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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Objective of study:
other: absorption, distribution, excretion
Principles of method if other than guideline:
Different groups of rats were treated with 14C-labeled test material followed by analysis of excrements, blood, organs and carcass to determine absorption, distribution and excretion of the test material.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium diethyl bis[[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate]
EC Number:
265-512-0
EC Name:
Calcium diethyl bis[[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate]
Cas Number:
65140-91-2
Molecular formula:
C17 H29 O4 P. 1/2Ca
IUPAC Name:
calcium diethyl bis[[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate]
Details on test material:
- Radiochemical purity: >99% (determination by radio thin layer chromatography)
- Specific activity (if radiolabelling): 59.388 µCi/mg
Radiolabelling:
yes
Remarks:
14C-radiolabelling

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, 8741 Sulzfeld/Germany
- Weight at study initiation: 172-182 g
- Housing: For 7 days before administration of the test substance and during the experimental phase the control and test rats were housed separately in metabolism cages.
- Individual metabolism cages: yes
- Diet: Dr. Rupprecht Schott Nachf. GmbH + Co., Hamburg/Germany, Art.-No. 253, ca. 22 g/day (except the day before administration of test substance, only 8 g)
- Water: tap water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-1
- Humidity (%): 55+/-5
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: A mixture of equal parts by weight of 1,2-dihydroxypropane and tap water.
Details on exposure:
The radioactive solution as well as the non-labelled solution were prepared shortly before administration to the test animals. Calculated amounts of 14-C-labelled or non-labelled test material were weighed in the glass vessels of an Ultrasonic homogeniser and dissolved in the defined amounts of the test vehicle at 30°C within 30 minutes. The rats were given the 14-C-labelled antioxidant Irganox 1425 in solution by stomach tube. First, each test animal was weighed shortly before treatment and the actual volume for intubation determined by its body weight, the formerly defined doses and by the concentration of the 14-C labelled test substance in the solution. The calculated volume of solution for intubation was administered with a tuberculin syringe via an infusion cannula with olive (stomach tube) directly into the stomach of the rat. To determine the precise amount of 14C- labelled Irganox 1425 intubated into the rats, the exact weight of the empty and full syringe was determined, and after application the empty syringe was reweighed. The rats of the test group received an total oral dose of 10.88 mg/kg bw (corresponding to 636 µCi/kg bw) of 14-C-labelled Irganox 1425. The rats of the control group received in the same way an average oral dose of about 10.5 mg per kg body weight of the non-labelled antioxidant Irganox 1425, in a mixture of 1.2-dihydroxypropane and tap water.
Duration and frequency of treatment / exposure:
Single oral exposures.
Doses / concentrations
Remarks:
Doses / Concentrations:
Control groups: 10.5 mg/kg bw non-labeled test substance
Test groups:
Distribution: 10.88 mg/kg bw labeled test substance (corresponding to 636 µCi/kg bw)
Absorption: 10.7 mg/kg bw labeled test substance (corresponding to 623 µCi/kg bw)
Excretion: 8.8 and 0.53 mg/kg bw labeled test substance (corresponding to 630 and 31 µCi/kg bw, respectively)
No. of animals per sex per dose / concentration:
Distribution: 5 test and 2 control animals
Absorption: 6 test and 2 control animals
Excretion: 6 low dose and 6 high dose test animals, 2 control animals
Control animals:
yes

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Only small amounts are absorbed from the gastrointestinal tracts into the blood, reaching a maximum within the first and second hour after administration.
Type:
distribution
Results:
Absorbed radioactivity was concentrated significantly but only temporarily in the livers, virtually completely eliminated during period of study.
Type:
excretion
Results:
Within 168 hours after oral administration an average of 87.6% and 86.3% (high dose and low dose, respectively) of the dose was excreted, mainly via the feces (85.4% and 84.9%). Further amounts of radioactivity were exhaled.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The absorption of the test substance from the gastrointestinal tract of the rat has a maximum between the first and second hour after oral administration. In this period, the average equivalent concentration amounted to about 0.78 µg test substance per g blood. The subsequent decrease of the average equivalent concentration of the test substance in the blood of the rats is clearly shown by the values at 48 and 168 hours after oral administration of 0.029 and 0.005 µg, resp., test substance per g blood (for details see table 1 "Any other information on results").
Details on distribution in tissues:
Autoradiograms showed that the substance was absorbed only in small portions from the gastrointestinal tracts, was concentrated significantly only in the liver of the test rats and only temporarily. These radioactivities and the clearly lower concentrations over the remaining organs and tissues of the test animals were almost completely eliminated during the progress of experiment.
The gastrointestinal tracts of the rats killed at 168 hours contained on average about 0.01% of the dose. As a consequence of the enormous elimination of the C-labelled test substance and/or its metabolites in faeces and urine, the results show that only small amounts of radioactivity were found in the blood, the organs, tissue samples and in the residual carcass. At the time of sacrifice, the blood of the rats contained an average of less than 0.01% of the dose and about 0.06% and 0.1% were present in the residual carcasses of high dose and low dose animals, respectively. The blood, organs and tissue samples taken at the time of sacrifice and the residual carcass of the rats from the high dose group contained average equivalent concentrations from 3.7 (testicles) to 29.5 ng test substance (liver) per g, whereas the blood, organs, tissue samples and the residual carcass of the rats from the low dose animals contained only average equivalent concentrations from 0.3 (blood) to 2.7 ng test substance (liver) per g (for details see table 2 and table 3 "Any other information on results").
Details on excretion:
An average of 85.4% and 84.9% of the given radioactivities were eliminated in the faeces by rats from the high dose and loe dose, respectively, within 168 hours after oral administration of the 14C-labelled test substance. In the same interval, an average of 2.2% and 1.4% of the radioactivity amounts orally administered in form of the 14C-labelled test substance were found in the urine of the rats. According to these results, the rats, excreted, an average of 87.6% (high dose) and 86.3% (low dose) within 168 hours after oral administration. As pre-tests showed, the test rats exhaled further amounts of radioactivity.

Any other information on results incl. tables

Table 1: Radioactivities, the average relative and equivalent concentrations of the orally administered test substance in the blood of rats after different time points.

 

Test substance

 

Radioactivity of blood [nCi/g] at time after administration [h]

 

Radioactivity

Dose

0.25

0.5

1

2

4

6

12

24

48

72

120

168

 

[µCi]

[µCi/g bw]

 [mg/kg bw]

 

 

 

 

 

 

 

 

 

 

 

 

Average

114.12

0.6228

10.711

17.39

36.52

45.67

41.09

17.06

12.67

5.988

4.066

1.714

0.9623

0.4406

0.2786

Standard deviation

3.4

0.018

0.32

9.84

23.55

32.79

25.70

3.6

3.62

1.54

1.42

1.33

0.53

0.14

0.07

Relative standard deviation (%)

3.0

3.0

3.0

56.6

64.5

71.8

62.5

21.3

28.6

25.7

34.8

77.6

54.8

32.0

27.9

Average relative concentration

 

 

 

27.780

58.339

72.955

65.636

27.249

20.233

9.565

6.496

2.738

1.537

0.704

0.4455

Average equivalent concentration

 

 

 

0.2976

0.6249

0.7814

0.7030

0.2919

0.2167

0.1025

0.0696

0.0293

0.0165

0.0075

0.0048

Relative concentration = average measured radioactivity per g test material/administered radioactivity per g body weight at time of intubation

Equivalent concentration = Relative concentration * dose administered (mg/g bw) * 1000 [µg/g test material]

Table 2: Excretion of radioactivity (%) in urine and feces by rats given 14C-labeled test material by intubation.

 

 

 

Average excreted radioactivity amounts [%(sd)]

Group

Number of animals

Route of excretion

0-3 h

3-6 h

6-24 h

24-48 h

48-72 h

72-96 h

96-120 h

120-144 h

144-168 h

high dose

6

urine

0.31 (0.26)

0.26 (0.08)

1.41 (1.46)

0.17 (0.11)

0.04 (0.02)

0.01 (0.01)

0.01

0.01

0.01

feces

0.03 (0.03)

76.99 (5.12)

7.95 (3.65)

0.36 (0.24)

0.07 (0.01)

0.03 (<0.01)

0.01 (<0.01)

0.01

low dose

6

urine

0.17 (0.09)

0.24 (0.1)

0.72 (0.12)

0.18 (0.10)

0.04 (0.01)

0.03 (0.01)

0.03 (0.01)

0.02

<0.01

feces

 

67.95 (6.13)

16.05 (4.39)

0.74 (0.43)

0.12 (0.05)

0.04 (0.02)

0.02 (0.01)

0.02 (0.01)

 

 

Table 3. Summary of the average radioactivity amounts in %, of the average relative (P) and equivalent concentrations (C) after 168 h.

tissue radioactivity amount (%) average relative concentration (P) equivalent concentration (C) (ng/g)
group high dose low dose high dose low dose high dose low dose
urine 2.2 1.4
feces 85.39 84.94
GI tract 0.01 0.01
blood < 0.01 < 0.01 0.53 0.66 4.6 0.3
liver 0.02 0.03 3.39 6.29 29.5 2.7
kidneys < 0.01 < 0.01 1.29 2.07 11.3 0.9
testicles < 0.01 < 0.01 0.43 0.88 3.7 0.4
muscle < 0.01 < 0.01 0.63 1.16 5.5 0.5
fat < 0.01 0.01 2.38 3.95 20.7 1.7
residual carcass 0.06 0.1 0.72 1.34 6.2 0.6
recovered radioactivity 87.68 86.49

Relative concentration P = average measured radioactivity per g test material/administered radioactivity per g body weight at time of intubation

Equivalent concentration C = Relative concentration * dose administered (mg/g bw) * 1000 [µg/g test material]

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The orally given test material and its possible metabolites are retained for only a limited time in male rats and are preferentially excreted in the feces, but also via the kidneys and by respiration.