations
Doses / Concentrations:
0.6 ppm, 2 ppm (0.004272 mg/l; 0.01424 mg/l conversion according to "The toxicologist's pocket handbook", Derelanko, Informa Healthcare, 2008)
No. of animals per sex per dose / concentration:
Control animals:
Details on dosing and sampling:
- following exposure animals were placed in metabolic cages for tissue and body fluid sampling
- Tissues and body fluids sampled: urine, feces, cage washes, expired CO2, tissues (liver, pancreas, nasal tissues, kidneys, spleen, skin (ears), lungs, adrenals, skeletal muscle, brain, testes, retroperitoneal fat, heart, thyroids, GI tract plus contents, carcass homogenates)

- Sacrifice:
one rat of each dose was sacrificed at the end of exposure or 4 h, 24 h and 96 h following exposure
- Sampling:
from rats sacrificed at 24 h, serial blood samples were taken by tail bleeding at 0, 0.5, 1, 2, 4, 6, 12, 24 h.
from rats sacrificed at 96 h urine and feces were sampled at 6, 12, 48 and 96 h

- Method types for identification:
Marcali method (indirect, colorimetric assay) for determination of the TDI concentration in the test atmosphere
Liquid scintillation counting for determination of overall radioactivity
High performance liquid chromatography for metabolic profiling / peak determination
Thin layer chromatography for metabolic profiling / differentiation of polar and non-polar metabolites

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
It is assumed that 100% of the TS inhaled is absorbed.
Details on distribution in tissues:
Most of the radioactivity was recovered in the GI tract. The concentration peaked after 4 h reaching 39.6 % (0.6 ppm) and 38.8 % (2 ppm), after 96 h this concentration declined to 1.5 % (0.6 ppm) and 2.2 % (2 ppm).
Furthermore the concentrations in blood, plasma and nasal tissue and lungs were highest directly after exposure (2.6% [blood], 1.8% [plasma], 2.1% [nasal tissue], 0.3% [lungs] for the 0.6 ppm dose; 2.1% [blood], 1.2% [plasma], 1.2% [nasal tissue] and 2.2% [lungs] for the 2 ppm dose). Those concentrations declined during the next 96 h to 0.5%, 0.3% 0.8% and 0.06% (0.6 ppm) or 0.4%, 0.2%, 0.026% and 0.2% (2 ppm). The concentrations of the remaining tissues were below 1%.
Details on excretion:
Urinary excretion was most rapid over 0 to 6 hr but was still continuing at 96 hr. More than 50% of the dose is excreted by feces, independently of the dose. The urinary excretion was ca. 24% for the 0.6 ppm dose and ca. 20% for the 2 ppm dose (see table 1).

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Chromotagraphic profiles of urine, feces and gastrointestinal contents were obtained. The HPLC profiles were complex therefore metabolite identification was not attempted. For comparison radioactivity was divided in polar and nonpolar. More polar products were recovered from the urine. There were no apparent differences in the distribution of polar and nonpolar products due to dose.

Any other information on results incl. tables

Table 1: Recovery of 14C (% of the dose) following a 4 h exposure to 14C-toluene diisocyanate

0.6 ppm 2 ppm
Tissue/ Excretum 0 h 4 h 24 h 96 h 0 h 4 h 24 h 96 h
Blood 2.623% 1.730% 1.642% 0.541% 2.107% 1.265% 0.911% 0.359%
Tissue 4.480% 2.902% 5.955% 1.637% 5.207% 3.661% 2.707% 1.147%
GI tract 12.693% 39.612% 16.248% 1.473% 6.551% 38.784% 12.917% 2.228%
Urine not sampled 5.761% 17.475% 24.095% not sampled 2.461% 13.531% 19.894%
Feces not sampled 0.020% 21.046% 54.073% not sampled not sampled 26.240% 52.716%
Carcass 80.194% 49.959% 37.590% 18.130% 86.131% 53.828% 43.674% 23.638%
Recovery 99.990% 99.984% 99.956% 99.949% 99.996% 99.999% 99.980% 99.982%

Applicant's summary and conclusion