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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD 417 guideline study (GLP)

Data source

Referenceopen allclose all

Reference Type:
study report
Report date:
Reference Type:
Route-dependent comparative metabolism of [14C]toluene 2,4-diisocyanate and [14C]toluene 2,4-diamine in Fischer 344 rats
Timchalk C, Smith FA & Bartels MJ
Bibliographic source:
Toxicol.Appl.Pharmacol. 124: 181-90

Materials and methods

Objective of study:
Test guideline
equivalent or similar to guideline
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Unlabelled TDA:
- Name of test material (as cited in study report): 2,4-toluene-diamine (2,4-TDA)
- Analytical purity: >99%
- Lot: AX13004AX
- Supplier: Aldrich Chemical Company (Milwaukee, USA)

Radiolabelled TDA:
- Lot No.: 030H9222
- Supplier: Sigma Chemical Company (St Louis, USA)
- Radiochemical purity (if radiolabelling): 97.7%
- Specific activity (if radiolabelling): 20.7 mCi/mmol
- Locations of the label (if radiolabelling): uniformly ring labelled

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratory, Kingston, NY, USA
- Weight at study initiation: approximately 200 g
- Individual metabolism cages: yes
- Diet: Rodent Chow ad libitum
- Water: tap water ad libitum
- Acclimation period: one week

- Photoperiod (hrs dark / hrs light): 12 h/ 12 h

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
The radiotracer was diluted with non-radiolabeled compound to obtain a target radioactivity of 67 µCi/g of dosing solution. Adequate non-radiolabeled 2,4-TDA was added to the 3 and 60 mg/kg dose solutions to obtain target concentrations of 1 and 20 mg 2,4-TDA/g dosing solution, respectively. The final administration volume was 3ml dosing solution/kg bw.
The dosing solutions were analyzed for radioactivity and 2,4-TDA. The amount of radioactivity in the TDA dose solutions ranged from 83% to 148% of target, and all solutions were within 10% of their target concentration.

Duration and frequency of treatment / exposure:
Single exposure
Doses / concentrations
Doses / Concentrations:
3 or 60 mg/kg bw
No. of animals per sex per dose / concentration:
Control animals:
Details on study design:
Two groups of four male rats each were administered single oral doses of 3 or 60 mg 14C-2,4-TDA/kg of bw. Following oral administration of 14C-2,4-TDA, four rats/group were placed in glass Roth-type metabolism cages, and urine and feces were collected for up to 48 hr and analyzed for radioactivity. At 48 hr post-dosing the rats were sacrificed and selected tissues were collected and analyzed. Pooled urine specimens were analyzed by GC/MS and GC/MS/MS.
Details on dosing and sampling:
- Body fluids sampled: urine, feces, cage washes
- Time and frequency of sampling: Urine 12 h intervals, feces 24 h intervals, expired air 24 h
- From how many animals: samples pooled from 4 animals
- Method types for identification:
Liquid Scintillation Counting: determination of overall radioactivity
HPLC-Analysis: separation of urinary metabolites and quantification of 2,4-TDA
GC/MS and GC/MS/MS analysis: analysis of free 2,4-TDA, acid-labile conjugates of 2,4-TDA and mono and diacetyl TDA.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
93-97% of the administered radioactivity was recovered in urine, feces, tissues, carcass and final cage wash.
Given that the majority of compound is excreted by urine it can be assumed that 14C-TDA is well orally absorbed.
Details on distribution in tissues:
No data
Details on excretion:
The urine was the primary excretion route accounting for ca. 64 % of the administered radioactivity, while 22 - 31 % was recovered in the feces. For all treatment groups the percent radioactivity recovered in the carcass/skin was comparable, accounting for 2 - 5% of the administered dose, and less than 0.5% was recovered in the final cage wash. Comparison of the oral 60 and 3 mg 14 C-2,4-TDA/kg body weight treatment groups indicated no quantitative dose dependent differences in the routes of elimination (table 1).
Half-lives derived from urinary excretion time course:
t1/2 (60mg/kg) = 8h
t1/2 (3mg/kg) = 4.6h

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Monoacetyl 2,4-TDA, Diacetyl 2,4-TDA, free 2,4-TDA and acid-labile conjugates were detected in urine (see table 2).
The amounts of acetylated metabolites and 2,4-TDA detected in the urine from all treatment groups were proportional to the administered dose. Comparison of the ratio between the free + acetylated TDA metabolites with the total acid-labile metabolites indicated that following an oral dose of 60 mg/kg 14C-2,4-TDA approximately 61% of detected metabolites existed as either free or acetylated 2,4-TDA while the remaining 39% existed as other conjugates of 2,4-TDA. Whereas, following the 3 mg/kg dose, between 84% and 87% of the detectable metabolites were identified as either acetylated or free 2,4-TDA. This indicates that at lower doses, 2,4-TDA does not undergo much conjugation other than acetylation.

Any other information on results incl. tables

Table 1: Distribution of radioactivity 48 h after male Fischer 344 rats were given oral doses of 3 or 60 mg 14C-2,4-TDA/kg bw.

Percentage of administered 14C-2,4-TDA
3 mg/kg bw dose group 60 mg/kg bw dose group
Urine  63.67 ± 15.0 64.96 ± 2.47
Feces 30.7 ± 3.78 22.57 ± 1.54
Skin&Caracass 2.02 ± 0.36 4.62 ± 1.67
Cage wash 0.24 ± 0.11 0.49 ± 0.12
Recovery 96.62 ± 12.08 92.63 ± 0.67

Table 2: Concentration of 2,4 -TDA metabolites expressed as 2,4-TDA equivalents in the 0-12 h urine specimen following oral exposure to 14C-2,4 -TDA; Values are given as µg equivalents 2,4-TDA/ g urine

3 mg/kg bw dose group 60 mg/kg bw dose group
Monoacetyl 2,4-TDA 1.13 24.36
Diacetyl 2,4-TDA 1.88 20.34
Free 2,4-TDA 0.73 18.03
free + acetylated  2,4-TDA 3.74 62.73
2,4-TDA acid-labile conjugate 4.47 102.41

Table 3: Concentration of 2,4 -TDA metabolites expressed as 2,4 -TDA equivalents in the 0 -12 h urine specimen following oral exposure to 14C-2,4 -TDA; Values are given as absoluteµg equivalents 2,4-TDA.

3 mg/kg bw dose group 60 mg/kg bw dose group
Monoacetyl 2,4-TDA 6.09 247.9
Diacetyl 2,4-TDA 10.13 206
Free 2,4-TDA 3.93 183.48
free + acetylated 2,4-TDA 20.15 638.37
2,4-TDA acid-labile conjugate 24.09 1042.18
 free+acetylated/acid labile  88%  62%

Applicant's summary and conclusion