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Link to relevant study record(s)

Reference
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
Objective of study:
toxicokinetics
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
Radiolabelling:
no
Species:
human
Strain:
other: healthy non-smoking volunteers
Sex:
male
Details on test animals 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
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.
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:
3 human male volunteers. Each volunteer was exposed to the three different concentrations.
Control animals:
no
Positive control:
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
Preliminary studies:
no information
Details on absorption:
no information
Details on distribution in tissues:
details on distribution in tissues not known
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.
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 2.8 h
Test no.:
#1
Toxicokinetic parameters:
other: urinary excretion was 27 % 
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.

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.

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.

Description of key information

Three healthy male volunteers were exposed in a 5.6 m3 exposure chamber to 3-isocyanatomethyl-3,5,5-trimethyl- cyclohexyl isocyanate concentrations of 0.0121, 0.0177, and 0.0507 mg/m3for 2 hours at day 1, 3, and 5, respectively. The average urinary elimination half-time was 2.8 hours. The average urinary excretion of the corresponding amine was 27% (range 19 -46%). (Tinnerberg et al., 1995).

Key value for chemical safety assessment

Additional information

Cited from SIAR for SIAM 18 (Paris, April 2004): "No studies with respect to these endpoints have been performed."

Human toxicokinetic inhalative in vivo data from the substance Isophorone diisocyanate (CAS: 4098-71-9) is available that can be used to describe some toxikokinetic properties of Isophorone diamine, because Isophorone diisocyanate hydrolyses rapidly and spontaneously to the corresponding amine (Isophorone diamine) after ingestion into the body. Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006): "Three healthy male volunteers were exposed in a 5.6 m3exposure chamber to 3-isocyanatomethyl-3,5,5-trimethyl- cyclohexyl isocyanate concentrations of 0.0121, 0.0177, and 0.0507 mg/m3for 2 hours at day 1, 3, and 5, respectively. All urine was collected for 16 days, and blood samples were taken before and half an hour after exposure, and daily on exposure-free days. After hydrolysis (…note: here hydrolysis with 3M NaOH during 4 hours…) 3-isocyanatomethyl-3,5,5-trimethyl- cyclohexyl isocyanate was determined as 3-aminomethyl-3,5,5-trimethylcyclo- hexylamine. When working up samples from exposed persons without hydrolysis, no 3-aminomethyl-3,5,5-trimethylcyclohexylamine was seen. This indicates that the test substance was available in the urine only as conjugates. Hydrolysis had to split the conjugates and convert any residual isocyanate functions that might have been stabilized by conjugation, to amine functions. The average urinary elimination half-time was 2.8 hours. The average urinary excretion of the corresponding amine was 27% (range 19 -46%). An association between the estimated inhaled dose and the total excreted amount was seen. No 3-aminomethyl-3,5,5-trimethylcyclo- hexylamine was found in hydrolyzed plasma (Tinnerberg et al., 1995)." The experimental study results derived from Isophorone diisocyanate indicate that Isophorone diamine may be predominantly eliminated via the urine with an average urinary elimination half-time of 2.8 hours. Furthermore, the experimental findings indicate that Isophorone diamine is present only as conjugates in the urine.

Because of the low partition coefficient n-octanol/water (log Pow = 0.99) and because of the low calculated bioaccumulation factor (BCF = 3.16) a significant accumulation of Isophorone diamine in the organism is not expected.