3-aminomethyl-3,5,5-trimethylcyclohexylamine

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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

Test material information

Constituent 1

Reference substance name:

isophorone diisocyanate (IPDI)

IUPAC Name:

isophorone diisocyanate (IPDI)

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.

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.