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Toxicological information

Basic toxicokinetics

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Administrative data

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:
other: 2e: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
[14C]methyl chloroform (1,1,1-trichloroethane): pharmacokinetics in rats and mice following inhalation exposure
Author:
SCHUMANN-AM; FOX-TR; WATANABE-PG
Year:
1982
Bibliographic source:
TOXICOL-APPL-PHARMACOL 62 390-401

Materials and methods

Objective of study:
metabolism
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Commercial formulation: Chloroethen Vg, Dow Chemical CO. Lot Nos TAO 2168-B and TAO 4259-1. Purity 94 % (stabilizers, 0.2 % aliphatic hydrocarbon impurities)
[14C]Methyl chloroform (2—14C), New England Nuclear, Boston (Lot no.1119-293; 2.51 mCi/mmol) >99 % purity
Refered to as methyl chloroform in the paper
Radiolabelling:
yes

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male
Details on test animals and environmental conditions:
7 days acclimatization. Temperature 22 0C and humidity 50 % with 12 hour light cycle.

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
Exposures conducted in a 30 litre glass chamber (5 or 10 litres/min airflow). Vapour was generated in 100-litre bags and metered into the exposure chamber with a Masterfex pump. The concentration in the chamber was analysed at 30-minute intervals by gas chromatography and was within 6 % of the target concetration.
Duration and frequency of treatment / exposure:
6 hours on at least 2 ocassions
Doses / concentrations
Remarks:
Doses / Concentrations:
150 or 1500 ppm of [14C]Methyl chloroform for mass balance experiments, and unlabelled substance for plasma level analysis.
No. of animals per sex per dose:
4 males/group
Control animals:
no
Details on study design:
Radio-labelled substance was used for mass balance experiments. Non-labelled for TK sampling.
Details on dosing and sampling:
For the radio-active metabolism experiment, animals were returned to metabolism cages immediately after their 6-hour exposure period. The amount of CO2 in expired air was measured at 3, 6, 12, 24, 36, 48 and 72 hours using activated charcoal columns. Urine was collected at 12 hour intervals and faeces at 24 hour intervals. After 72 hours skin, liver, kidney and fat sample were removed and the carcass homogenized. Radio activity was measured using liquid scintillation spectrometry.
Blood sampling for plasma levels was conducted in 3 to 4 anesthetized rats/group, at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 150 and 180 minutes after exposure. Analysis was by gas chromatography.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Found in fat, liver and kidney (no other individual tissues examined)
Plasma levels (estimated from graph) were:
1500 ppm: 100, 18, 9, 6 and 5.5 μg/g at 0, 30, 60, 120 and 180 minutes after exposure, respectively
150 ppm: 12, 1.5, 0.8, 0.7 and 0.5 μg/g at 0, 30, 60, 120 and 180 minutes after exposure, respectively
Details on excretion:
>96 % in 24 hours
Pulmonary - 87 - 97% of total body burden. 80-90% of which was eliminated in the first 3 hours
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Tmax: 0 hours (end of exposure period)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 100 ug/g (after 1500 ppm)
Test no.:
#2
Toxicokinetic parameters:
Cmax: 12 ug/g (after 150 ppm)
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 2.0 min (1500 ppm rapid phase)
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: 12.8 min (1500 ppm slow phase)
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 1.9 (150 ppm rapid phase)
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: 14.8 min (1500 ppm slow phase)

Any other information on results incl. tables

Recovery of radioactivity after 6 hours inhalation exposure to 150 or 1500 ppm 1,1,1-trichloroethane in male B6C3F1 mice

Exposure concentration

150 ppm

1500 ppm

N = 4

Mean + SD

Methyl chloroform (μmol-eq)

Percentage (of total recovered)

Methyl chloroform (μmol-eq)

Percentage (of total recovered)

Expired air

  Methyl chloroform

4.32 + 0.97

86.7 + 5.0

38.70 + 12.93

96.7 + 1.5

  Carbon Dioxide

0.06 + 0.01

1.2 + 0.4

0.18 + 0.09

0.4 + 0.2

Urine

0.43 + 0.21

8.8 + 3.9

0.82 + 0.26

2.3 + 1.4

Faeces

0.03 + 0.02

0.8 + 0.7

0.19 + 0.05

0.5 + 0.2

Carcass

0.01 + 0.00

0.2 + 0.1

ND

ND

Cage wash

0.12 + 0.07

2.5 + 1.2

ND

ND

Body burden

  μmol-eq/rat

4.97 + 0.96

39.90 + 12.89

  μmol-eq/kg body wt

183 + 30

1416 + 471

  μmol-eq metabolised

0.65 + 0.27

13.3 + 5.0

1.19 + 0.26

3.3 + 1.5

  μmol-eq metabolized/kg body wt

24.26 + 10.28

42.06 + 8.61

ND = not detected

Table # Distribution and clearance of radioactivity following a 6 hours inhalation exposure to 150 or 1500 ppm 1,1,1-trichloroethane

N = 4

Mean + SD

nmol-eq 1,1,1-trichloroethane/g of tissue

0

24

48

72

150 ppm

Liver

76.0 + 7.5

5.0 + 0.8

2.8 + 1.0

4.4 + 0.7

Kidney

74.6 + 6.7

7.0 + 2.0

5.8 + 0.6

3.0 + 1.5 (3)

Fat

1329 + 123

10.2 (1)

7.6 (1)

ND

1500 ppm

Liver

631 + 144

ND

ND

ND

Kidney

1103 + 579

ND

ND

ND

Fat

16198 + 1792

ND

ND

ND

ND = not detected

Value in paranthesis is number above the detection limit

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results Cleared rapidly from the fat
Male mice were exposed to radio-labeled 1,1,1-trichloroethane vapour for 6 hours at 150 or 1500 ppm. At the end of the exposure period the elimination of 14C activity was measured for 72 hours. Blood samples, following exposure to non-labeled test material were also analysed for 1,1,1-trichlorethane.
The major route of elimination was exhalation of unchanged chemical and 87 – 97% of the total radio activity was recovered from this route. The remaining 2 – 13 % was detected as metabolized 1,1,1-trichlorethane in the expired air (14 CO2) and as nonvolatile radioactivity in the urine, faeces, carcass and cage wash. The radio labeled substance was more concentrated in the fat, than in the liver or kidneys, however it was rapidly cleared from the fate so that by 24 hours less than 2 % of the initial radioactivity remained; showing little potential for significant bioaccumulation.
Executive summary:

Male mice were exposed to radio-labeled 1,1,1-trichloroethane vapour for 6 hours at 150 or 1500 ppm.   At the end of the exposure period the elimination of 14C activity was followed for 72 hours.  Blood samples, following exposure to non-labeled test material were also analysed for 1,1,1-trichlorethane.

The major route of elimination was exhalation of unchanged chemical and 87 to 97% of the total radio activity was recovered from this route. The remaining 2 to 13 % was detected as metabolized 1,1,1-trichlorethane in the expired air (14 CO2) and as nonvolatile radioactivity in the urine, faeces, carcass and cage wash.  The radio labeled substance was more concentrated in the fat, than in the liver or kidneys, however it was rapidly cleared from the fate so that by 24 hours less than 2 % of the initial radioactivity remained; showing little potential for significant bioaccumulation.