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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 August 2000 - 30th November 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Principles of method if other than guideline:
To determine the absorption and urinary elimination profiles of dimethyltin dichloride in rats after a single oral dose as compared to an intravenous dose.

Three protocol deviations occurred during the study:
1. The protocol stated that the temperature and relative humidity ranges for the animal rooms would be 72° ± 4°F and 30% to 70%, respectively. On four days, a temperature of 78-79°F was measured. On six days a relative humidity of 71-74% was measured.
2. The protocol stated that feeders will be changed and sanitized at least once per week. There were two weeks where this was not documented.
3. Several blood samples were collected at times that differed from the target times by more than 10%. For these samples, the actual time of collection was used in calculating individual AUC values, however, mean plasma concentrations were based on the target collection times.

These deviations did not negatively impact the quality or integrity of the data nor the outcome of the study.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyltin dichloride
EC Number:
212-039-2
EC Name:
Dimethyltin dichloride
Cas Number:
753-73-1
Molecular formula:
C2H6Cl2Sn
IUPAC Name:
dimethyltin dichloride
Test material form:
solid: crystalline
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: 8 weeks (males); 9 weeks (females)
- Weight at dose administration: 226-247 g (males); 212-245 g (females)
- Housing: individually in suspended wire-mesh cages
- Individual metabolism cages: yes (animals designated for urine collection)
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rodent LabDiet® 5002 ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: approximately 1 week.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71-79
- Humidity (%): 48-71
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: oral and intravenous
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The dosing formulation was prepared by dissolving 0.25 g of the test substance in 50 mL of sterile water for injection, U.S.P. in a plastic, autoclaved injection vial. The vial was sealed with a septum cap and inverted until the solution appeared uniform. Three 1 mL samples were removed from the vial, placed in plastic sample containers, and transferred to the Analytical Chemistry Department at WTI, Research for analysis of total tin. The formulation was homogeneous and contained the appropriate concentration of tin (94.5% of target).

DOSE ADMINISTRATION:
On the day of dose administration, each animal was weighed. The amount of dosing formulation needed for each animal was calculated based on a dose volume of 2 mL/kg. The dose for Groups 1 and 2 was administered as a bolus intravenous dose into a tail vein; the dose for Groups 3 and 4 was administered orally by gavage.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
10 mg/kg (orally and intravenously)
No. of animals per sex per dose / concentration:
Three
Control animals:
yes
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma, urine
- Time and frequency of sampling: Groups 1 (intravenous) and 3 (oral), approximately 0.3 mL of blood was collected from a tail vein of each animal at 10 and 30 minutes and 1, 2, 4, 8, 12, 18, 24, 48, 72, and 96 hours after dose administration. For Groups 2 (intravenous) and 4 (oral), urine was collected from each animal over the following intervals after dose administration: 0-8, 8-16, 16-24, 24-48, 48-72 and 72-96 hours.
Statistics:
All calculations for this report were performed with Microsoft® Excel spreadsheets using full floating decimal point calculations. Equations other than those used for toxicokinetic data analysis and for standard statistical parameters (e.g., mean, standard deviation [SD], percent coefficient of variation [%CV], and linear regression) are presented with the tables. Slightly different results can be expected if calculations are based on the values as presented in the tables because some numbers have been rounded for display.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Based on the mean AUC0-∞ values, comparative bioavailability was 0.52 for males and 0.71 for females.
Type:
distribution
Results:
For males, mean (±SD) apparent volume of distribution was 44.3 (±26.7) L/kg and 52.7 (±31.7) L/kg following intravenous and oral administration, respectively. For females, mean (±SD) values were 109 (±92.9) L/kg and 138 (±98.1) L/kg.
Type:
excretion
Results:
For males, renal clearance was 0.105 and 0.0816 L/hr/kg following intravenous and oral administration, respectively. For females, renal clearance was 0.559 and 0.282 L/hr/kg following intravenous and oral administration, respectively.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Concentrations of tin were generally higher in males than in females following the single intravenous dose. Inter-animal variability in the plasma concentrations of tin was high, with coefficients of variation frequently near or exceeding 100%. Concentrations of tin in both males and females typically fluctuated during the first 8 hours after dose administration; tmax ranged from 10 minutes to 4 hour post dosing. Mean (±SD) Cmax values were 3834 (±2983) µg/mL for males and 1088 (±656) µg/mL for females. Mean (±SD) AUC0-∞ values were 51.3 (±53.7) µg-hour/mL for males and 11.0 (±0.31) µg-hour/mL for females.

Concentrations of tin were also generally higher in males than in females following the single oral dose. Inter-animal variability in the plasma concentrations of tin tended to be less following oral administration than following intravenous administration. There was also less fluctuation in the concentrations of tin following dosing although the range for tmax was high: 10 minutes to 8 hour post-dosing. Mean (±SD) Cmax values were 1255 (±917) µg/mL for males and 481 (±189) µg/mL for females. Mean (±SD) AUC0-∞ values were 26.7 (±4.3) µg-hour/mL for males and 7.87 (±0.79) µg-hour/mL for females. Based on the mean AUC0-∞ values, comparative bioavailability was 0.52 for males and 0.71 for females.
Details on distribution in tissues:
Following the distribution phase, which lasted at least 8 hours regardless of the route of administration, plasma concentrations of tin at 12 hour post-dosing had decreased by approximately an order of magnitude. After this rapid clearance phase, tin was cleared from plasma more slowly. Plasma concentrations of tin during the terminal elimination phase were higher for males than for females, but were similar between the two routes of administration. Terminal elimination rate constants were similar between the two routes of administration. For males, mean (±SD) terminal half-lives were 184 (±73) hours and 173 (±80) hours following intravenous and oral administration, respectively. For females, mean (±SD) terminal half-lives were 157 (±137) hours and 146 (±114) hours following intravenous and oral administration, respectively. The rapid decrease after the distribution phase and the long terminal half-life suggests that some fraction of tin is retained within the animal that is capable of maintaining an equilibrium with the plasma, at least over the duration examined in this study.

Clearance and apparent volume of distribution were lower for males than for females, but were similar between the two routes of administration. The differences in these parameters between the sexes are consistent with the differences in the AUC0-∞ values. For males, mean (±SD) clearance was 0.203 (±0.153) L/hour/kg and 0.204 (±0.033) L/hour/kg following intravenous and oral administration, respectively. For females, mean (±SD) clearance was 0.486 (±0.014) L/hour/kg and 0.685 (±0.069) L/hour/kg following intravenous and oral administration, respectively. For males, mean (±SD) apparent volume of distribution was 44.3 (±26.7) L/kg and 52.7 (±31.7) L/kg following intravenous and oral administration, respectively. For females, mean (±SD) apparent volume of distribution was 109 (±92.9) L/kg and 138 (±98.1) L/kg following intravenous and oral administration, respectively.
Details on excretion:
Following the single intravenous dose, mean (±SD) percent of dose (as total tin) eliminated in the urine was 103 (±29.9)% for males and 112 (±43.4)% for females. Urinary elimination of tin appeared to be biphasic, with the initial phase occurring through 24 hour post-dosing. The terminal phase was slower than the initial phase and coincided with the low, relatively constant terminal plasma concentrations.

Following the single oral dose, mean (±SD) percent of dose (as total tin) eliminated in the urine was 40.1 (±4.08)% for males and 42.0 (±4.66)% for females. Percent of dose eliminated via the urine following oral dosing was lower than would be expected based on the comparative bioavailability of approximately 50—70%. Urinary elimination of tin following oral dosing appeared to be triphasic: the first phase coincided with the distribution phase, the second phase was similar to the initial phase following intravenous administration, and the third phase was similar to the terminal phase following intravenous administration.

The terminal elimination rate constants for urinary elimination of tin were similar between the sexes and routes of administration. For males, the urinary half-life, based on mean amounts of urine eliminated, was 13 and 11 hours following intravenous and oral administration, respectively. For females, the urinary half-life, based on mean amounts of urine eliminated, was 10 hours regardless of route of administration. Renal clearance was lower in males than in females and lower following oral administration than following intravenous administration because of the differences in the AUC0-∞ values. For males, renal clearance was 0.105 and 0.0816 L/hour/kg following intravenous and oral administration, respectively. For females, renal clearance was 0.559 and 0.282 L/hour/kg following intravenous and oral administration, respectively.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
Cmax: Intravenous dosage to males: 3834 (±2983) ng/ml
Toxicokinetic parameters:
Cmax: Intravenous dosage to females: 1088 (±656) ng/ml
Toxicokinetic parameters:
Cmax: Oral dosage to males: 1255 (±917) ng/ml
Toxicokinetic parameters:
Cmax: Oral dosage to females: 481 (±189) ng/ml
Toxicokinetic parameters:
AUC: Intravenous dosage to males: 51327 (±53673) ng-hr/ml
Toxicokinetic parameters:
AUC: Intravenous dosage to females: 11032 (±306) ng-hr/ml
Toxicokinetic parameters:
AUC: Oral dosage to males: 26675 (±4301) ng-hr/ml
Toxicokinetic parameters:
AUC: Oral dosage to females: 7868 (±794) ng-hr/ml
Toxicokinetic parameters:
half-life 1st: Intravenous dosage to males: 184 (±73) hr-¹
Toxicokinetic parameters:
half-life 1st: Intravenous dosage to females: 157 (±137) hr-¹
Toxicokinetic parameters:
half-life 1st: Oral dosage to males: 173 (±80) hr-¹
Toxicokinetic parameters:
half-life 1st: Oral dosage to females: 146 (±114) hr-¹

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Summary of Pharmacokinetic Parameters for Tin in Rat Plasma following Administration of 10 mg/kg Dimethyltin Dichloride

Cmax(ng/mL)

 

Intravenous

Oral

Mean

SD

Mean

SD

Males

3834

2983

1255

917

Females

1088

656

481

189

 

AUC0-∞(ng-hr/mL)

 

Intravenous

Oral

Mean

SD

Mean

SD

Males

51327

53673

26675

4301

Females

11032

306

7868

794

 

Elimination Rate Constant(hr-¹)

 

Intravenous

Oral

Mean

SD

Mean

SD

Males

0.00412

0.00133

0.00449

0.00208

Females

0.00712

0.00620

0.00685

0.00536

 

Half Life(hr)

 

Intravenous

Oral

Mean

SD

Mean

SD

Males

184

73

173

80

Females

157

137

146

114

 

Clearance(L/hr/kg)

 

Intravenous

Oral

Mean

SD

Mean

SD

Males

0.203

0.153

0.204

0.0328

Females

0.486

0.0135

0.685

0.0691

 

Apparent Volume of Distribution(L/kg)

 

Intravenous

Oral

Mean

SD

Mean

SD

Males

44.3

26.7

52.7

31.7

Females

109

92.9

138

98.1

Table 2: Mean Tin Plasma Concentrations and Pharmacokinetic Parmacokinetic Parameters Based on Mean Values in Rats following Intravenous or Oral Administration of 10 mg/kg Dimethyltin Dichloride

Group Summary

Route

Intravenous

Oral

Sex

Male

Female

Male

Female

Mean (±SD) Plasma Concentrations (ng/mL)*

10 min

2955 (3705)

334 (228)

702 (570)

387 (259)

30 min

1593 N/A

680 (455)

533 (406)

301 (67.1)

1 hr

2057 (2126)

330 (32.5)

547 (333)

327 (101)

2 hr

2213 (1889)

1032 (749)

685 (459)

376 (85.6)

4 hr

1545 (1616)

695 (468)

1396 (628)

382 (89.5)

8 hr

3874 (3883)

508 (262)

1169 (852)

285 (43.1)

12 hr

75.1 (55.3)

20.1 (3.14)

73.0 (65.3)

19.9 (2.12)

18 hr

94.1 (86.5)

21.4 (21.2)

77.0 (74.0)

21.7 (6.27)

24 hr

87.8 (63.7)

27.0 (9.69)

78.0 (62.5)

26.1 (18.5)

48 hr

51.9 (27.1)

13.5 (12.4)

71.7 (61.9)

16.9 (5.90)

72 hr

104 (112)

11.9 (10.3)

60.8 (49.4)

16.7 (8.55)

96 hr

59.2 (48.6)

5.94 (10.3)

59.2 (39.1)

15.3 (3.77)

Linear Regression of log Plasma Concentrations vs. Time**

Slope

-0.00146

-0.00745

-0.00168

-0.00253

Y-intercept (ng/mL)

91.2

34.1

84.1

25.6

Coefficient of Determination (r²)

0.130

0.919

0.943

0.745

Pharmacokinetic Parameters

Cmax(ng/mL)

3874

1032

1396

387

tmax(hr)

0.5

2

4

0.17

AUC0-∞

(ng-hr/mL)

50710

7941

31896

7557

Comparative Bioavailability

N/A

N/A

0.63

0.95

Kel(hr-¹)

0.00337

0.0172

0.00387

0.00583

Half-life (hr)

206

40

179

119

Cl (L/hr/kg)

0.106

0.675

0.168

0.709

Vd (L/kg)

31.4

39.4

43.5

122

 

* Individual vales below the limit of quantification were treated as zero

N/A = not applicable

** For terminal phase: 18 hr post dosing to last point above the quantification limit

Table 3: Summary of Percent of Dose Eliminated in Urine following Administration of 10 mg/kg Dimethyltin Dichloride to Rats*

 

INTRAVENOUS

Collection Interval

Mean % of Dose (±SD)

Males

Females

0 – 8 hr

82.2 (27.7)

84.9 (38.3)

8 – 16 hr

17.8 (4.20)

18.0 (0.77)

16 – 24 hr

2.51 (1.21)

7.65 (4.40)

24 – 48 hr

0.71 (0.18)

1.08 (0.37)

48 – 72 hr

0.27 (0.10)

0.36 (0.10)

72 – 96 hr

BLQ N/A

BLQ N/A

TOTAL:

103 (29.9)

112 (43.4)

 

ORAL

Collection Interval

Mean % of Dose (±SD)

Males

Females

0 – 8 hr

13.0 (3.80)

17.8 (3.13)

8 – 16 hr

20.6 (0.33)

19.1 (3.15)

16 – 24 hr

5.75 (1.35)

4.01 (0.58)

24 – 48 hr

0.60 (0.05)

0.83 (0.17)

48 – 72 hr

0.17 (0.04)

0.20 (0.11)

72 – 96 hr

BLQ N/A

BLQ N/A

TOTAL:

40.1 (4.08)

42.0 (4.66)

 

* Means based on 3 animals per sex. BLQ = below the limit of quantification (5 ng/mL). N/A = not applicable

Table 4: Kinetics of the Urinary Elimination of Tin following Intravenous Administration of 10 mg/kg Dimethyltin Dichloride to Rats

Amount Eliminated per Interval (µg)*

 

Males

Females

Collection Interval

50040

50048

50053

Mean ( ±SD)

50058

50069

50071

Mean ( ±SD)

 

0 – 8 hr

664

1041

1348

1018 (343)

1526

997

591

1038 (469)

8 – 16 hr

164

266

232

220 (52.0)

227

223

209

220 (9.4)

16 – 24 hr

48.3

20.6

24.4

31.1 (15.0)

156

66.4

58.7

93.5 (53.8)

24 – 48 hr

6.26

9.60

10.3

8.74 (2.18)

17.2

8.39

14.2

13.3 (4.47)

48 – 72 hr

2.14

3.28

4.53

3.32 (1.20)

5.79

3.78

3.85

4.39 (1.22)

72 – 96 hr

BLQ

BLQ

BLQ

BLQ N/A

BLQ

BLQ

BLQ

BLQ N/A

 

Amount Remaining To Be Eliminated (ARE; µg)

0 hr

884

1340

1619

1281

1932

1299

877

1369

8 hr

221

299

271

264

406

301

286

331

16 hr

56.7

33.5

39.3

43.2

178

78.6

76.4

111

24 hr

8.40

12.9

14.9

12.1

23.0

12.2

17.8

17.6

48 hr

2.14

3.28

4.53

3.32

5.79

3.78

3.58

4.39

 

Elimination Kinetics (Linear Regression of log ARE vs. Time from 24-48 hr)

Slope (b)

-0.0247

-0.0247

-0.0215

-0.0233

-0.0249

-0.0212

-0.0290

-0.0290

Y-Intercept (µg)

33.0

50.6

48.9

43.8

91.0

39.2

88.4

88.4

Coefficient of Determination (r²)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Elimination rate Constant (hr-¹)

0.0570

0.0570

0.0495

0.0537

0.0574

0.0487

0.0668

0.0668

Half-life (hr)

12

12

14

13

23

14

10

10

Clr(L/hr/kg)**

N/A

N/A

N/A

0.105

N/A

N/A

N/A

0.559

 

* BLQ = below the limit of quantification (5 ng/mL).

** Renal clearance only calculated using mean values

N/A =not applicable

Table 5: Kinetics of the Urinary Elimination of Tin following Oral Administration of 10 mg/kg Dimethyltin Dichloride to Rats

Amount Eliminated per Interval (µg)*

 

Males

Females

Collection Interval

50040

50048

50053

Mean ( ±SD)

50058

50069

50071

Mean ( ±SD)

 

0 – 8 hr

186

113

206

168 (49.1)

255

206

181

214 (37.6)

8 – 16 hr

264

263

271

266 (4.27)

258

187

244

230 (37.8)

16 – 24 hr

54.4

81.6

86.8

74.2 (17.4)

41.5

55.4

47.6

48.2 (6.98)

24 – 48 hr

7.62

8.57

7.25

7.82 (0.68)

9.15

8.44

12.2

9.93 (2.01)

48 – 72 hr

1.59

2.52

2.56

2.22 (0.55)

3.17

3.20

0.98

2.45 (1.28)

72 – 96 hr

BLQ

BLQ

BLQ

BLQ N/A

BLQ

BLQ

BLQ

BLQ N/A

 

Amount Remaining To Be Eliminated (ARE; µg)

0 hr

513

468

573

518

567

460

486

504

8 hr

327

355

367

350

312

254

305

290

16 hr

63.6

92.7

96.6

84.3

54

67.1

60.8

60.6

24 hr

9.22

11.1

9.8

10.0

12.3

11.6

13.2

12.4

48 hr

1.59

2.52

2.56

2.22

3.17

3.20

0.98

2.45

 

Elimination Kinetics (Linear Regression of log ARE vs. Time from 24-48 hr)

Slope (b)

-0.0318

-0.0268

-0.0243

-0.0273

-0.0246

-0.0233

-0.0471

-0.0293

Y-Intercept (µg)

53.3

48.9

37.6

45.3

47.9

42.3

178

62.6

Coefficient of Determination (r²)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Elimination rate Constant (hr-¹)

0.0732

0.0618

0.0560

0.0628

0.0566

0.0537

0.109

0.0675

Half-life (hr)

9.5

11

12

11

12

13

6.4

10

Clr(L/hr/kg)**

N/A

N/A

N/A

0.0816

N/A

N/A

N/A

0.282

 

* BLQ = below the limit of quantification (5 ng/mL).

** Renal clearance only calculated using mean values

N/A =not applicable

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Except for differences in plasma concentrations, the toxicokinetics of tin in plasma of rats following a single intravenous or oral dose of 10 mg dimethyltin dichloride/kg were generally similar, however, there were sex-related differences. Concentrations of tin in plasma and AUC0-∞ values were higher in males than in females. Following the distribution phase, which lasted at least 8 hours regardless of the route of administration, plasma concentrations of tin at 12 hours post-dosing had decreased by approximately an order of magnitude. After this rapid clearance phase, tin was cleared from plasma more slowly, with a terminal half-life ranging from 60-268 hours. The rapid decrease after the distribution phase and the long terminal half-life suggests that some fraction of tin is retained within the animal, possibly in the red blood cells, that is capable of maintaining an equilibrium with the plasma, at least over the duration examined in this study.

Urinary kinetics of tin in rats following a single intravenous or oral dose of 10 mg dimethyltin dichloride/kg were similar between the sexes, however there were differences related to the route of administration. On average, only approximately 40% of the oral dose of tin was eliminated in the urine whereas approximately 100% of dose was eliminated in the urine following an intravenous dose. The amount eliminated in the urine following oral administration was lower than would be expected based on the comparative bioavailability of approximately 50-70%. Terminal urinary half-lives ranged from 6.4-14 hours.
Executive summary:

Dimethyltin dichloride was administered either intravenously or orally to rats at 10 mg/kg to determine the toxicokinetic parameters of tin in plasma and urine. Two groups of three male and three female rats received the test substance intravenously via a lateral tail vein and two groups of three male and three female rats received the test substance orally by gavage. One group from each route of administration was used for blood collections and the other group was used for urine collections. Blood samples were collected at target times of 5, 10, 15, and 30 minutes and 1, 2, 4, 6, 12, 24, 48, and 72 hours post-dosing. Plasma and the blood cellular fraction were separated by centrifugation and stored separately at approximately -20°C. Urine samples were collected at 0-8, 8-16, 16-24, 24-48, 48-72, and 72-96 hours post-dosing. Urine samples were stored at approximately -20°C. Plasma and urine samples were analysed for total tin by graphite furnace atomic absorption spectrometry. Data for tin concentrations in plasma and urine were subjected to toxicokinetic analysis.

Except for differences in plasma concentrations, the toxicokinetics of tin in plasma of rats were generally similar, however, there were sex-related differences. Concentrations of tin in plasma and AUC0 -∞ values were higher in males than in females. Following the distribution phase, which lasted at least 8 hours regardless of the route of administration, plasma concentrations of tin at 12 hours post-dosing had decreased by approximately an order of magnitude. After this rapid clearance phase, tin was cleared from plasma more slowly, with a terminal half-life ranging from 60-268 hours. The rapid decrease after the distribution phase and the long terminal half-life suggests that some fraction of tin is retained within the animal, possibly in the red blood cells, that is capable of maintaining an equilibrium with the plasma, at least over the duration examined in this study.

Urinary kinetics of tin in rats were similar between the sexes, however there were differences related to the route of administration. On average, only approximately 40% of the oral dose of tin was eliminated in the urine whereas approximately 100% of dose was eliminated in the urine following an intravenous dose. The amount eliminated in the urine following oral administration was lower than would be expected based on the comparative bioavailability of approximately 50-70%. Terminal urinary half-lives ranged from 6.4-14 hours.