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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
In a toxicokinetic study, groups of pregnant CD-1 mice were administered with sodium arsenate (As+5) at 20 (i.p.) or 40 (p.o.) mg/kg bw on gestation Day 18 and all tissues were analysed for arsenic levels at intervals up to 24 hours following treatment.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sodium arsenate
- Source: Fisher Scientific, Atlanta, USA
Radiolabelling:
no

Test animals

Species:
mouse
Strain:
CD-1
Sex:
female

Administration / exposure

Route of administration:
other: intraperitoneal and oral (gavage)
Vehicle:
water
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
- Intraperitoneal: 20 mg/kg bw
- Oral gavage: 40 mg/kg bw
No. of animals per sex per dose:
No data
Control animals:
no

Results and discussion

Preliminary studies:
No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No data
Details on distribution in tissues:
- Following sodium arsenate administration, arsenic was detected in every sample obtained regardless of sampling time or treatment route, with the exceptions of 10 minute and 24-hour urines. All samples had declined to their lowest arsenic levels by 18-24 hours.

INTRAPERITONEAL ADMINISTRATION (As-IP):
- Total arsenic levels peaked in maternal blood, liver, kidney and urine at 10 minutes, 0.5 hours, 20 minutes and 1 hour respectively.
- Fetal and placental arsenic were highest at 2 hours.

ORAL ADMINISTRATION (As-PO):
- Maternal blood and solid tissue samples peaked at 1 hour, while urine values were highest at 2 hours after treatment.
- Fetal and placental arsenic were highest at 6 hours and 1 hour, respectively.
Transfer into organs
Test no.:
#1
Transfer type:
blood/placenta barrier
Observation:
distinct transfer
Details on excretion:
- Arsenic distribution in maternal samples was essentially complete at 0.5 hour and was followed by uniform washout in the blood, kidney and urine over the remaining period of study. Following an initial rapid uptake and distribution phase, both groups exhibited essentially linear elimination, showing some tendency toward tailing after 12 hours.
- Arsenic elimination in liver, kidneys and blood was fitted to a first-order one-compartment model with an elimination rate constant for the various tissues of ~0.06 and 0.04 hr-1 for As-IP and As-PO groups, respectively. Disappearance of arsenic from urine showed a parallel rate of elimination.
- Biological half-life for arsenic in maternal tissues was estimated at approximately 10 days for both groups.
- Arsenic was found to be reasonably homogeneous in its tissue distribution.
Toxicokinetic parameters
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 10 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Arsenic metabolites (mono and dimethyl arsenic) were found in the fetuses up to 83% of total fetal arsenicals by 24 hours.

Any other information on results incl. tables

Table 1: Arsenic content of maternal samples following i.p. (20 mg/kg bw) or p.o. (40 mg/kg bw) sodium arsenate administration to mice on gestation Day 18

Sampling time (hour)

Sample assayed and route of exposure1

Liver2

Kidneys2

Blood3

Urine3

i.p.

p.o.

i.p.

p.o.

i.p

p.o.

i.p.

p.o.

10 min

3.79 ± 1.13

NA4

20.41 ± 3.61

NA

6.93 ± 1.00

NA

0

NA

20 min

5.43 ± 0.78

NA

25.39 ± 1.30

NA

2.97 ± 0.49

NA

115.30 ± 62.56

NA

0.5

7.85 ± 4.65

7.18 ± 2.40

23.76 ± 4.05

9.77 ± 0.24

3.45 ± 0.93

1.80 ± 0.26

294.905

195.30 ± 190.42

1

3.19 ± 2.95

11.70 ± 3.44

9.33 ± 7.80

11.04 ± 2.29

1.92 ± 0.54

2.05 ± 1.05

712 .305

304.30 ± 264.96

2

3.66 ± 1.12

9.17 ± 5.41

9.35 ± 2.87

6.95 ± 2.23

1.68 ± 1.09

0.83 ± 0.35

168.605

341.50 ± 274.27

4

2.91 ± 1.62

2.55 ± 0.58

5.89 ± 2.11

5.10 ± 1.07

1.13 ± 0.65

0.57 ± 0.16

234.20 ± 160.92

237.90 ± 162.14

6

0.99 ± 0.57

4.27 ± 3.18

1.81 ± 1.02

5.07 ± 2.68

0.53 ± 0.08

0.81± 0.14

29.405

302.505

12

0.28 ± 0.09

1.14 ± 0.50

0.47 ± 0.18

1.90 ± 1.54

0.10 ± 0.03

0.32 ± 0.16

46.80 ± 43.99

75.00 ± 60.57

18

0.14 ± 0.11

0.62 ± 0.12

0.28 ± 0.21

0.78 ± 0.02

0.07 ± 0.08

0.17 ± 0.06

10.30 ± 3.71

54.50 ± 11.01

24

0.14 ± 0.04

0.69 ± 0.35

0.23 ± 0.13

1.19 ± 0.77

0.06 ± 0.04

0.25 ± 0.17

0

0

1 Each value represents the mean ± SD for samples from three or more individuals.

2 µg As/g wet weight

3 µg As/mL

4 Not available

5 Three urine samples were not available for all sampling times and SDs were not calculated in such cases.

Table 2: Arsenic content of fetal tissues following i.p. (20mg/kg bw) or p.o. (40 mg/kg bw) sodium arsenate administration to mice on gestation Day 18

Tissues assayed and route of exposure1

Sampling time (hour)

Placentas2

Fetuses2

 

i.p.

p.o.

i.p.

p.o

10 min

2.49 ± 1.21

NA

0.18 ± 0.08

NA

20 min

3.06 ± 1.71

NA

0.40 ± 0.07

NA

0.5

3.54 ± 2.54

1.04 ± 0.32

0.78 ± 0.26

0.14 ± 0.05

1

8.46 ± 5.22

2.27 ± 0.57

1.25 ± 1.09

0.56 ± 0.24

2

9.30 ± 4.32

1.95 ± 0.38

3.49 ± 2.95

0.56 ± 0.18

4

5.01 ± 2.46

1.14 ± 0.27

2.92 ± 2.29

0.51 ± 0.17

6

4.82 ± 1.91

1.72 ± 0.54

1.12 ± 0.87

0.77 ± 0.27

12

0.59 ± 0.33

0.69 ± 0.19

1.08 ± 1.48

0.48 ± 0.05

18

0.26 ± 0.14

0.68 ± 0.38

0.33 ± 0.22

0.38 ± 0.05

24

0.74 ± 0.55

0.57 ± 0.23

0.22 ± 0.08

0.33 ± 0.09

1 Each value represents the mean ± SD of samples from three or more litter

2 µg As/g

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the test conditions, arsenate injection (i.p.) induces very high concentration peak in the conceptus when compared to oral route and reproductive studies conducted by this route should be interpreted in the light of this finding.
Executive summary:

In a toxicokinetic study, groups of pregnant CD-1 mice were administered with sodium arsenate (As+5) at 20 (i.p.) or 40 (p.o.) mg/kg bw on gestation Day 18. Individual fetuses, pooled placentas and maternal blood, urine, liver and kidneys were obtained from three or more litters at intervals up to 24 hours following treatment. Acid-digested samples were analyzed for total arsenic by hydride generation atomic absorption spectrophotometry. Also fetuses were analyzed for the arsenic metabolites.

 

Administration route did not affect the rate of arsenic elimination from various maternal samples. First-order elimination followed a brief period of distribution and the biological half-life was approximately 10 hours. Arsenic was found in most samples, with mean peak concentrations expressed as µg/g (wet wt.) or /mL (values listed are post-treatment sampling times in minutes or hours and concentrations for i.p. and for p.o. treated groups, respectively) as follows: fetuses-2, 3.5; 6, 0.8, placentas-2, 9.3; 1, 2.3, blood-10 minutes, 6.9; 1, 2.0, urine-1, 712; 2, 342, kidney-20 minutes, 25.4; 1, 11.0, liver-0.5, 7.9; 1, 11.7. Arsenic levels in fetuses and placentas had declined to 0.22 µg/g and 0.74 µg/g for i.p. and 0.33 µg/g and 0.57 µg/g for p.o. treatments, respectively in 24 hours. Fetal arsenic uptake and loss were more rapid following i.p. than p.o. and peak fetal As+5 was almost five fold higher following i.p. treatment. Arsenic metabolites (MMA and DMA) were found in the fetuses up to 83% of total fetal arsenicals by 24 hours.

 

Under the test conditions, arsenate injection (i.p.) induces very high concentration peak in the conceptus when compared to oral route and reproductive studies conducted by this route should be interpreted in the light of this finding.