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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
(partly limited documentation, e.g. no details about the test substance)

Data source

Reference
Reference Type:
publication
Title:
Dermal absorption of N,N-dimethylacetamide in human volunteers
Author:
Nomiyama TP, Omae K, Ishizuka C, Yamauchi T, Kawasumi Y, Yamada K, Endoh H, Sakurai H
Year:
2000
Bibliographic source:
Int Arch Occup Environ Health 73: 121-126

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
basic toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Dermal versus inhalation absorption of DMAC vapour in human vonluteers, and half-lives of DMAC and N-methylacetamide (NMAC) in urine were determined.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
N,N-dimethylacetamide
EC Number:
204-826-4
EC Name:
N,N-dimethylacetamide
Cas Number:
127-19-5
Molecular formula:
C4H9NO
IUPAC Name:
N,N-dimethylacetamide
Test material form:
liquid
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.

Method

Type of population:
general
Subjects:
- Number of subjects exposed: 12
- Sex: male
- Mean body weight: 69 ± 13 kg
- Age: mean age of 25.2 years (range 21-43 years)
- Race: Japanese
- None had health problems as determined by the pre-experimental medical examinations, which included hernatological and serurn biochemical examinations and urinary examinations, and the results of the self administered
questionnaires . All the volunteers had normal skin appearances. They were requested not to drink alcohol from 24 h before exposure until 72 h after the experiment .
Ethical approval:
confirmed, but no further information available
Route of exposure:
dermal
inhalation
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
1) dermal or 2) inhalation

1) dermal exposure: Volunteers wore cotton pants, and 90 % of their skin were naked; volunteers were exposed to DMAC vapour while inhaling fresh air via a respirator in a sitting position in an exposure chamber of 1.7 m³ (L x W x H: 1.2 x 0.8 x 1.8 m).
2) Inhalation exposure: Volunteers sat outside the chamber and inhaled the air in the chamber.

Duration and frequency of treatment/exposure: 4 h in each trial (interval ≥96 h)
Doses/concentrations: 6.1 ppm, Mean. +/- 1.3 ppm (SD)
- Dose selection rationale: 10 ppm was the OEL recommended by ACGIH and JSOH.

Vapour generation: DMAC was evaporated by an organic solvent vapour generator (VG-2S, Shibata Scientific Technology, Tokyo, Japan), diluted, and supplied from the top of the chamber at a rate of 6 m³/h (air change in the chamber 3.5 times/h). The concentration of DMAC in air was monitored every 10 min and kept at a steady concentration.

Analytics:Air in the exposure chamber was bubbled with 10 mL water in an impinger at 4 °C for 5 min; the sample was introduced to a gas chromatograph with a flame ionization detector.
Examinations:
From all the subjects urine was collected up to 36 h after exposure; spot urine was collected at 48 h and 72 h after exposure; volume, creatinine level, and specific gravity were measured (all samples stored at -20 °C until analysis). GC methods were used for analysis of NMAC and DMAC.
Dermal and respiratory absorption was calculated as the area under the urinary concentrations (AUCs); extrapolation was obtained by a linear relation between log-transformed DMAC concentrations in air and log-transformed urinary NMAC concentrations (mg/g creatinine); dermal absorption of AUCs was compared with the AUCs of
respiratory plus dermal absorption after an extrapolation to 10-ppm exposure in each volunteer; biological half-life (t 1/2 = -ln2/k) of NMAC in urine was calculated for each worker; k was calculated from the decline in metabolite.
Values for NMAC excretion after dermal and inhalation exposure were added and resulted in total creatinine-adjusted NMAC concentration. This simple addition of the two values could be conducted because there was no saturation of metabolism up to 30 ppm in workers exposed to DMAC (see Spies et al . 1995 in Section 7.10.2).

Statistics: Means ± standard deviation (SD) were calculated.

Half-lives of NMAC in urine were calculated using all urine up to 36 h and spot urine samples between 36 h and 72 h

Results and discussion

Results of examinations:
Details on absorption: The individual dermal absorption rates defined as dermal absorption over dermal plus respiratory absorption fluctuated widely between 12.9 and 73.3 % (mean: 40 %); this was possibly related to intra-individual differences in absorption dynamics, metabolism, accumulation, and excretion of DMAC.
Details on excretion: The mean urinary NMAC value after 4-h DMAC exposure at 6.1 ppm was 11.2 mg/g creatinine; extrapolation to 8 h exposure duration and exposure concentration of 10 ppm: 31.1 mg/g creatinine (no saturation of metabolism at <=30 ppm).
Half-lives obtained in this study (see below) indicated little accumulation of NMAC over a span of workdays; the estimated NMAC value after 5 consecutive workdays (8 h per day) at concentrations of 10 ppm DMAC was 30.7 mg/g creatinine (16.5-65 .9 mg/g Cr).
The biological half-lives were 9.0 ± 1 .4 h and 5 .6 ± 1 .3 h via skin and lung, respectively.
Metabolites identified: NMAC. No further metabolites were investigated.

Applicant's summary and conclusion

Conclusions:
In human volunteers the dermal absorption was 40 % of the total DMAC uptake; the biological half-lives of NMAC in urine after DMAC exposure were 9.0 ± 1.4 h and 5.6 ± 1.3 h via skin and respiratory tract, respectively. No accumulation was observed at the OEL of 10 ppm.
Executive summary:

Dermal versus inhalation absorption of DMAC vapour in 12 human volunteers, and half-lives of DMAC and N-methylacetamide (NMAC) in urine were determined.


In the dermal exposure group, the volunteers wore cotton pants, and 90 % of their skin were naked; volunteers were exposed to DMAC vapour while inhaling fresh air via a respirator in a sitting position in an exposure chamber of 1.7 m³ (L x W x H: 1.2 x 0.8 x 1.8 m). In the inhalation exposure group, volunteers sat outside the chamber and inhaled the air in the chamber.


The individual dermal absorption rates defined as dermal absorption over dermal plus respiratory absorption fluctuated widely between 12.9 and 73.3 % (mean: 40 %); this was possibly related to intra-individual differences in absorption dynamics, metabolism, accumulation, and excretion of DMAC. The mean urinary NMAC value after 4-h DMAC exposure at 6.1 ppm was 11.2 mg/g creatinine; extrapolation to 8 h exposure duration and exposure concentration of 10 ppm:  31.1 mg/g creatinine (no saturation of metabolism at <=30 ppm). Half-lives obtained in this study (see below) indicated little accumulation of NMAC over a span of workdays; the estimated NMAC value after 5 consecutive workdays (8 h per day) at concentrations of 10 ppm DMAC was 30.7 mg/g  creatinine (16.5-65 .9 mg/g Cr).


Conclusion: In human volunteers the dermal absorption was 40 % of the total DMAC uptake; the biological half-lives of NMAC in urine after DMAC exposure were 9.0 ± 1.4 h and 5.6 ± 1.3 h via skin and respiratory tract, respectively. No accumulation was observed at the OEL of 10 ppm.