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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
distribution
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study to investigate the pharmacokinetics of MDEA following acute intravenous dosing in the rat.
GLP compliance:
no
Specific details on test material used for the study:
RADIOLABELLING INFORMATION
- Radiochemical purity: > 99%
- Specific activity: 1.95 mCi/mmol
Radiolabelling:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc . Indianapolis
- Age at study initiation: 8-10 weeks
- Weight at study initiation: males: 216 g; females: 162 g (average)
- Diet: food and water were available ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled temperature and humidity conditions (not further specified)
- Photoperiod 12 hrs dark / 12 hrs light
Route of administration:
intravenous
Vehicle:
not specified
Duration and frequency of treatment / exposure:
single application
Dose / conc.:
50 other: mg/kg bw
Dose / conc.:
500 other: mg/kg bw
No. of animals per sex per dose:
4 male
Control animals:
not specified
Details on study design:
The pharmacokinetics and tissue distribution of N-methyldiethanolamine were study in Fischer 344 rats after a single intravenous dose (50 or 500 mg/kg bw).
 
One day prior to dosing, animals had an indwelling jugular vein cannula implanted by a modification of the method of Harms and Ojeda and then acclimated to individual Roth-type glass metabolism cages. For the intravenous dosing study four male rats per group were given 50 or 500 mg/kg bw [14C] MDEA (10 μCi ) via the cannula at a dose volume of 2 mL/kg, and held for 72 h in metabolism cages.
 
Urine, feces, and expired 14CO2 were collected at various intervals up to 72 h postdosing from animals held in individual metabolism cages. Blood was collected via the jugular cannula, except for the last sample, which was by cardiac puncture.

The amounts of radioactivity in various samples were measured by liquid scintillation spectrometry. Unchanged MDEA concentrations in the plasma and urine were determined by high-performance liquid chromatography in conjunction with an in-line radioactivity monitor.
Details on distribution in tissues:
Distribution of MDEA was relatively uniform throughout the major organs, with the highest concentrations being in the liver and kidney.
Details on excretion:
The predominant excretion route for MDEA was in the urine. Urinary excretion of MDEA was slow. Metabolites constituted the major fraction in urine, indicating that metabolism plays an important role in MDEA elimination.
Details on metabolites:
MDEA was substantially metabolised. Metabolism could be saturated at high dosages since nonlinear kinetic behavior was observed in rats dosed i.v. with 500 mg/kg bw.
Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study to investigate the pharmacokinetics of MDEA following acute cutaneous dosing in the rat.

GLP compliance:
no
Specific details on test material used for the study:
RADIOLABELLING INFORMATION
- Radiochemical purity: > 99%
- Specific activity: 1.95 mCi/mmol

Radiolabelling:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc . Indianapolis
- Age at study initiation: 8-10 weeks
- Weight at study initiation: males: 216 g; females: 162 g (average)
- Diet: food and water were available ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled temperature and humidity conditions (not further specified)
- Photoperiod 12 hrs dark / 12 hrs light
Type of coverage:
occlusive
Vehicle:
not specified
Duration of exposure:
6 h or 72 h contact

Doses:
500 mg/kg bw
No. of animals per group:
4 male or female
Details on study design:
The pharmacokinetics and tissue distribution of N-methyldiethanolamine were study in Fischer 344 rats after a cutaneous dose (500 mg for 6h or 72 h contact).

For the percutaneous dosing study, the interscapular area of the cannulated animals was first clipped free of fur. [14C] MDEA (500 mg/kg, 25 μCi) was applied to a 2 x 4 cm or a 2 x 3 cm area of four males or four females, respectively. The application site was occluded with polyethylene sheeting held in place with adhesive tape and secured with an elastic wrapping bandage. In one group of rats cutaneous contact with the applied dose was maintained for 72 h, while in the the applied dose was removed after 6 hours of contact.

For the cutaneous dosing portions of liver, kidney, bone marrow, spleen, brain, heart, lung, muscle, fat, uterus, and ovaries/testes were collected. Cages were washed, and the wash was collected.

The amounts of radioactivity in various samples were measured by liquid scintillation spectrometry.
Absorption in different matrices:
Topically applied substance was well absorbed by both male and female rats (17-21% and 41-50% after 6 and 72 h contact respectively), after apparently being the first sequestered in the skin and later slowly released into the bloodstream. Distribution of MDEA was relatively uniform throughout the major organs, with the highest concentrations being in the liver and kidney. The predominant excretion route for MDEA was in the urine. Urinary excretion of MDEA was slow, with an excretion half-life in excess of 30 h following cutaneous dosing.
Dose:
500 mg/kg bw
Parameter:
percentage
Absorption:
>= 17 - <= 21 %
Remarks on result:
other: 6 hours
Dose:
500 mg/kg bw
Parameter:
percentage
Absorption:
>= 41 - <= 50 %
Remarks on result:
other: 72 hours

Description of key information

Key value for chemical safety assessment

Absorption rate - oral (%):
100
Absorption rate - dermal (%):
20
Absorption rate - inhalation (%):
100

Additional information

The pharmacokinetics and tissue distribution of MDEA were studied in the Fischer 344 rat after a single intravenous (50 or 500 mg/kg bw) or cutaneous dose (500 mg/kg bw for 6 or 72 h contact; Leung et al, 1996). Topically applied MDEA was well absorbed by both male and female rats (17-21% and 41-50% after 6 and 72 h contact, respectively), after apparently being first sequestered in the skin and later slowly released into the bloodstream. Distribution of MDEA was relatively uniform throughout the major organs, with the highest concentrations being in the liver and kidney. MDEA was substantially metabolised. Metabolism of MDEA could be saturated at high dosages since nonlinear kinetic behavior was observed in rats dosed intravenously with 500 mg/kg bw. The predominant excretion route for MDEA was in the urine. Urinary excretion of MDEA was slow, with an excretion half-life in excess of 30 h following cutaneous dosing. Metabolites (not identified) constituted the major fraction in urine, indicating that metabolism plays an important role in MDEA elimination. Based on these results, a dermal absorption rate of 20% will be used for DNEL derivation. No data on inhalation or oral absorption are available. Therefore, for the DNEL derivation the defaults as reported in the REACH guidance will be used (100% absorption for both routes).