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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
07.06.1995 to 21.09.1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant and designded according to the extant draft guidelines available at time of study conduct

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
no guideline available
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
not applicable
Principles of method if other than guideline:
The study design followed the available draft OECD guidelines extant at the time- OECD guideline for testing of chemicals ‘Percutaneous absorption: in vitro method’, draft document, March 1994. Methods for measuring dermal penetration of pesticides, MAFF, UK, Working Document 5/9, November 1992.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
Refer to table presented below and attached file 14C
Radiolabelling:
yes

Test animals

Species:
other: Rat and human skin samples
Strain:
other: Tif: RAI f rats, human Caucasian donors
Sex:
not specified

Administration / exposure

Type of coverage:
other: Diffusion cell apparatus
Vehicle:
other: For the radiolabeled compound toluene served as solvent. The formulated test substances in the aqueous suspension were stable as checked by TLC. Two sets of formulations designated A and B were prepared with the blank formulation containing [U-14C]phenyl
Duration of exposure:
8 hours
Doses:
[14C]- CGA 184927 - Rat : 0.04, 0.41, 4.05 mg/cm2; human: 0.04, 0.4, 3.87 mg/cm2
[14C]- CGA 185072 - Rat : 0.01, 0.09, 0.99 mg/cm2; human: 0.01, 0.1, 1.11 mg/cm2
No. of animals per group:
Between 5 and 7 skin replicates for rat and human membranes per test group
Control animals:
no
Details on study design:
See table presentd below

Results and discussion

Percutaneous absorption
Remarks on result:
other: Cloquintocet-mexyl: within 8 hours, 68%, 32%, and 2% of the dose penetrated the rat epidermis, but only 6%, 5% and 0.1% of the dose the human epidermis at the low, middle, and high concentration, respectively
Conversion factor human vs. animal skin:
At steady state conditions, reached after a lag time of less than 2 hours in both species (except in rat epidermis at the high concentration, i.e. 8 hours), the species difference is reflected in the flux constants determined to 4.9, 13.3 and 48.2 µg×cm-2×h-1 through rat epidermis and 0.8, 0.9, and 2.4 µg×cm-2×h-1 through human epidermis at the low, middle, and high concentration, respectively. This results in a rat/human ratio of the flux constants of 6:1, 16:1, and 20:1

Any other information on results incl. tables

Dermal penetration of clodinafop-propargyl and cloquintocet-mexyl formulated as TOPIK 15 WP (A-9526 A) through rat and human skin in vitro

Test compound

[14C]- CGA 184927

Species

Rat

Human

Dose

(mg/cm2)

0.04

0.41

4.05

0.04

0.4

3.87

Penetration
(% of dose)

within    8 h

             24 h

             48 h

61.0

73.1

77.7

20.6

45.9

nd

3.5

17.8

43.9

9.3

20.2

31.3

1.0

2.2

4.6

0.3

0.8

1.2

Flux constant

[mg/(cm2 x h)]

4.94

13.34

48.22

0.76

0.86

2.41

Lag time (h)

0.3

1.0

8.2

1.1

1.4

0.7

[14C]- CGA 185072

Dose

(mg/cm2)

0.01

0.09

0.99

0.01

0.1

1.11

Penetration
(% of dose)

within    8 h

             24 h

             48 h

68.0

72.8

75.0

32.4

50.9

63.8

1.7

4.7

10.1

6.4

13.5

20.8

4.5

7.1

8.8

0.1

0.2

0.2

Flux constant

[mg/(cm2 x h)]

1.79

4.69

4.66

0.12

0.81

0.25

Lag time (h)

0.3

0.4

1.2

1.3

1.3

0.9

nd : not determined

Applicant's summary and conclusion

Conclusions:
A skin penetration study through rat and human skin in vitro with TOPIK® 15 WP formulation (A-9526 A) showed that based on the absorption rate (flux) the human skin compared to the rat skin is 6 fold less permeable to clodinafop-propargyl when diluted as used in field applications. When applying the concentrated formulation 20 times less clodinafop-propargyl penetrated the human skin compared to the rat skin. The corresponding figures for the safener cloquintocet-mexyl resulted in human/rat ratios of 1: 15 and 1:19 for the field dilution and the concentrate respectively.
Executive summary:

Within 8 hours the portion of clodinafop-propargyl penetrating the rat epidermis decreased from 61% to 21% and 4% of the dose with increasing concentrations. The human epidermis was consistently less permeable with corresponding values of  9%, 1%, and 0.3% of the dose.At steady state conditions, reached after a lag time of less than 2 hours in both species (except in rat epidermis at the high concentration, i.e. 8 hours), the species difference is reflected in the flux constants determined to 4.9, 13.3 and 48.2 µg·cm-2·h-1 through rat epidermis and 0.8, 0.9, and 2.4  µg·cm-2·h-1 through human epidermis at the low, middle, and high concentration, respectively. This results in a rat/human ratio of the flux constants of 6:1, 16:1, and 20:1 .

Within 8 hours, 68%, 32%, and 2% of the dose of cloquintocet-mexyl penetrated the rat epidermis, but only 6%, 5% and 0.1% of the dose the human epidermis at the low, middle, and high concentration, respectively. The lag time was again less than two hours for both species. At steady state conditions the flux constants through rat epidermis accounted for 1.8, 4.6, and 4.7 µg·cm-2·h-1 through rat epidermis and 0.8, 0.9, and 2.4  µg·cm-2·h-1 at the low, middle, and high concentration, respectively. The corresponding values for human epidermis accounted for 0.1, 0.8, and 0.3 µg·cm-2·h-1 resulting in a rat/human ratio of flux constant of 15:1, 6:1, and 19:1 for the low, middle, and high concentration, respectively.

Clodinafop-propargyl and cloquintocet-mexyl remained unchanged while exposed to and penetrating through rat and human epidermis

A skin penetration study through rat and human skin in vitro showed that based on the absorption rate (flux) the human skin compared to the rat skin is 6 fold less permeable to clodinafop-propargyl when diluted as used in field applications. When applying the concentrated formulation 20 times less clodinafop-propargyl penetrated the human skin compared to the rat skin. The corresponding figures for the safener cloquintocet-mexyl resulted in human/rat ratios of 1: 15 and 1:19 for the field dilution and the concentrate respectively.