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Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
unknown
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
Year:
1995
Bibliographic source:
Int. Arch. Occup. Environ. Health 67, 367-374
Report Date:
1995

Materials and methods

Type of study / information:
Type of experience: Human inhalative exposure to the test item Isophorone diisocyanate (IPDI). Determination of the IPDI content in blood and urine (via determination of Isophorone diamine (IPDA)) and determination of urinary IPDI excretion.
Endpoint addressed:
basic 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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Isophorone diisocyanate (IPDI) was obtained from Aldrich Chemie (Steinham, Germany); purity not reported

Method

Ethical approval:
other: Study was approved by Ethics Committee at Lund University. All participants gave written informed consent.
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 
(CAS No.  2855-13-2).
- This diamine was determined as its pentafluoropropionic amide by liquid  chromatography / mass spectrometry.
Exposure assessment:
estimated
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.

Results and discussion

Results:
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.

Any other information on results incl. tables


It was observed that 55%-70% of IPDI were lost in the exposure chamber (probably due to irreversible reactions with the walls and surfaces of the exposure chamber).

It has been implied that isophorone diisocyanate conjugates or reacts  with biological molecules in the lung, which then enter the 

systemic  circulation. Hydrolysis releases the adducted isocyanate as amine. The  analytical methods used would not distinguish 

between isocyanate and  amine.

Applicant's summary and conclusion

Conclusions:
IPDI in blood and urine could be detected indirectly as IPDA-pentafluoropropionic anhydride and urinary IPDI excretion was determined. 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.
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.