3-aminomethyl-3,5,5-trimethylcyclohexylamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: Human inhalative exposure to the test item Isophorone diisocyanate (IPDI).

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Test chamber exposure of humans to 1,6-hexamethylene diisocyanate and isophorone diisocyanate

Author:

Tinnerberg H, Skarping G, Dalene M and Hagmar L

Bibliographic source:

Int. Arch. Occup. Environ. Health 67, 367-374

Report date:

1995

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Human inhalative exposure to the test item Isophorone diisocyanate (IPDI). Determination of the IPDI content in blood and urine (analytical determination of the corresponding Isophorone diamine (IPDA) determined as IPDA-pentafluoropropionic anhydride) and determination of urinary IPDI excretion.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Isophorone diisocyanate

IUPAC Name:

Isophorone diisocyanate

Constituent 2

Reference substance name:

3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate

EC Number:

223-861-6

EC Name:

3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate

Cas Number:

4098-71-9

Molecular formula:

C12H18N2O2

IUPAC Name:

5-Isocyanato-1-(isocyanatomethyl)-1,3,3-trimethylcyclohexane

Details on test material:

Isophorone diisocyanate (IPDI) was obtained from Aldrich Chemie (Steinham, Germany); purity not reported; Note: Isophorone diisocyanate (IPDI) hydrolyses rapidly and spontaneously to the corresponding amine Isophorone diamine(IPDA) after ingestion into the body.

Radiolabelling:

no

Test animals

Species:

human

Strain:

other: healthy non-smoking volunteers

Sex:

male

Details on test animals or test system and environmental conditions:

- Three male healthy non-smoking volunteers
- 26, 28 and 50 years of age
- Body weights: 70 kg; 81 kg; 70 kg
- volunteers were interwieved for health history and exmined by a physican before the experimental phase
- Study was approved by the Ethics Committee at Lund University. all participiants gave written informed consent

Administration / exposure

Route of administration:

inhalation: aerosol

Vehicle:

other: air

Details on exposure:

- Three healthy male volunteers were exposed simultaneously in a 5.6 m3 exposure chamber to concentrations of 12.1 (Tuesday),
 17.7 (Thursday),  and 50.7 (Saturday) ug isophorone diisocyanate/m3 for 2 hours per  concentration level. 
- The inhaled doses were estimated by pulmonary ventilation x exposure  level x duration of exposure.

Duration and frequency of treatment / exposure:

Each volunteer was exposed to three different concentrations of the test item (12.1 (Tuesday),
 17.7 (Thursday),  and 50.7 (Saturday) ug isophorone diisocyanate/m3). The duration of each exposure was 2 hours.

Doses / concentrations

Remarks:

Doses / Concentrations:
Each volunteer was exposed to three different concentrations of the test item (12.1 (Tuesday),
17.7 (Thursday),  and 50.7 (Saturday) ug isophorone diisocyanate/m3)

No. of animals per sex per dose / concentration:

3 human male volunteers. Each volunteer was exposed to the three different concentrations.

Control animals:

no

Positive control reference chemical:

no positive control

Details on study design:

- Three healthy male volunteers were exposed simultaneously in a 5.6 m3  exposure chamber to concentrations of 12.1 (Tuesday),
 17.7 (Thursday),  and 50.7 (Saturday) ug isophorone diisocyanate/m3 for 2 hours per  concentration level. 
- The inhaled doses were estimated by pulmonary ventilation x exposure  level x duration of exposure.
- All urine was collected for 16 days.
- Blood samples were taken before and half an hour after exposure plus daily on exposure-free days.
- Samples were hydrolyzed, i.e. conjugates were split and any residual  isophorone diisocyanate was converted to isophorone diamine (IPDA)
(CAS No.  2855-13-2).
- This diamine was determined as its pentafluoropropionic amide by liquid  chromatography / mass spectrometry.

Details on dosing and sampling:

- Three healthy male volunteers were exposed simultaneously in a 5.6 m3  exposure chamber to concentrations of 12.1 (Tuesday),
 17.7 (Thursday),  and 50.7 (Saturday) ug isophorone diisocyanate/m3 for 2 hours per  concentration level. 
- The inhaled doses were estimated by pulmonary ventilation x exposure  level x duration of exposure.
- All urine was collected for 16 days.
- Blood samples were taken before and half an hour after exposure plus  daily on exposure-free days.
- Samples were hydrolyzed, i.e. conjugates were split and any residual  isophorone diisocyanate was converted to isophorone diamine (IPDA)
(CAS No.  2855-13-2).
- This diamine was determined as its pentafluoropropionic amide by liquid  chromatography / mass spectrometry.

Statistics:

not reported

Results and discussion

Preliminary studies:

no information

Toxicokinetic / pharmacokinetic studies

Details on absorption:

no information

Details on distribution in tissues:

details on distribution in tissues not known

Transfer into organs

Test no.:

#1

Transfer type:

other: not described; No isophorone diamine (IPDA) could be detected in hydrolysed plasma

Observation:

not determined

Details on excretion:

Urinary excretion:
-The average urinary elimination half-time was 2.8 hours. 
-The average  urinary excretion was 27 % (range 19-46%). 
- An association between the  estimated inhaled dose and the total excreted amount was seen.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 2.8 h

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

other: urinary excretion was 27 % 

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Isophorone diisocyanate (IPDI) hydrolyses to the corresponding amine Isophorone diamine(IPDA). Because no IPDA was found in unhydrolysed urine samples the authors conclude that IPDA is covalently bonded.

Any other information on results incl. tables

The detection limit was about 0.1 µg/l in urine and  0.1 µg/l in plasma. No isophorone diamine was found in hydrolyzed plasma. When working up samples from exposed persons without hydrolysis, no isophorone diamine was seen.

Applicant's summary and conclusion

Conclusions:

The average urinary elimination half-time was 2.8 hours. The average  urinary excretion was 27 % (range 19-46%). An association 
between the  estimated inhaled dose and the total excreted amount was seen. The detection limit was about 0.1 µg/l in urine and < 0.1 µg/l in plasma. No isophorone diamine was found in hydrolyzed plasma. When working up samples from exposed persons without hydrolysis, no  isophorone diamine was seen. The authors conclude that IPDA is covalently bonded. Analysis of urine regarding Isophorone diamine, which is a hydrolysis product of Isophrone diisocyanate (IPDI) can be used as biomarker for exposure to IPDI.

Executive summary:

A method was developed to determine the test item Isophorone diisocyanate (IPDI) in blood and urine via detection of Isophorone diamine (IPDA) measured as as IPDA-pentafluoropropionic anhydride in humans exposed to IPDI by inhalation. The optimal hydrolysis condition was found giving the highest yield of IPDA in urine (hydrolysis with 3M NaOH during 4 h). The average urinary elimination half-time was 2.8 hours. The average  urinary excretion was 27 % (range 19-46%). An association between the estimated inhaled dose and the total excreted amount was seen. When working up samples from exposed persons without hydrolysis, no isophorone diamine (IPDA) was seen. This means, that no free IPDA was present in the urine after exposure to IPDI. Hence, IPDA is covalently bonded in urine. No IPDA could be found in hydrolysed plasma ( ca 0.1µg/l), which could not be explained.