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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: Accepable, well- documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Uptake, distribution, and elimination of carbon tetrachloride in rat tissues following inhalation and ingestion exposures.
Author:
Sanzgiri UY, Srivatsan V, Muralidhara S, Dallas CE, Bruckner JV.
Year:
1997
Bibliographic source:
Toxicol Appl Pharmacol. vol. 143, no. 1, p. 120-9.

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Male Sprague-Dawley rats exposed to 1000 ppm CTC for 2 hr or to 179 mg/Kg bw CTC as a single oral bolus or or by constant gastric infusion over a period of 2 hr.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): carbon tetrachloride
- Physical state: liqid
- Analytical purity: Analytical-grade (99.9% pure)
- Lot/batch No.: not reported
- supplier: EM Science (EM Industries, Cherry Hill, NJ, U.S.A.)
- Stability under test conditions: stable
- Storage condition of test material: not reported
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC, U.S.A.
- Age at study initiation: not reported
- Weight at study initiation: 325-375 g
- Fasting period before study: 18 hr prior to CTC exposure
- Housing: not reported
- Individual metabolism cages: no
- Diet (e.g. ad libitum): Purina Lab Chow 5001, St. Louis, MO, U.S.A., ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 1 wk


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12
- other: room reported to be environmentally controled

Administration / exposure

Route of administration:
other: inhalation, oral: gavage, oral: gastric infusion
Vehicle:
other: inhalation: unchanged (no vehicle); gavage and gastric infusion: emulphor
Details on exposure:
inhalation exposure:
TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: 1 m³ Rochester-type dynamic flow chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols: not applicable, substance is a volatile solvent
- Composition of vehicle (if applicable): no vehicle use in inhalation experiment
- Concentration of test material in vehicle (if applicable): not applicable
- Method of particle size determination: not applicable
- Treatment of exhaust air: not reported

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: not applicable
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):


oral administration:
PREPARATION OF DOSING SOLUTIONS: 179 mg/Kg bw CTC,kg was administered per oral as an aqueous emulsion using 5% Emulphor in 0.9% saline,
in a volume of 5 ml/kg bw.


GAVAGE:
- administration: 179 mg/kg bw by gavage as a single oral bolus (5 mL/kg bw)

GASTRIC INFUSION:
- infusion installation: gastric cannula (PE-50 tubing), surgically implanted days prior to the exposure
- exposure: infusion of 5 mL/Kg bw solution (CTC in vehicle) with gastight syringes mounted on a Harvard microinfusion pump at a constant rate into the stomach (via the indwelling cannula) of each rat for 2 hr

VEHICLE
- Justification for use and choice of vehicle (if other than water): Emulphor ( a polyethoxylated vegetable oil is a common vehicle for volatine solvents
- Concentration in vehicle: 5% (v/v) in 0.9% (v/v) saline
- Amount of vehicle (if gavage): 250 µL/Kg bw (in 5 mL/kg bw water)
- Identity: Alkamuls
- Source: GAF Co. (New York, NY, U.S.A.)

Duration and frequency of treatment / exposure:
- inhalation: once for 2 h
- gavage: single oral bolus dose
- gastric infusion: once for 2 h
Doses / concentrations
Remarks:
Doses / Concentrations:
- inhalation: 1000 ppm (= 6.4 g/m³)
- gavage: 179 mg/Kg bw in 5 mL/Kg bw
- gastric infusion: 179 mg/Kg bw in 5 mL/Kg bw
No. of animals per sex per dose:
- inhalation: 25
- gavage: 45
- gastric infusion: 50
Control animals:
no
Positive control:
no
Details on study design:
- Dose selection rationale:
The total systemically absorbed dose in rats inhaling 1000 ppm CTC for 2 hr was determined to be 179 mgkg bw. The procedure of Dallas et al. (Dallas, C. E., Bruckner, J. V., Maedgen, J. L., and Weir, F. W. (1986). A method for direct measurement of systemic uptake and elimination of volatile organics in small animals. J. Pharmacol. Methods 16,239-250. Dallas, C. E., Ramanathan, R., Muralidhara, S., Gallo, J. M., and Bruckner, J. V. (1989). The uptake and elimination of l,l,l-trichloroethane during and following inhalation exposures in rats. Toxicol. Appl. Pharmacol. 98, 385-397.) was utilized to measure CTC uptake in individual rats inhaling through a miniaturized one-way breathing valve. The minute volume and inhaled and exhaled CCI, concentrations were monitored for 2 hr. Subtraction of the quantity of CC1, exhaled from the quantity of CCI, inhaled yielded the amount of CC1, absorbed during each sampling period. Summing these quantities over time yielded the cumulative uptake, or total dose of the chemical absorbed over 2 hr (i.e., 179 mgkg).
Therefore 179 mg/Kg bw was chosen to be the adequate dose for the gavage and the gastric infusion experiments

- Animals were terminated at selected time intervals during and postexposure and tissues (liver, kidney, lung, brain, fat, skeletal muscle, spleen, heart, and GI tract) removed for measurement of their CTC content by headspace gas chromatography
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: see experimental desidn for details
- Time and frequency of sampling:
inhalation: 0, 120, 240, 480, 1440 min post start of exposure
gavage: 0, 5, 15, 60, 120, 240 480, 720 1080 and 1440 min post exposure
gastric infusion: 30, 60, 120, 150, 180, 360, 450, 720, 1080, 1440 min post start of exposure


METABOLITE CHARACTERISATION STUDIES
only the parent compound (=test item) was analyzed
- Method type(s) for identification GC
- Limits of detection and quantification: 1 ng
- see experimental design for details

Results and discussion

Preliminary studies:
none

Toxicokinetic / pharmacokinetic studies

Details on absorption:
CTC is readily absorbed via the gastro intestinal tract: Liver levels were highest at 1 min post dosing, but declined quite rapidly thereafter.
see table 1 for details
Details on distribution in tissues:
CTC is readily distributed via the blood circulation: Maximum CTC concentrations in most tissues other than liver were reached 5 to 15 min postdosing. CTC uptake and elimination in fat tissue were considerably slower than in other tissues leading to much higher CTC levels in fat. Cmax, CLmax and AUC values were comparable for tissues other than fat and liver.
see table 1 for details
Details on excretion:
mainly via exhalation and partly via metabolism
Toxicokinetic parameters
Toxicokinetic parameters:
other: CTC is absorbed readily from the gastrointestinal and respiratory tracts, and more slowly through the skin. It is distributed to all major organs, with highest concentrations in the fat, liver, bone marrow, adrenals, blood, brain, spinal cord, and kidney.

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

- Table 1: pharmacokinetics of CTC in tissues of rats following the different applications

Inhalation (1000 ppm for 2 h)

Tissue

t1/2

(min)

AUC (0 – 1440 min) (µg × min/mL)

Clapp (mL/min/kg)

Cmax (µg/g)

Tmax (min)

Liver

249

2,823

63

20

30

Kidney

204

3,064

58

25

30

Lung

226

2,952

61

24

30

Brain

248

3,255

55

28

30

Fat

665

230,699

0.8

1506

240

Heart

274

2,571

70

18

30

Muscle

218

3,248

55

18

30

GI tract

224

1,139

158

20

30

Spleen

273

2,035

88

13

30

Gavage (179 mg/Kg bw, single oral dose)

Tissue

t1/2

(min)

AUC (0 – 1440 min) (µg × min/mL)

Clapp (mL/min/kg)

Cmax (µg/g)

Tmax (min)

Liver

323

1,023

175

58

1

Kidney

278

3,029

59

14

5

Lung

442

2,908

62

10

15

Brain

313

4,223

42

15

15

Fat

780

235,471

0.8

246

120

Heart

490

2,747

65

10

5

Muscle

649

4,117

43

7

60

Spleen

472

4,096

44

12

5

Gastric infusion

Tissue

t1/2

(min)

AUC (0 – 1440 min) (µg × min/mL)

Clapp (mL/min/kg)

Cmax (µg/g)

Tmax (min)

Liver

269

149

1,198

0.5

120

Kidney

190

800

224

4

120

Lung

249

2,842

72

6

180

Brain

250

2,683

67

10

150

Fat

358

165,983

1

179

360

Heart

216

1,900

94

8

120

Muscle

262

2,164

83

10

150

Spleen

208

1,660

108

6

150

tmax calculated from start of exposure

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results (liver, kidney, lung, brain, fat, skeletal muscle, spleen, heart, and GI tract)
Very low bioaccumulation potential.
Executive summary:

The study (Sanzgiri 1997) describes the uptake, the distribution and the elimination of CTC in rats after exposure through 3 different routes (inhalation, 1000 ppm, 2 h; gavage, 179 mL/Kg bw single bolus dose; gastric infusion, 179 mg/Kg bw within 2 h). The study is not conducted according to an official guideline.

The pharmacokinetic properties of CTC were analyzed by treating male Sprague-Dawle rats with either 1000 ppm CTC for 2 hr by inhalation, by a single oral dose of 179mg/Kg bw via gavage and by a constant gastric infusion over a period of 2 hr also with totally 179 mg/Kg bw. Animals were terminated at selected time intervals during and post exposure and tissues (liver, kidney, lung, brain, fat, skeletal muscle, spleen, heart, and GI tract) removed for measurement of their CTC content by headspace gas chromatography. By gavage maximal tissue concentrations were reached fastest followed by inhalation and then gastric infusion. In all routes the distribution of CTC was comparable for all tissues except for liver after gavage, where higher levels were attained faster than by the other two routes.

Concentrations in fat tissues were found to reach much higher levels than any other tissue regardless of the route while the kinetics of absorption as well as the release of CTC was much slower in fat than in all other tissues. In general the total tissue concentrations over time (AUC (0 – infinity)) were comparable between inhalation and gavage and lower in gastric infusion. Compared to inhalation, lower tissue levels after gastric infusion (same exposure period) are due to first pass elimination in the latter route (exhalation and metabolism + excretion through the liver). This elimination works more efficient when continuous low concentrations are absorbed as in gastric infusion as compared to a fast peaking absorption after single bolus exposure via gavage. This explains the differences between the two moral routes. In summary the absorption and desorption of CTC is fast for all tissues except for fat. Absorption of identical amounts of CTC via inhalation and gavage are comparable. The absorption after a single bolus dose via gavage is higher than after gastric infusion as the first pass elimination is overloaded. Therefore gavage is a worst case scenario for assessment of risks of CTC contaminations in food and drinking water.

Due to the low elimination half life of CTC in the tissues low to no bioaccumulation potential for CTC is expected.