Registration Dossier

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19/01/1998 - 27/01/2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study
Objective of study:
other: to assess the extent of absorption, distribution, elimination and biotransformation of [14C] dinotefuran given to rats by 2 routs of administration
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF 59 NohSan no. 4200
Deviations:
no
GLP compliance:
yes
Radiolabelling:
yes
Species:
rat
Strain:
other: Crl:CD(SD) BR (male), Hla(SD)CVF (male and female bile duct-cannulated rats)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Charles River Laboratories Inc, USA except for bile duct-cannulated rats were supplied by Hilltop Lab Animals Inc.
Age/weight at study initiation: >4 weeks old, weighing 76 - 282g or 228 - 329g (time-mated female rats) at arrival
Route of administration:
other: Administered orally by gavage or intravenously
Vehicle:
other: 0.5% carboxymethyl cellulose (0.5% CMC) for oral administration, or 0.9% saline for intravenous administration
Details on exposure:
- Dose selection rationale: the results of a Sponsor toxicology study indicated that the low dose was without effect, and the high dose had limited toxicological or pharmacological effects.
Duration and frequency of treatment / exposure:
Duration of treatment: Single intravenous or oral dose, or after multiple daily oral doses for 7 or 15 days
Frequency of exposure: Daily
Post exposure period: Up to 168 hours
Remarks:
Doses / Concentrations:
0, 50, 1000 mg/kg
No. of animals per sex per dose / concentration:
7 - 9 animals per sex per dose
Control animals:
other: (0.5% CMC) only, oral
Positive control reference chemical:
None
Details on study design:
STUDY ELEMENTS:
Preliminary study (PRE): groups P-1 and P-2
Absorption and excretion (AE): groups A, B, C, C-1 and D
Pharmacokinetic (PK): groups E, F, F-1 and G
Tissue distribution (TD): groups H, I, I-1 and J
Biliary excretion (BE): groups K and L
Placental transfer (PT): group M
Milk transfer (MT): group N
Qualitative whole-body autoradiography (WBA): groups O and Q
Vehicle Control: group R

Housing and feeding condition: animals were housed individually and fed rodent diet #5002 (PMI Feeds, Inc,) ad libitum except when fasted for dosing procedres. All animals received water ad libitum, provided fresh daily.
Details on dosing and sampling:
SAMPLES AND OBSERVATIONS:
Types and timing of observations and sampling regime for each study element: see Table 1.
-PRE and vehicle control: preliminary study and vehicle control animals were housed in individual metabolism cages for the separate collection of urine and feces, and expired air for preliminary study animals. Whole blood/ plasma was collected at termination. After final excreta collection, carcasses retained.
-AE: animals were housed in individual metabolism cages for the separate collection of urine and feces. Whole blood/ plasma was collected at termination. After final excreta collection, major organs and tissues, and carcasses were collected.
- PK: whole blood was collected via a jugular vein into heparinized tubes and plasma was harvested at each time point. The cellular fraction was discarded. After final collection, carcasses discarded.
- TD: whole blood and plasma from all animals was collected at termination. The major tissues and organs, and carcasses were collected from 3 animals at each sacrifice, and then excised, rinsed with saline, blotted dry, weighed, and placed on ice.
- BE: bile samples were collected in containers surround by ice. Urine and faeces were collected separately. Whole blood/plasma, major organs and tissues, and carcasses were collected at termination.
-PT: 3 animals/time point were sacrificed via exsanguination. Two whole foetuses/animal, selected tissues from 2 further foetuses/animal (placenta, amniotic fluid, blood, brain, heart, liver, lungs, kidneys, carcass), maternal tissues were collected. Tissues were excised, rinsed with saline, blotted dry, weighed, and place on ice.
- MT: milk were collected from 3 animals/time point. Pups were removed from the mothers approximately 4 hours before collection of milk. Animals received a subcutaneous injection of oxytocin before milking to stimulate lactation, and then anesthetized immediately before the start of milk collection and milk (approximately 1 mL) was collected using a specially constructed milking machine. Whole blood and plasma was collected after milk collection. Carcasses discarded.
- WBA: 1 animal/sex/time point was sacrificed. All samples, except blood, were stored at -20C. Blood was stored at approximately 5 ºC until radioanalysis. Plasma from remaining blood was taken by centrifugation.
Cage rinse, wash and wipe in the groups P-1, P-2, A, B, C, C-1, D, K and L were performed and analysed.
All samples collected were weighed.
All tissues and fluids collected were homogenised unless the entire sample was used, sampled, and then analysed, in duplicate if sample size permitted. Specific tissues were digested in NaOH before analysis. Sample weights added to the appropriate scintillant were 0.5ml trapping solution (CO2), 0.03 or 0.1g (urine), whole sample (faeces, and plasma from groups E, F, F-1 and G), 0.2g (whole blood), 0.2g (plasma from all other groups), 0.02g (bile), 0.1g (milk), 0.5g (cage wash / rinse / wipe), and 0.2 - 0.5g (tissues). Scintillation counts were automatically corrected for counting efficiency.
Statistics:
See below
Preliminary studies:
See Table 2.
Treatment of the two preliminary groups with F-labelled and G-labelled dinotefuran demonstrated that the distribution of radioactivity between urine, faeces and carcass was similar, and that radioactivity in expired air amounted to 0.01 - 0.05% of administered dose. Therefore, the definitive study was performed with an approximate 1:1 ratio of both radiolabelled forms. Expired air was not collected.
Details on absorption:
See Table 3.
The total mean recovery of radioactivity ranged from 92.7 to 103% of administered dose, with 87.7 to 99.8% recovered in urine, 1.06 to 3.16% recovered in faeces, 0.62 to 6.42% recovered from the cages. The similar, and extensive, recoveries in urine following oral and intravenous administration indicate almost complete absorption of [14C]-dinotefuran from the gastrointestinal tract. Radioactivity was eliminated rapidly with 84.3 to 98.9% of administered single doses excreted in urine within 24 hours. The absorption and route and rate of elimination were not influenced by sex, dose level or dose regimen.
Details on distribution in tissues:
See Table 5.
Radioactivity was widely distributed in all tissues examined 0.5 hours after a single oral dose of 50mg/kg. At this time, only the concentrations in the kidneys (79.4ppm), stomach (67.3ppm) and urinary bladder (45.8ppm) were higher than in plasma (40.6ppm) for male. Tissue concentrations declined quickly and at 168 hours after dosing all tissues, with the exception of male skin (0.05ppm), kidneys (0.01ppm) and mammary gland (0.02ppm), were below the limits of detection (0.001ppm). All tissues were below the limits of detection 168 hours after a single intravenous dose. With the exceptions of male and female skin (0.007 and 0.014ppm), female bone (0.004ppm), female intestinal tract (0.003ppm) and female mammary gland (0.018ppm), all tissues were below the limit of detection 168 hours after 15 oral doses of 50mg/kg/day). Radioactivity was widely distributed in most tissues examined following 7 daily oral doses of 50mg/kg and after a single oral dose of 1000mg/kg. In these groups, low concentrations occurred in plasma (0.002 - 0.028ppm) and the highest concentrations occurred in female mammary gland (0.324 - 0.703ppm) and in the skin (0.193 - 0.692ppm). The results indicate that the disposition of radioactivity is similar following single or multiple dosing regimens and after low or high doses.
Details on excretion:
See Details on absorption
Metabolites identified:
yes
Details on metabolites:
Unchanged dinotefuran in urine accounted for 92.5 - 97.2% of total urine radioactivity. A group of urinary metabolites, PHP and its isomers, 446-DO and its isomers, 446-CO, 446-DO-Ac, 446-OH-Ac and 446-OH+COOH, represented 2.08 - 5.95% administered radioactivity. Other minor urine metabolites, UF, FNG and DN, each accounted for no more than 0.53% administered radioactivity. Trace amounts (< 0.1% administered radioactivity) of 9 other metabolites were also detected in urine. Unchanged dinotefuran for 0.29 to 3.57 % of total administrated radiolabel was the major component of faecal radioactivity, but numerous minor metabolites were identified, and 0.01 - 1.75% administered radioactivity represented unidentified polar metabolites. Unchanged dinotefuran for 0.52 to 0.77 % of total administrated radiolabel was the major component of bile radioactivity, and minor metabolites were similar to those found in urine and faeces. Unchanged dinotefuran was the major component of plasma radioactivity (> 80%) with possible metabolites of MNG, 446-DO-Ac and PHPs. Overall, more than 90% of the radioactivity derived from [14C]- dinotefuran is excreted as unchanged parent compound following oral or intravenous administration. Dinotefuran is the major radioactive component in most tissues examined, and less than 10% of dinotefuran is metabolised. There were no apparent differences related to treatment regimen or sex in the metabolic handling of dinotefuran. Initially, enzymatic hydroxylation on the tetrahydrofuran ring occurs to form PHP isomers, followed by further oxidation, reduction and acetylation of PHP to produce possible isomers of 446-CO, 446-DO, PHP-Ac and 446-OH+COOH. Other routes of metabolism involve desmethylation to FNG, nitro-reduction to 446-NH2 and further hydrolysis to DN and UF. The combination of these reactions at certain stages produced numerous metabolites such as UF-DM, FNG-DN, BCDN, DN-OH and isomers and DN-CO. Trace amounts of MNG, MG and MG-Ac indicate a small degree of cleavage at the C-N bond to yield the furan and guanidine moieties.

TOXIC EFFECTS AND CLINICAL SIGNS:

All animals appeared clinically healthy throughout the study, with the exception of following animals.

One animal in group E appeared pale and hypoactive between the 1- and 4-hour blood collections and recovered by the 24-hour collection. In an animal in Group F, there were difficulties in obtaining the 4-hour blood sample, and then the animal died shortly after the collection. The animals in group G appeared lethargic approximately 45 minutes to 1 hour postdose.Animals had recovered by 4 hours postdose.

PHARMACOKINETICS (PK):

See Table 4.

The mean maximum plasma concentration of [14C]-dinotefuran ranged from 40.8 to 47.4ppm at 0.25 to 0.625 hours after administration of single or repeated low oral doses. A single high oral dose produced Cmaxvalues of 566 and 471ppm in males and females, respectively, at approximately 2 hours after administration. The elimination half-life ranged from 3.64 to 16.1 hours for single and repeated low oral doses. A single high oral dose produced T1/2values of 13.8 and 15.2 hours in males and females, respectively. AUC values following single and repeated low oral doses were in the range 69.0 to 110ppm.hr, compared with values of 2660 and 2360 ppm.hr in males and females respectively after a single high oral dose. Since the ratios of dose to AUC were comparable for low and high dose levels, absorption and pharmacokinetic characteristics of [14C]- dinotefuran are considered to be linear within the dose range 50 - 1000mg/kg. BILIARY EXCRETION (BE):

See Table 6.

A small amount of radioactivity (0.58 - 0.88% dose) was detected in bile samples after single doses of either 50 or 1000mg/kg, indicating very limited enterohepatic re-circulation of radioactivity.

PLACENTAL TRANSFER (PT):

See Table 7.

Radioactivity was rapidly transferred to foetuses and rapidly distributed to the foetal tissues. Maximum foetal concentrations occurred in all tissues examined within 0.5 hours of maternal treatment. Subsequently, radioactivity declined rapidly to low levels within 4 hours. Similar concentrations occurred in maternal and foetal blood suggesting a rapid equilibration and similar tissue distribution in maternal and foetal tissues. MILK TRANSFER (MT):

See Table 8.

Radioactivity was rapidly transferred from maternal blood to the milk of lactating animals at day 12post partum. Cmaxvalues for maternal plasma and milk were 29.3 and 34.8mg equivalents/g, respectively, 0.5 hours post dose. Concentrations in milk declined rapidly to 6.51mg equivalents/g after 4 hours. Calculation of pharmacokinetic parameters gave an elimination T1/2of 1.39 hours in milk, indicating that within 14 hours of administration the expected concentration of radioactivity would be lower than the limit of detection (0.002ppm).

QUALITATIVE WHOLE-BODY AUTORADIOGRAPHY (WBA):

Whole body autoradiography after single oral doses of 50 or 1000mg/kg were consistent with the results obtained for the tissue distribution groups mentioned previously. Tissue radioactivity derived from [14C]-dinotefuran was widely distributed and highest at the first sampling interval, 0.5 hours and 1.5 hours, for 50 and 1000mg/kg, respectively. Thereafter, levels of radioactivity were declining 1.5 hours after administration of 50mg/kg and 8 hours after administration of 1000mg/kg. Elimination was almost complete after 24 hours (50mg/kg) and 72 hours after 1000mg/kg, no detectable radioactivity was apparent in either sex. The highest levels of radioactivity were generally found in the urine, followed by the gastrointestinal contents. Low levels of radioactivity were detected in the brain and gonads of both sexes after 50 or 1000mg/kg. There were no apparent sex-related or dose-related differences in the overall distribution trends.

ANALYTICS AND RADIOACTIVE COMPONENTS:

Unchanged dinotefuran in urine accounted for 92.5 - 97.2% of total urine radioactivity. A group of urinary metabolites, PHP anditsisomers, 446-DO anditsisomers, 446-CO, 446-DO-Ac, 446-OH-Ac and 446-OH+COOH, represented 2.08 - 5.95% administered radioactivity. Other minor urine metabolites, UF, FNG and DN, each accounted for no more than 0.53% administered radioactivity. Trace amounts (< 0.1% administered radioactivity) of 9 other metabolites were also detected in urine. Unchanged dinotefuranfor 0.29 to 3.57 % of total administrated radiolabelwas the major component of faecal radioactivity, but numerous minor metabolites were identified, and 0.01 - 1.75% administered radioactivity represented unidentified polar metabolites. Unchanged dinotefuranfor 0.52 to 0.77 % of total administrated radiolabelwas the major component of bile radioactivity, and minor metabolites were similar to those found in urine and faeces. Unchanged dinotefuran was the major component of plasma radioactivity (> 80%) with possible metabolites of MNG, 446-DO-Ac and PHPs. Overall, more than 90% of the radioactivity derived from [14C]- dinotefuran is excreted as unchanged parent compound following oral or intravenous administration. Dinotefuran is the major radioactive component in most tissues examined, and less than 10% of dinotefuran is metabolised. There were no apparent differences related to treatment regimen or sex in the metabolic handling of dinotefuran. Initially, enzymatic hydroxylation on the tetrahydrofuran ring occurs to form PHP isomers, followed by further oxidation, reduction and acetylation of PHP to produce possible isomers of 446-CO, 446-DO, PHP-Ac and 446-OH+COOH. Other routes of metabolism involve desmethylation to FNG, nitro-reduction to 446-NH2and further hydrolysis to DN and UF. The combination of these reactions at certain stages produced numerous metabolites such as UF-DM, FNG-DN, BCDN, DN-OH and isomers and DN-CO. Trace amounts of MNG, MG and MG-Ac indicate a small degree of cleavage at the C-N bond to yield the furan and guanidine moieties.

Table 1   Treatment schedule and sampling regime

Group

Study element

Dose

(mg/kg)

Number doses

(1 dose/day)

Route

Position of radiolabel

No. animals

(M + F)

Sampling regime

P-1

PRE

50

1a

oral

[F-14C] dinotefuran

3 + 3

Expired air: 24-hour intervals for 7 days

Urine / faeces: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96, 96 - 120, 120 - 144 and 144 - 168hrs

Whole blood / plasma: at termination

Cage rinse: 0 - 24hrs

Cage wash / wipe: after final excreta collection

Termination: after final excreta collection, carcasses retained

P-2

50

1a

oral

[G-14C] dinotefuran

3 + 3

A

AE

50

1

intravenous

1:1 mixture

5 + 5

Urine / faeces: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96, 96 - 120 and 120 - 144, 144 - 168hrs

Whole blood / plasma: at termination

Cage rinse: 0 - 24hrs

Cage wash / wipe: after final excreta collection

Termination: after final excreta collection, major organs / tissues + carcasses collected

B

50

1

oral

1:1 mixture

5 + 5

C

50

14b+1

oral

1:1 mixture

5 + 5

D

1000

1

oral

1:1 mixture

5 + 5

C-1

50

7

oral

1:1 mixture

5 + 5

Urine / faeces: 0 -24, 24 - 48, 48 - 72, 72 - 96, 96 - 120, 120 - 144 and 144 - 168hrs + 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96, 96 - 120, 120 - 144 and 144 - 168hrs

Whole blood / plasma: at termination

Cage rinse: 24 hr intervals

Cage wash / wipe: after final excreta collection

Termination: after final excreta collection, major organs / tissues + carcasses collected

E

PK

50

1

oral

1:1 mixture

5 + 5

Blood plasma: pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 8, 12, 24, 48 and 72hrs

Termination: after final collection, carcasses discarded

F

50

14b+1

oral

1:1 mixture

5 + 5

F-1

50

7

oral

1:1 mixture

5 + 5

G

1000

1

oral

1:1 mixture

5 + 5

H

TD

50

1

oral

1:1 mixture

9 + 9

Whole blood and plasma: at termination

Termination: 3 animals sacrificed at 0.5, 1.5 and 4hrs after final dose, 30 major organs / tissues + carcasses collected

I

50

14b+1

oral

1:1 mixture

9 + 9

I-1

50

7

oral

1:1 mixture

9 + 9

J

1000

1

oral

1:1 mixture

9 + 9

Whole blood and plasma: at termination

Termination: 3 animals sacrificed at 1.5, 4 and 8hrs after dose, 30 major organs / tissues + carcasses collected

K

BE

50

1

bile duct

1:1 mixture

4 + 4

Urine / faeces: 0 - 6, 6 - 12, 12 - 24, 24 - 48hrs

Whole blood / plasma: at termination

Bile: 24hrs pre-dose, 0 -6, 6 - 12, 12 - 24 and 24 - 48hrs

Cage rinse: 0 - 24hrs

Cage wash / wipe: after final excreta collection

Termination: after final excreta collection, major organs / tissues + carcasses collected

L

 

1000

1

bile duct

1:1 mixture

4 + 4

M

PT

50

1

oral

1:1 mixture

0 + 9c

Whole blood and plasma: at termination

Termination: 3 animals/time point sacrificed at 0.5, 1.5 and 4hrs after dose, 2 whole foetuses/animal, selected tissues from 2 further foetuses/animal (placenta, amniotic fluid, blood, brain, heart, liver, lungs, kidneys, carcass), maternal tissues collected

N

MT

50

1

oral

1:1 mixture

0 + 9d

Milk: 0.5, 1.5 and 4hrs

Whole blood and plasma: at termination

Termination: 3 animals/time point sacrificed at 0.5, 1.5 and 4hrs after milk collection, carcasses discarded

O

WBA

50

1

 

 

oral

1:1 mixture

4 + 4

Termination: one animal/sex/time point sacrificed at 0.5, 1.5, 4 and 24hrs post-dose and subjected to qualitative WBA

Q

1000

1

oral

1:1 mixture

4 + 4

Termination: one animal/sex/time point sacrificed at 1.5, 4, 8 and 72hrs post-dose and subjected to qualitative WBA

R

Vehicle control

(0.5% CMC)

0

1

oral

 

2 + 2

Urine / faeces: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96, 96 - 120, 120 - 144 and 144 - 168hrs

Whole blood / plasma: at termination

Termination: after final excreta collection, carcasses retained

aone group treated with[F-14C]-dinotefuran, one group treated with[G-14C]-dinotefuran;b14 days non-radiolabelled treatment followed by one radiolabelled dose; pregnant females on day 10 of gestation at first dose;cpregnant females at approximately day 18 of gestation;dlactating females ca. 12 dayspost partum; PRE preliminary study; AE absorption and excretion; PK pharmacokinetic; TD tissue distribution; BE biliary excretion; PT placental transfer; MT milk transfer; WBA whole-body autoradiography (qualitative)

 

Table 2. Total recovery of radioactivity at 168 hours (preliminary study)

Sex

Test substance

% administered dose in:

Urine

Faeces

Cage

Expired air

Carcass

Total

Male

[F-14C]-dinotefuran

90.3

1.39

5.73

0.01

0.09

97.5

[G-14C]-dinotefuran

90.6

4.02

2.97

0.05

0.10

97.8

Female

[F-14C]-dinotefuran

82.0

7.32

8.23

0.02

0.44

98.0

[G-14C]-dinotefuran

93.5

1.22

2.51

0.05

0.08

97.3

 

Table 3. Total recovery of radioactivity at 168 hours (main study)

Sex

Dose / frequency / route

(mg/kg x no. doses)

% administered dose in:

Urine

Feces

Cage

Tissues & carcass

Total

Male

50 x 1 i.v.

96.7

1.06

1.90

0.09

99.7

50 x 1 oral

98.9

1.66

1.33

0.06

102

50 x 15 oral

96.8

1.54

2.83

0.06

101

50 x 7 oral

98.3

1.85

2.42

0.10

103

1000 x 1 oral

90.1

2.15

2.52

0.10

94.7

Female

50 x 1 i.v.

96.6

1.26

1.42

0.05

99.2

50 x 1 oral

99.8

1.19

0.62

0.08

102

50 x 15 oral

89.7

3.16

6.42

0.21

99.3

50 x 7 oral

95.8

1.53

4.88

0.10

102

1000 x 1 oral

87.7

2.39

2.67

0.06

92.7

 

Table 4. Pharmacokinetic parameters calculated for [14C]-dinotefuran

Sex

Dose/ frequency/ route

(mg/kg x no. doses)

Mean values for:

Cmax(ppm)

Tmax

(hrs)

T1/2

 (hrs)

AUC0-T

(ppm.hour)

AUC0

(ppm.hour)

Male

50 x 1/ oral

40.8

0.50

3.64

83.3

83.3

50 x 15/ oral

47.4

0.45

5.65

92.1

92.1

50 x 7 oral

41.5

0.63

6.28

91.2

91.2

1000 x 1 oral

566

2.10

13.8

2660

2660

Female

50 x 1 oral

45.6

0.25

7.86

110

110

50 x 15 oral

42.2

0.38

6.89

76.0

76.0

50 x 7 oral

43.8

0.31

16.1

69.0

69.2

1000 x 1 oral

471

2.00

15.2

2360

2370


Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
It is concluded that the absorption, distribution, metabolism and elimination of [14C]-dinotefuran are unaffected by sex within dosing groups and also no apparent differences among the examined dosing regimens.
Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10/05/1999 - 28/01/2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study
Objective of study:
other: The purpose of this study was to determine the absorption, distribution, metabolism and excretion of radioacivity in 12-day-old rats follwing a single oral administration of [G14C] dinotefuran
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF 59 NohSan no. 4200
Deviations:
no
GLP compliance:
yes
Radiolabelling:
yes
Species:
rat
Strain:
other: Crl:CD(SD) BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Charles River Laboratories Inc, USA
Age/weight at study initiation: 12 days old pups, weighing 26.5 – 33.0g (time-mated female rats) at dosing
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% CMC
Details on exposure:
Total volume applied: 10 mL/kg
Duration and frequency of treatment / exposure:
Single oral dose
Post exposure period up to 4 hours
Remarks:
Doses / Concentrations:
50 mg/kg
No. of animals per sex per dose / concentration:
25 pups/sex/group and 3 pups/sex/group for whole-body autoradiographic analysis (WBA).
Control animals:
no
Positive control reference chemical:
No
Details on study design:
- Dose selection rationale: the rat is a preferred species for developing data on the absorption, distribution, metabolism and excretion of a test material. No information on administration to newborn animals is available. Potential exposure is by the oral route. The dose level was selected based on previous toxicology studies, toxicity and detection limit.

Housing condition: all animals were housed individually.
Details on dosing and sampling:
Absorption, distribution, metabolism and excretion (group 1):

Urine and faeces;
-collected together as excreta from shoebox cages.

Pup wipe and cage wipe;
-following the excreta collection, the pups and the cages were wiped with gauze pads and added to the excreta.

Terminal sacrifice and collection;
- 5 pups/sex at 0.5 and 1.5 hours and 15 pups/sex at 4 hours were killed by cardiac puncture under halothane anesthesia.
- blood samples were collected and transferred into heparinized tubes on ice. An aliquot of each blood sample was retained for radioanalysis. Plasma samples were taken from the residual blood sample by centrifugation. The cellular component was discarded.
- liver, kidneys, intestinal tract and contents, stomach, stomach contents and residual carcass were excised, rinsed, blotted dry, weighed and placed on ice.
Excreta samples, blood/plasma samples, tissue samples were pooled to form a single sample for each sex and sampling interval. The weight of each pooled sample was recorded, and stored at -20ºC except blood samples which were stored at 5 ºC.

Qualitative whole body autoradiography (WBA) (group 2):
-one pup/sex from group 2 was killed at 0.5, 1.5 and 4 hours post-dose by halothane anesthesia and the carcasses prepared for whole body autoradiography.

Observation:
Mortality/ moribundity: twice daily.
Clinical signs: daily.
Body weights: on the day of treatment.

Analytics:
Radioanalysis procedures were validated in triplicate on fortified control samples of representative tissues and fluids. All sample combustion was performed using Packard model 306 or 307 sample oxidisers and analysed using Packard model 1900TR or 2300TR liquid scintillation counters for at least 5 minutes or 105 accumulated counts. All tissues and fluids collected were weighed, and homogenised unless the entire sample was used, sampled, and then analysed, in duplicate if sample size permitted. Scintillation counts were automatically corrected for counting efficiency.
Pooled samples of liver, kidneys, stomach, plasma, excreta, and intestinal tract with contents collected 4 hours post-dose from group 1 pups were extracted with methanol:water (8:2). The extracts were analysed by LSC to determine radioactivity recovery and by comparative HPLC to determine metabolite profiles. 14C-UF and 14C-DN were used for cochromatography with test sample extracts.
WBA: frozen carcasses were embedded in chilled carboxymethylcellulose, frozen at -20ºC and sectioned at approximately 40µm. Sections from appropriate levels in the sagittal plane, including all major organs, tissues and fluids, were collected. Single section sets from each animal were exposed to Molecular Dynamics PhosphorImaging screens and scanned using a Molecular Dynamics 445 SI PhosphorImager. The autoradiographic standard image data were sampled using AIS software (Imaging Research Inc.), to create a calibrated standard curve. Tissue concentrations in specified tissues, organs and fluids were interpolated from each standard curve as nanoCuries/g and converted to µg equivalents/g based on specific activity.

Sampling time: 0.5, 1.5 and 4.0 hours
Statistics:
Statistical analyses were limited to simple expressions of variation, such as mean and standard deviation.
Preliminary studies:
None

TOXIC EFFECTS AND CLINICAL SIGNS:

There were no treatment-related clinical signs of toxicity in any of the study animals.

RECOVERY OF LABELLED COMPOUND:

See Table 1.

Radioactivity was rapidly and extensively absorbed, widely distributed and rapidly eliminated from all tissues sampled. The mean total recovery of radioactivity from both sexes of pups was within the range 87.6 - 98.2% for all sampling intervals. The recovery of radioactivity at 4 hours post-dose amounted to 36.3 and 31.8% in excreta, 22.2 and 20.7% in stomach, and 30.6 and 31.8% in the residual carcass, in males and females, respectively. Absorption from the gastrointestinal tract amounted to at least 75% within 4 hours in both sexes.

Comparison of neonatal and young adult rats (see Section A6.2-1):

See Table 5.

Plasma radioactivity in neonatal rats is approximately 52% that of the adult ratat0.5 hours post-dose, whereas at 4 hours the neonatal plasma concentration is more than 4 times the adult concentration. A similar pattern is evident in liver. The concentrations in the kidneys and stomach contents of neonatal pups are markedly higher than in adults at 4 hours post-dose. These data indicate oral absorption and urinary elimination in neonates are slower than in the adult animal. Possible reasons for rate differences include incomplete development of the gastrointestinal tract and kidneys in the neonate, the absence of the maternal stimulus for neonatal micturition and the presence of food in the gut. TISSUE DISTRIBUTION (TD):

See Table 2.

The maximum plasma concentration of radioactivity in both sexes was approximately 21ppm and occurred at 0.5 hours post-dose. Thereafter it declined to approximately 9ppm at 4 hours post-dose. Concentrations in the stomach and kidneys were higher than in plasma at all sampling intervals, but were comparable in liver and plasma. Concentrations in blood and plasma were also comparable, indicating that radioactivity was not associated with the cellular elements of blood. There were no apparent sex differences in the absorption and elimination of radioactivity.

Comparison of neonatal and young adult rats (see section A6.2-1):

See Table 6.

The gastrointestinal tract and contents of neonatal pups contained between 55 and 60% of administered radioactivity 0.5 hours post-dose, in contrast to 10 to 15% in adults. Concentrations had declined by 4 hours post-dose to 22 - 25% administered dose in pups and to less than 3% in adults. Thus, at 0.5 hours, oral absorption in pups amounted to approximately 50% compared to approximately 90% in adults. The kidneys of pups contained less radioactivity than adult kidneys at 0.5 hours and more after 4 hours. These data also support the contention that oral absorption and urinary elimination in neonatal pups are slower than in the adult animal. ANALYTICS AND RADIOACTIVE COMPONENTS:

See Table 3.

The recovery of radioactivity from all matrices for metabolite profiling ranged from 96.6 - 100%. In all matrices, [G-14C]-dinotefuran was the major component and accounted for 97.0 - 100% of radioactivity in plasma, kidneys, stomach and excreta. In the liver, [G-14C]-dinotefuran accounted for 61.1% (males) and 66.5% (females) of radioactivity, and in the intestinal tract with contents accounted for 83.3% (males) and 76.3% (females). Metabolism was limited

Comparison of neonatal and young adult rats (see section A6.2-1):

See Table 7.

Metabolite patterns were similar in pups and adult when the metabolite profiles were comparable to those of the young adult, but fewer metabolites were detected in neonates. These data suggest slower metabolism of[G-14C]-dinotefuran in pups, possibly due to incomplete development of neonatal liver function. QUALITATIVE WHOLE BODY AUTORADIOGRAPHY (WBA):

See Table 4.

Autoradiographic data indicated that [G-14C]-dinotefuran-derived radioactivity was widely distributed throughout the organs and tissues in male and female pups. Most of the radioactivity was contained in the stomach and contents, kidneys, urinary bladder and urine. Maximum tissue concentrations occurred either 0.5 or 1.5 hours post-dose. Overall, the concentration of radioactivity in most tissues declined during the 4 hours post-dose. In contrast, the concentrations in the renal medulla and cortex, the urinary bladder and urine increased from 0.5 to 4 hours post-dose indicating predominantly urinary elimination. Elimination from most tissues was incomplete at 4 hours post-dose. Low levels of radioactivity occurred in the brain. There were no apparent sex differences in the tissue distribution of radioactivity.

Table 1. Total recovery of radioactivity after a single oral dose of 50 mg/kg [G-14C]-dinotefuran

Matrix

Pup sex

Mean % radioactive dose administered recovered at:

 

 

0.5hr

1.5hr

4hr

Blood

Male

1.84

1.38

0.69

Excreta

 

3.23

22.1

36.3

Intestinal tract + contents

 

2.91

2.28

1.80

Kidneys

 

0.95

0.28

1.15

Liver

 

1.47

1.05

0.64

Residual carcass

 

31.5

34.3

30.6

Stomach

 

1.14

0.45

0.88

Stomach contents

 

52.2

36.4

22.2

Total

 

95.3

98.2

94.2

 

Blood

Female

1.42

1.26

0.53

Excreta

 

5.75

26.3

31.8

Intestinal tract + contents

 

3.37

2.25

1.42

Kidneys

 

0.84

0.89

0.59

Liver

 

1.43

0.97

0.52

Residual carcass

 

25.1

26.1

31.8

Stomach

 

1.93

0.31

0.18

Stomach contents

 

54.1

36.0

20.7

Total

 

94.0

94.1

87.6

Table 2. Concentration of radioactivity in tissues after a single oral dose of 50 µg/kg [G-14C]-dinotefuran

Matrix

Pup sex

mgequivalents[G-14C]-dinotefuran /g (ppm) at:

 

 

0.5hr

1.5hr

4hr

Blood

Male

20.3

18.2

9.06

Intestinal tract + contents

 

28.8

21.8

14.2

Kidneys

 

36.1

10.2

45.8

Liver

 

23.7

15.1

10.2

Plasma

 

21.3

19.1

9.42

Residual carcass

 

18.7

20.5

17.9

Stomach

 

76.1

33.7

59.9

Stomach contents

 

70.8

48.3

33.4

 

Blood

Female

17.0

15.4

6.97

Intestinal tract + contents

 

28.3

20.2

12.3

Kidneys

 

30.9

34.3

22.6

Liver

 

21.3

15.1

7.66

Plasma

 

21.2

18.9

8.71

Residual carcass

 

15.3

16.1

19.5

Stomach

 

110

23.2

13.7

Stomach contents

 

78.1

38.4

32.7

 Table 3. Metabolites detected in neonatal rats after a single oral dose of 50 mg/kg [G-14C]-dinotefuran

Matrix

Sex

% radioactivity recovered in fraction:

 

 

dinotefuran

1

2

3

4

1+2+3+4

Liver

Male

61.1

6.69

4.89

19.5

7.82

38.9

Kidneys

 

97.1

1.62

0.73

0.53

0.00

2.88

Stomach

 

99.0

0.21

0.78

0.00

0.00

0.99

ITCa

 

83.3

0.00

15.4

1.40

0.00

16.8

Excreta

 

98.5

1.49

0.00

0.00

0.00

1.49

Plasma

 

100

0.00

0.00

0.00

0.00

0.00

Liver

Female

66.5

5.17

3.76

23.0

1.62

33.6

Kidneys

 

97.0

2.28

0.68

0.00

0.00

2.96

Stomach

 

100

0.00

0.00

0.00

0.00

0.00

ITCa

 

76.3

21.6

0.00

2.16

0.00

23.8

Excreta

 

100

0.00

0.00

0.00

0.00

0.00

Plasma

 

100

0.00

0.00

0.00

0.00

0.00

Fraction 1 (RT: 4.5 - 9.4) - Possible mixture of MNG, 446-DO-Ac and others

Fraction 2 (RT: 12.1 - 19.8) - Possible mixture of PHPs, 446-DO, 446-CO, 446-OH-COOH, UF-DM, PHP-Ac, UF, FNG

Fraction 3 (RT: 38.1 - 44.0) - Possible mixture of MG, MG-Ac, DN-DO, DN-Ohs, DN-CO, BCDN, DN

Fraction 4 (RT: 46.8 - 47.0) - unknown

aintestinal tract with contents

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Absorption of [G-14C]-dinotefuran from the neonatal gastrointestinal tract is rapid and extensive. It undergoes a wide distribution within the body tissues and is eliminated predominantly in the urine. [G-14C]-dinotefuran undergoes minimal metabolism in the neonatal rat. The absorption, distribution, metabolism and elimination is not affected by the sex of the neonate.
The absorption, distribution, metabolism and elimination of [G-14C]-dinotefuran are similar in neonatal and young adult rats. However, absorption and elimination in the neonate proceed at a slower rate than in young adults, and although metabolite profiles are similar, fewer metabolites are formed in the neonate.
Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20/09/2005 - 05/04/2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.7600 (Dermal Penetration)
Version / remarks:
(1998)
Deviations:
no
GLP compliance:
yes
Radiolabelling:
yes
Remarks:
[14C- guanidine]dinotefuran ([G-14C])
Species:
rat
Strain:
other: Sprague Dawley, SPF quality (outbred)
Sex:
male
Details on test animals or test system and environmental conditions:
Source: RCC Ltd, Laboratory Animal Services, Füllinsdorf, Switzerland
Age: 8 – 9weeks at acclimatization
Body weight: approximately 260 g
Type of coverage:
open
Vehicle:
water
Remarks:
MilliQ
Duration of exposure:
Exposre period: 24 hours, with interim kills of 4 rats per group after 0.5, 1, 2, 4 and 10 hours exposure.
Doses:
Concentration of test substance: 3.2, 30 and 302 µg/cm2
Specific gravity: 156 µCi/mg (5760 kBq/mg)
No. of animals per group:
24 males/6 subgroups/group
Control animals:
no
Details on study design:
Preparation of test site: Clipped and wiped with acetone under anaesthesia with isofluorane. O-ring (inside area of approximately 25 - 35 cm2) was used.
Volume applied: 100µL of application solution was applied to the skin inside the O-ring using a syringe and spread evenly.
Size of test site: 10 cm²
Sampling time: 0.5, 1, 2, 4, 10 and 24 hours after initiation of skin contact

Housing and feeding condition: animals were housed individually throughout the experiment and fed certified standard diet ad libitum.
Details on in vitro test system (if applicable):
Not applicable
Signs and symptoms of toxicity:
no effects
Remarks:
The slight weight loss of animals was attributed to the stress and discomfort during the experiment. At dissection urinary calculi were found in the urinary bladder with cloudy urine of one animal of group 3.
Dermal irritation:
no effects
Remarks:
There was no evidence of skin irritation.
Absorption in different matrices:
Percutaneous absorption:

Low dose group (see Table 2):
After dermal application, systemic absorption was increased with the exposure time from 0.5 hours to 10 hours, but thereafter it remained almost constant. Therefore systemic absorption during a 24-hour exposure was calculated to be 0.81% of the applied dose. The concentration of radioactivity (RA) in blood was below the limit of quantification (LOQ) at all sampling time points. A major part of the applied RA was found in the skin wash which decreased with exposure time from 85% of dose after 0.5 hours to 60% of dose after 10 hours but no further change was observed between 10 hours and 24 hours. Correspondingly, the RA in the stratum corneum (tape strips) increased from 7.4% after 0.5 hours to 35% of the applied dose after 10 hours of exposure. The lower skin layers, corium and subcutis, showed very low amounts of RA (less than 1%) and 0.3-4.8% of the dose was recovered in the cover and O-ring. The systemically absorbed test item was rapidly excreted with the urine and only 0.11 % of the dose remained in the animals 24 hours after the start of exposure. The mean penetration rate for the 24-hour exposure time was calculated to be 0.0011 µg/cm2/hour.

Middle dose group (See Table 3):
After dermal application, absorption was only 0.48% during an exposure of 24 hours. The highest values were found 1 and 4 hours after start of exposure accounting for 1.43% and 1.15% of the applied dose, respectively, but a high inter-individual variation was observed. The concentrations of RA in blood were below the limit of quantification (LOQ) at most of the sampling time points, and 0.0033 and 0.0134 ppm dinotefuran equivalents were determined after 0.5 and 1 hour, respectively. A major part of the applied RA was recovered in the skin wash which was decreased with exposure time from 90% of dose after 0.5 hours to 69% of dose after 10 hours but no further change was observed between 10 hours and 24 hours. Correspondingly, the RA in the stratum corneum increased with exposure time and reached 26% of the applied dose after an exposure period of 24 hours. The lower skin layers, corium and subcutis, showed very low amounts of RA (less than 0.5%) and in the range 0.05-3.2% of the dose were recovered in the cover and O-ring. The systemically absorbed test item was rapidly excreted with the urine and only 0.09 % of the dose remained in the animals 24 hours after the start of exposure. The mean penetration rate for the 24 hours exposure time was calculated to be 0.0060 µg/cm2/hour.

High dose group (see Table 4):
After dermal application, absorption was 1.04% during an exposure of 24 hours. Higher values of dermal absorption were found at 1, 4 and 10 hours after start of exposure accounting for 1.41%, 2.10% and 1.44% of the applied dose, respectively, but a high inter-individual variation was observed. The highest concentration in blood was found 1 hour after the start of exposure accounting for 0.1773 ppm dinotefuran equivalents. Thereafter the concentrations decreased rapidly to values close to the limit of quantification. A large amount of RA was found in the skin wash. It decreased only slightly with ongoing exposure time, i.e. 93% of the dose after 0.5 hours to 86% of the dose after 10 hours. After 1 hour of exposure 8% of the applied dose had penetrated into the stratum corneum. This level was almost constant until 24 hours. The lower skin layers, corium and subcutis, showed very low amounts of RA. The systemically absorbed test item was rapidly excreted with the urine and only 0.09 % of the dose was still remaining in the animals 24 hours after start of exposure. The mean penetration rate for the 24 hours exposure time was calculated to be 0.1309 µg/cm2/hour.

Analysis of skin wash:
See Table 5
The skin wash samples of the individual animals were pooled for every sampling time point and dose level, and analyzed by HPLC. In all analyses more than 96% of the RA was found as unchanged dinotefuran. Therefore it was concluded that the applied test substance remained stable at the application site over the whole exposure period.
Total recovery:
See Table 1
Mean total recoveries of radioactivity were high (95.4-99.1%) in all dose groups at all time points and the systemically absorbed dose was rapidly excreted, predominantly in urine.
Dose:
3.2 µg/cm²
Parameter:
percentage
Absorption:
97.2 %
Remarks on result:
other: 0.5 h
Dose:
3.2 µg/cm²
Parameter:
percentage
Absorption:
99.1 %
Remarks on result:
other: 4 h
Dose:
3.2 µg/cm²
Parameter:
percentage
Absorption:
96.9 %
Remarks on result:
other: 24 h
Dose:
30 µg/cm²
Parameter:
percentage
Absorption:
96.6 %
Remarks on result:
other: 0.5 h
Dose:
30 µg/cm²
Parameter:
percentage
Absorption:
97.7 %
Remarks on result:
other: 4 h
Dose:
30 µg/cm²
Parameter:
percentage
Absorption:
97.7 %
Remarks on result:
other: 24 h
Dose:
302 µg/cm²
Parameter:
percentage
Absorption:
97 %
Remarks on result:
other: 0.5 h
Dose:
302 µg/cm²
Parameter:
percentage
Absorption:
95.4 %
Remarks on result:
other: 4 h
Dose:
302 µg/cm²
Parameter:
percentage
Absorption:
96.3 %
Remarks on result:
other: 24 h

Table 1: Summary of mean mass balance and systemic absorption

Dose level

(µg/cm2)

Matrix

Radioactivity in%of applied dose:

0-0.5 h

0-1 h

0-2 h

0-4 h

0-10 h

0-24 h

3.2

Systemic absorption

0.2

0.2

0.4

0.7

1.2

0.8

Dislodged dose

89.5

78.7

67.4

68.9

61.5

60.7

Stratum corneum (outer skin)

7.4

18.1

31.0

29.2

34.8

34.6

Corium+subcutis (inner skin)

0.1

0.2

0.3

0.5

0.6

0.8

Total

97.2

97.2

99.1

99.1

97.9

96.9

30

Systemic absorption

0.3

1.4

0.3

1.2

0.8

0.5

Dislodged dose

90.5

83.8

74.5

77.6

71.9

71.2

Stratum corneum (outer skin)

5.6

12.5

21.9

18.8

24.7

25.6

Corium+subcutis (inner skin)

0.2

0.5

0.2

0.1

0.2

0.4

Total

96.6

98.3

96.9

97.7

97.6

97.7

302

Systemic absorption

0.2

1.4

0.9

2.1

1.4

1.0

Dislodged dose

93.3

85.8

88.9

86.7

86.1

86.1

Stratum corneum (outer skin)

3.4

8.0

7.8

6.4

7.8

9.0

Corium+subcutis (inner skin)

0.1

0.5

0.1

0.2

0.1

0.2

Total

97.0

95.7

97.7

95.4

95.4

96.3

 

Table 2:Balance of radioactivity and excretion pattern – low dose group (3.2µg/cm2)

Matrix

Radioactivity in%of applied dose:

0-0.5 hours

0-1 hours

0-2 hours

0-4 hours

0-10 hours

0-24 hours

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Urine

<0.01

<0.01

0.02

0.01

0.14

0.16

0.45

0.49

0.97

0.50

0.62

0.48

Faeces

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

0.02

<0.01

Cage wash

<0.01

<0.01

<0.01

<0.01

<0.01

0.01

0.03

0.01

0.02

0.01

0.05

0.07

TOTAL EXCRETION

0.01

<0.01

0.03

0.02

0.16

0.18

0.48

0.49

1.00

0.51

0.69

0.53

Blood

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

Untreated skin

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

GI tract + contents

0.02

<0.01

0.02

<0.01

0.03

<0.01

0.03

0.01

0.03

<0.01

0.02

<0.01

Carcass

0.13

0.01

0.15

0.02

0.16

0.03

0.14

0.05

0.12

0.02

0.09

0.02

Sub-total

0.16

0.02

0.18

0.03

0.19

0.04

0.18

0.06

0.15

0.02

0.11

0.02

SYSTEMICABSORPTION

 

0.17

 

0.02

 

0.20

 

0.03

 

0.35

 

0.21

 

0.65

 

0.55

 

1.15

 

0.52

 

0.81

 

0.52

TapeStrips

(stratum corneum)

7.42

0.31

18.06

6.04

30.97

4.40

29.15

2.88

34.77

5.40

34.63

1.08

Remaining treated skin

0.09

0.03

0.17

0.03

0.31

0.10

0.45

0.37

0.56

0.25

0.77

0.47

APPRICATION SITE

7.51

0.33

18.24

6.07

31.27

4.37

29.60

3.20

35.33

5.28

35.40

1.55

Skin wash

84.70

6.55

78.04

3.04

66.83

3.72

68.60

4.11

59.78

6.09

59.10

5.46

O-ring/covers

4.79

6.08

0.67

1.07

0.60

0.76

0.30

0.30

1.68

3.04

1.62

2.70

DISLODGEDDOSE

89.49

0.68

78.71

2.70

67.43

3.40

68.90

3.98

61.46

5.43

60.72

2.99

TOTALRECOVERY

97.18

0.56

97.15

3.38

99.05

0.98

99.14

0.80

97.93

0.58

96.93

1.63

 


Table 3:Balance of radioactivity and excretion pattern – middle dose group(30 µg/cm2)

Matrix

Radioactivity in%of applied dose:

0-0.5 hours

0-1 hours

0-2 hours

0-4 hours

0-10 hours

0-24 hours

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Urine

0.04

0.04

0.40

0.42

0.12

0.02

0.88

0.88

0.65

0.66

0.36

0.26

Faeces

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

0.01

<0.01

Cage wash

<0.01

<0.01

0.03

0.05

<0.01

<0.01

0.05

0.05

<0.01

<0.01

<0.01

<0.01

TOTAL EXCRETION

0.04

0.04

0.43

0.46

0.13

0.02

0.93

0.93

0.67

0.67

0.38

0.27

Whole blood

<0.01

<0.01

0.03

0.02

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

Untreated skin

<0.01

<0.01

0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

GI tract + contents

0.02

0.01

0.09

0.09

0.02

<0.01

0.03

0.02

0.02

<0.01

0.01

<0.01

Carcass

0.20

0.10

0.87

0.57

0.14

0.01

0.17

0.04

0.10

<0.01

0.08

<0.01

Sub-total

0.24

0.12

1.00

0.67

0.17

0.02

0.21

0.06

0.12

0.01

0.09

<0.01

SYSTEMICABSORPTION

 

0.28

 

0.16

 

1.43

 

1.13

 

0.30

 

0.03

 

1.15

 

0.98

 

0.78

 

0.68

 

0.48

 

0.27

TapeStrips

(stratum corneum)

5.59

1.62

12.51

4.33

21.87

1.35

18.75

3.43

24.73

5.40

25.62

3.34

Remaining treated skin

0.15

0.12

0.49

0.44

0.20

0.07

0.14

0.03

0.16

0.05

0.40

0.22

APPRICATION SITE

5.74

1.70

13.00

4.63

22.06

1.39

18.89

3.43

24.89

5.35

26.02

3.31

Skin wash

90.49

3.23

83.62

5.58

71.30

1.75

74.44

4.48

69.12

3.75

70.07

4.67

O-ring/covers

0.05

0.02

0.22

0.27

3.22

2.70

3.17

6.11

2.82

2.81

1.12

1.95

DISLODGEDDOSE

90.54

3.23

83.84

5.69

74.51

1.02

77.61

2.90

71.94

5.58

71.19

3.72

TOTALRECOVERY

96.55

3.37

98.27

0.96

96.88

0.83

97.65

1.34

97.62

1.22

97.69

1.04

 

Conclusions:
A large proportion of the dermally applied dinotefuran (60.7 – 93.3%) remained on the surface of the skin and could be dislodged by washing, and was not available for absorption into the skin or systemic circulation. Therefore, systemic absorption of dinotefuran was very low at all time points for all dose levels.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
75
Absorption rate - inhalation (%):
100

Additional information