1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Biochemistry Protocol 68-861

Principles of method if other than guideline:

The objective of this study was to determine the magnitude of skin absorption of up to a 10-hour exposure period at three different rates of application. This study was done utilising a 14C-test substance 3.6EC formulated product in an aqueous suspension. The percent of the dose absorbed, excreted and the amount remaining on the skin were used to estimate the magnitude of dermal absorption and to calculate a total 14C-balance. This study was conducted in accordance with Biochemistry Protocol 68-861.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

EC Number:

262-104-4

EC Name:

1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

Cas Number:

60207-90-1

Molecular formula:

C15H17Cl2N3O2

IUPAC Name:

1-{[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl}-1H-1,2,4-triazole

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Harlan

Sex:

male

Administration / exposure

Type of coverage:

unoccluded

Vehicle:

water

Duration of exposure:

10-hour

Doses:

0.1, 1.0 and 10.0 mg/rat, equivalent to 0.01, 0.1 and 1.0 mg/square centimeter, respectively.

No. of animals per group:

12

Control animals:

no

Results and discussion

Absorption in different matrices:

The rate of absorption of 14C-test substance is inversely related to the dosage level (as the dosage level increases, the total percent absorbed decreases). After a 4-hour period, the total amount absorbed was 52.0 %, 48.5 % and 34.4 % for the low, mid and high dose levels, respectively. After a 10-hour period, the total amount absorbed was 71.0 % and 42.0 % for the low and mid dose levels, respectively. In this study, dermal absorption = % in blood + % in carcass + % in skin + % in urine + % in faeces + % in cage wash

Total recovery:

The range of total 14C recovery mean values for the three dosage levels and sacrifice times was from 63.7 % to 119.9 %

Percutaneous absorption

Percutaneous absorption 1

Time point:

2 h

Concentrate / Dilution:

dilution

Dose:

0.11 mg/Rat

Parameter:

percentage

Absorption:

53.1 %

Remarks on result:

other: 0.11 mg/Rat

Percutaneous absorption 2

Time point:

4 h

Concentrate / Dilution:

dilution

Dose:

0.11 mg/Rat

Parameter:

percentage

Absorption:

52 %

Remarks on result:

other: 0.11 mg/Rat

Percutaneous absorption 3

Time point:

10 h

Concentrate / Dilution:

dilution

Dose:

0.11 mg/Rat

Parameter:

percentage

Absorption:

71 %

Remarks on result:

other: 0.11 mg/Rat

Percutaneous absorption 4

Time point:

24 h

Concentrate / Dilution:

dilution

Dose:

0.11 mg/Rat

Parameter:

percentage

Absorption:

66.5 %

Remarks on result:

other: 0.11 mg/Rat

Percutaneous absorption 5

Time point:

82 h

Concentrate / Dilution:

dilution

Dose:

0.12 mg/Rat

Parameter:

percentage

Absorption:

57.1 %

Remarks on result:

other: 0.12 mg/Rat

Percutaneous absorption 6

Time point:

96 h

Concentrate / Dilution:

dilution

Dose:

0.11 mg/Rat

Parameter:

percentage

Absorption:

65.8 %

Remarks on result:

other: 0.11 mg/Rat

Percutaneous absorption 7

Time point:

2 h

Concentrate / Dilution:

dilution

Dose:

1.1 mg/Rat

Parameter:

percentage

Absorption:

28.4 %

Remarks on result:

other: 1.1 mg/Rat

Percutaneous absorption 8

Time point:

4 h

Concentrate / Dilution:

dilution

Dose:

1.2 mg/Rat

Parameter:

percentage

Absorption:

48.5 %

Remarks on result:

other: 1.2 mg/Rat

Percutaneous absorption 9

Time point:

10 h

Concentrate / Dilution:

dilution

Dose:

1.2 mg/Rat

Parameter:

percentage

Absorption:

42 %

Remarks on result:

other: 1.2 mg/Rat

Percutaneous absorption 10

Time point:

96 h

Concentrate / Dilution:

dilution

Dose:

1.3 mg/Rat

Parameter:

percentage

Absorption:

43.5 %

Remarks on result:

other: 1.3 mg/Rat

Percutaneous absorption 11

Time point:

2 h

Concentrate / Dilution:

dilution

Dose:

8.6 mg/Rat

Parameter:

percentage

Absorption:

37.9 %

Remarks on result:

other: 8.6 mg/Rat

Percutaneous absorption 12

Time point:

4 h

Concentrate / Dilution:

dilution

Dose:

8.6 mg/Rat

Parameter:

percentage

Absorption:

34.4 %

Remarks on result:

other: 8.6 mg/Rat

Percutaneous absorption 13

Time point:

24 h

Concentrate / Dilution:

dilution

Dose:

8.7 mg/Rat

Parameter:

percentage

Absorption:

38 %

Remarks on result:

other: 8.7 mg/Rat

Percutaneous absorption 14

Time point:

82 h

Concentrate / Dilution:

dilution

Dose:

8.9 mg/Rat

Parameter:

percentage

Absorption:

42.9 %

Remarks on result:

other: 8.9 mg/Rat

Percutaneous absorption 15

Time point:

96 h

Concentrate / Dilution:

dilution

Dose:

9.6 mg/Rat

Parameter:

percentage

Absorption:

76.7 %

Remarks on result:

other: 9.6 mg/Rat

Any other information on results incl. tables

RECOVERIES
The range of total 14C recovery mean values for the three dosage levels and sacrifice times was from 63.67 % to 119.92 %. In line with the EFSA guidance on dermal absorption (2017) only the recoveries between 90 and 110% were used for further assessment.

 

ABSORPTION
The rate of absorption of 14C-test substance is inversely related to the dosage level (as the dosage level increases, the total percent absorbed decreases). After a 10-hour period, the total amount absorbed was 71.0 % and 42.0 % for the low and mid dose levels respectively, while the high dose level at this time point did not show acceptable recovery levels for further assessment. Within each dose level, the dermal absorption results varied enormously between the individual animals. At the low dose level, the dermal absorption ranged from 25.17 to 64.61 %, with an average and standard deviation of respectively 52.86 % and 9.96. At the mid dose level, the dermal absorption ranged from 24.97 to 44.28 %, with an average and standard deviation of respectively 33.64 % and 6.30. And at the high dose level, the dermal absorption ranged from 26.34 to 60.23 %, with an average and standard deviation of respectively 34.20 % and 8.16.

 

EXCRETION

For all dose levels less than 20 % of the dose was excreted in a 10-hour period. The main route of excretion was in the urine.

 

SKIN RESIDUES

Ten hours after treatment, total skin residue values were on average 50.0 % (Skin I, Skin II, soap rinse and water rinse) for the low dose and 79.8 % for the mid-dose level. A large proportion of the radioactivity on the skin was removed by the soap and water rinses; on average 33.9 and 54.4 % of the applied dose for the low and mid dosage levels, respectively. For these levels, about 70 % of the radioactivity on the skin could be removed with soap and water rinses. Except for the 4-hour time point at the high dose leveland time points and measurments performed after 24 hours of  dosing, the amount of radioactivity in Skin Sections I were greater than Skin Sections II indicating that the applied dose did not migrate appreciably from the treated area during the washing process. The amount of radioactivity remaining in the skin as residue is possibly available for further absorption and these values were considered as part of the total percent absorbed.

 

Table 1. Low Dose (0.11 mg/Rat): Summary of absorption

2 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.30	0.31	0.14	0.15
Carcass	16.99	15.77	12.66	7.61
Skin I	20.63	18.13	16.61	14.50
Skin II	2.25	2.41	3.65	2.05
Urine	1.83	1.39	0.00	0.33
Faeces	0.00	0.00	0.00	0.02
Bandage rinse	2.44	0.76	2.48	3.16
Bridge rinse	0.87	2.90	4.39	2.43
Soap rinse	52.00	45.54	44.67	39.11
Water rinse	5.29	4.54	9.31	5.00
Gauze A	5.19	11.71	15.46	27.39
Gauze B	0.18	0.23	0.15	0.22
Paper	0.06	2.07	0.53	2.85
Paper rinse	2.38	4.09	9.16	1.28
Cage wash	0.31	1.23	0.71	0.51
Recovery	110.72	111.08#	119.92#	106.61
Total absorbed	42.31	39.24	33.77	25.17
			Average	33.7
			SD	12.1
			k-factor	1.6
			Absorp%	53.1

# data not taken into account, outside the acceptable recovery range

 

Table II. Low Dose (0.11 mg/Rat): Summary of absorption

4 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.15	0.11	0.14	0.07
Carcass	9.53	7.83	12.00	7.30
Skin I	31.40	27.64	29.00	29.40
Skin II	3.29	9.25	8.02	8.93
Urine	1.45	1.18	1.22	0.29
Faeces	0.01	0.00	0.01	1.00
Bandage rinse	0.53	1.00	0.75	1.00
Bridge rinse	0.99	0.99	0.65	0.86
Soap rinse	51.40	26.36	39.77	46.75
Water rinse	11.59	12.82	11.33	8.06
Gauze A	1.66	0.90	1.26	1.16
Gauze B	0.53	0.65	0.49	0.34
Paper	0.15	0.11	0.02	0.08
Paper rinse	3.83	3.25	0.83	2.12
Cage wash	0.43	0.56	0.50	0.33
Recovery	116.94#	92.65	105.99	107.69
Total absorbed	46.26	46.57	50.89	47.32
			Average	48.3
			SD	2.3
			k-factor	1.6
			Absorp%	52.0

# data not taken into account, outside the acceptable recovery range

 

Table III. Low Dose (0.11 mg/Rat): Summary of absorption 

10 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.31	0.28	0.16	0.28
Carcass	37.48	30.36	20.55	32.38
Skin I	10.92	14.61	15.69	6.59
Skin II	1.38	2.57	2.48	1.88
Urine	13.00	7.46	3.87	11.99
Faeces	0.00	0.01	0.16	0.26
Bandage rinse	5.99	0.60	3.85	0.65
Bridge rinse	1.86	3.48	<0.00	0.59
Soap rinse	31.54	24.53	30.85	23.67
Water rinse	3.71	2.89	7.87	2.39
Gauze A	1.07	5.14	2.92	3.03
Gauze B	0.12	0.18	0.21	0.10
Paper	0.04	1.46	0.18	0.02
Paper rinse	1.61	5.33	2.44	1.08
Cage wash	0.76	0.91	0.50	0.89
Recovery	109.79	99.81	91.73	85.80#
Total absorbed	63.85	56.2	43.41	54.27
			Average	54.5
			SD	10.3
			k-factor	1.6
			Absorp%	71.0

# data not taken into account, outside the acceptable recovery range

 

Table IV. Low Dose (0.12 mg/Rat): Animal data

24 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.21	0.14	0.23	0.18
Carcass	26.63	19.22	19.23	10.09
Skin I	7.48	6.89	2.64	14.63
Skin II	1.56	1.68	2.22	1.69
Urine	20.10	18.89	13.98	16.37
Faeces	11.54	13.86	8.15	10.89
Bandage rinse	0.53	0.56	0.67	1.18
Bridge rinse	1.14	0.94	0.64	2.21
Soap rinse	36.36	39.10	37.22	32.88
Water rinse	2.51	2.31	3.15	3.40
Gauze A	1.77	1.66	4.26	2.24
Gauze B	0.58	0.56	0.94	0.06
Paper	0.05	0.04	0.15	0.07
Paper rinse	1.16	1.62	2.06	3.32
Cage wash	1.73	1.91	2.38	1.29
Recovery	113.35#	109.38	97.92	100.50
Total absorbed	69.25	62.59	48.83	55.14
			Average	55.5
			SD	6.9
			k-factor	1.6
			Absorp%	66.5

# data not taken into account, outside the acceptable recovery range

 

Table V. Low Dose (0.11 mg/Rat): Animal data

82 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.05	0.00	0.00	0.00
Carcass	1.51	1.57	1.45	1.56
Skin I	2.55	1.75	2.33	2.70
Skin II	5.55	3.80	3.15	1.69
Urine 10	5.53	5.25	4.10	5.65
Urine 34	10.87	11.37	10.48	11.72
Urine 58	3.56	4.38	3.66	3.64
Urine 82	1.32	1.80	1.54	1.54
Faeces 10	0.00	0.13	0.25	1.69
Faeces 34	12.57	15.19	12.10	13.98
Faeces 58	4.11	3.78	4.00	3.93
Faeces 82	2.21	2.05	0.82	1.41
Bandage Rinse	0.78	0.00	0.86	2.02
Bridge Rinse	0.94	2.00	2.17	2.46
Soap Rinse I	46.31	41.20	49.42	37.89
Water Rinse I	4.13	4.33	5.19	5.09
Soap Rinse II	1.52	1.13	1.09	0.88
Water Rinse II	0.75	0.70	0.74	0.65
Paper Rinse	2.26	0.63	0.00	1.59
Gauze A	2.61	3.21	3.95	2.41
Gauze B	0.27	0.35	0.26	0.24
Gauze C	0.05	0.03	0.06	0.05
Gauze D	0.03	0.02	0.02	0.02
Cage Wash I	0.94	0.80	0.60	0.76
Cage Wash II	1.24	2.01	1.00	1.01
Paper	0.06	0.05	0.04	0.08
Recovery	111.72	107.53	109.28	104.66
Total absorbed	52.01	53.88	45.48	51.28
			Average	50.21
			SD	4.30
			k-factor	1.60
			Absorp%	57.1

 

Table VI Low Dose (0.11 mg/Rat): Animal data

96 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.00	0.09	0.00	0.00
Carcass	1.06	1.36	2.13	1.28
Skin I	1.61	1.80	5.39	2.80
Skin II	0.92	1.37	2.11	2.80
Urine 24	21.84	17.23	11.76	17.01
Urine 48	0.80	7.81	9.33	9.88
Urine 72	6.44	2.55	3.17	2.81
Urine 96	0.00	1.02	2.27	1.04
Faeces 24	18.64	12.01	4.84	12.25
Faeces 48	6.90	11.50	11.41	7.84
Faeces 72	1.43	2.13	2.48	2.88
Faeces 96	0.64	0.90	1.22	0.87
Bandage Rinse	0.61	0.00	0.80	0.60
Bridge Rinse	2.58	4.47	3.31	0.00
Soap Rinse I	11.27	18.53	25.30	17.80
Water Rinse I	3.08	3.08	5.27	3.97
Soap Rinse II	1.07	0.99	1.11	0.63
Water Rinse II	0.58	0.62	1.01	0.63
Paper Rinse	6.59	10.87	1.84	7.65
Gauze A	5.48	2.67	4.53	3.89
Gauze B	0.22	0.09	0.80	0.38
Gauze C	0.04	0.03	0.07	0.03
Gauze D	0.01	0.02	0.02	0.02
Cage Wash I	1.48	0.78	1.31	0.88
Cage Wash II	2.85	0.66	1.64	0.73
Paper	0.46	0.31	1.18	0.95
Total Percent Recovered	96.60	102.89	104.30	99.62
Recovery	96.60	102.89	104.30	99.62
Total absorbed	64.61	61.21	59.06	63.07
			Average	61.99
			SD	2.40
			k-factor	1.60
			Absorp%	65.8

 

Table VII. Mid Dose (1.1 mg/Rat): Summary of absorption

2 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.09	0.05	0.04	0.02
Carcass	3.61	2.77	1.73	1.70
Skin I	18.53	17.51	18.81	16.68
Skin II	5.05	3.84	6.06	7.00
Urine	0.30	0.00	0.09	0.00
Faeces	0.01	0.00	0.00	0.00
Bandage rinse	0.25	0.64	0.30	0.86
Bridge rinse	0.09	0.10	0.28	0.16
Soap rinse	71.28	68.87	68.68	61.58
Water rinse	4.28	4.85	5.25	5.40
Gauze A	5.34	5.72	5.15	3.18
Gauze B	0.15	0.20	0.13	0.11
Paper	0.02	0.07	0.11	0.21
Paper rinse	0.35	0.49	0.83	0.76
Cage wash	0.28	0.80	0.07	0.12
Recovery	109.63	105.91	107.53	97.78
Total absorbed	27.87	24.97	26.803	25.52
			Average	26.3
			SD	1.3
			k-factor	1.6
			Absorp%	28.4

 

Table VIII. Mid Dose (1.2 mg/Rat): Summary of absorption

4 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.04	0.03	0.05	0.03
Carcass	0.31	2.32	3.94	3.36
Skin I	13.21	11.97	10.80	13.60
Skin II	2.52	2.50	2.40	4.87
Urine	24.05	9.32	27.02	9.24
Faeces	0.01	1.00	0.00	0.00
Bandage rinse	0.06	0.14	0.07	0.36
Bridge rinse	4.52	4.75	4.22	1.24
Soap rinse	51.81	35.91	39.43	50.17
Water rinse	4.17	4.44	4.75	6.22
Gauze A	4.81	5.39	4.50	3.47
Gauze B	0.26	0.33	0.04	0.11
Paper	0.68	1.23	0.30	0.09
Paper rinse	8.41	17.28	13.21	4.03
Cage wash	0.10	0.10	0.07	0.07
Recovery	114.96#	96.71	110.80	96.86
Total absorbed	40.24	27.24	44.28	31.17
			Average	34.2
			SD	8.9
			k-factor	1.6
			Absorp%	48.5

# data not taken into account, outside the acceptable recovery range

 

Table IX Mid Dose (1.2 mg/Rat): Summary of absorption

10 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.09	0.10	0.09	0.09
Carcass	9.09	9.31	8.18	9.60
Skin I	18.06	21.23	19.86	19.53
Skin II	3.74	7.81	5.17	4.55
Urine	2.37	2.07	1.51	2.21
Faeces	0.00	0.00	0.00	0.03
Bandage rinse	0.18	0.15	2.97	2.98
Bridge rinse	1.07	0.15	0.53	0.11
Soap rinse	52.84	48.08	52.94	44.54
Water rinse	4.33	4.43	4.87	3.11
Gauze A	4.54	2.33	2.01	6.59
Gauze B	0.21	0.31	0.16	0.06
Paper	0.08	0.04	0.01	0.02
Paper rinse	2.53	1.66	0.45	0.47
Cage wash	1.80	0.90	1.12	1.47
Recovery	100.93	98.57	99.87	95.36
Total absorbed	35.15	41.42	35.93	37.48
			Average	37.5
			SD	2.8
			k-factor	1.6
			Absorp%	42.0

 

Table X. Mid Dose (1.3 mg/Rat): Animal data

24 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.05	0.09	0.07	0.10
Carcass	6.53	6.57	7.28	9.03
Skin I	9.50	12.67	19.95	16.04
Skin II	1.46	2.09	2.07	3.90
Urine	4.28	0.79	0.24	0.19
Faeces	1.74	1.24	1.30	1.36
Bandage rinse	1.02	0.18	0.00	1.96
Bridge rinse	5.86	1.57	1.84	0.63
Soap rinse	25.01	35.81	34.02	22.95
Water rinse	5.04	3.17	3.06	19.58
Gauze A	1.62	2.97	5.82	2.54
Gauze B	0.29	0.16	0.27	0.18
Paper	2.29	0.42	0.21	2.61
Paper rinse	16.58	15.01	4.97	0.28
Cage wash	0.27	0.45	1.54	0.18
Recovery	81.54#	83.19#	82.64#	81.53#
Total absorbed	23.83	23.9	32.45	30.80

# data not taken into account, outside the acceptable recovery range

 

Table XI. Mid Dose (1.2 mg/Rat): Animal data

82 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.01	0.01	0.01	0.02
Carcass	0.82	0.81	1.05	0.84
Skin I	2.31	2.45	1.95	1.63
Skin II	1.16	2.08	2.82	0.37
Urine 10	2.35	0.56	2.69	2.12
Urine 34	7.68	3.69	8.03	7.83
Urine 58	2.38	2.38	2.69	3.45
Urine 82	0.80	1.04	1.19	1.06
Faeces 10	0.04	0.01	0.02	0.11
Faeces 34	5.15	3.42	6.97	5.74
Faeces 58	1.81	1.58	1.75	2.60
Faeces 82	0.68	0.84	0.87	0.70
Bandage Rinse	0.61	0.12	0.11	0.10
Bridge Rinse	1.36	8.41	2.66	3.99
Soap Rinse I	33.36	34.80	31.93	38.13
Water Rinse I	4.74	2.62	3.06	3.95
Soap Rinse II	0.60	0.86	0.54	0.21
Water Rinse II	0.35	0.42	0.21	0.11
Paper Rinse	15.78	19.24	5.58	9.42
Gauze A	1.93	0.91	5.82	2.71
Gauze B	0.12	0.06	0.10	0.10
Gauze C	0.06	0.04	0.03	0.01
Gauze D	0.07	0.03	0.02	0.01
Cage Wash I	0.10	0.11	0.23	0.21
Cage Wash II	0.32	0.27	0.53	0.40
Paper	0.31	1.51	3.12	0.60
Recovery	84.90#	88.27#	83.98#	86.42#
Total absorbed	25.61	19.25	30.80	27.08

# data not taken into account, outside the acceptable recovery range

 

Table XII. Mid Dose (1.3 mg/Rat): Animal data

96 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.02	0.01	0.01	0.02
Carcass	2.20	1.34	1.14	1.35
Skin I	2.01	2.74	2.77	3.34
Skin II	4.31	2.47	2.97	1.47
Urine 24	7.66	6.71	5.64	5.51
Urine 48	6.56	7.39	5.83	5.72
Urine 72	3.35	2.06	2.34	2.88
Urine 96	1.21	1.16	1.08	1.41
Faeces 24	3.13	4.37	1.12	2.00
Faeces 48	5.52	6.76	7.29	4.43
Faeces 72	2.45	2.65	1.48	2.57
Faeces 96	1.07	1.56	0.90	1.31
Bandage Rinse	0.44	1.27	0.78	0.60
Bridge Rinse	1.44	0.19	0.27	2.10
Soap Rinse I	46.89	42.95	48.90	50.06
Water Rinse I	4.87	4.02	5.18	4.18
Soap Rinse II	0.42	0.20	0.85	1.00
Water Rinse II	0.23	0.16	0.44	0.64
Paper Rinse	1.05	1.06	2.61	1.06
Gauze A	2.25	3.88	3.00	1.12
Gauze B	0.15	0.20	0.12	0.05
Gauze C	0.01	0.02	0.05	0.05
Gauze D	0.01	0.01	0.03	0.02
Cage Wash I	0.20	0.61	0.27	0.14
Cage Wash II	0.52	0.63	1.05	1.15              1.15
Paper	0.05	0.05	0.10	0.04
Total Percent Recovered	98.02	94.47	96.22	94.22
Recovery	98.02	94.47	96.22	93.07
Total absorbed	40.21	40.46	33.89	32.15
			Average	36.68
			SD	4.28
			k-factor	1.60
			Absorp%	43.53

 

Table XIII. High Dose (8.6 mg/Rat): Summary of absorption

2 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.03	0.30	0.03	0.02
Carcass	1.51	1.13	1.43	1.21
Skin I	24.47	22.13	23.70	33.82
Skin II	2.51	3.05	2.85	2.17
Urine	0.10	0.00	0.00	0.03
Faeces	0.00	0.00	0.00	0.00
Bandage rinse	0.80	0.26	0.15	0.12
Bridge rinse	0.89	2.32	1.66	2.66
Soap rinse	69.27	57.94	58.93	51.09
Water rinse	5.97	4.92	6.80	5.82
Gauze A	1.08	1.99	3.40	4.83
Gauze B	0.09	1.08	0.14	0.10
Paper	0.03	0.08	0.10	0.03
Paper rinse	1.45	5.65	0.73	0.97
Cage wash	0.05	1.00	0.07	0.12
Recovery	108.25	101.85	99.99	102.99
Total absorbed	28.67	27.61	28.08	37.37
			Average	30.4
			SD	4.6
			k-factor	1.6
			Absorp%	37.9

 

 

Table XIV. High Dose (8.6 mg/Rat): Summary of absorption

4 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.03	0.06	0.05	0.04
Carcass	1.32	1.29	0.06	1.43
Skin I	5.13	5.08	4.89	9.92
Skin II	24.39	21.99	27.71	5.07
Urine	0.29	0.14	0.16	0.16
Faeces	0.01	0.00	0.00	0.00
Bandage rinse	0.48	0.91	0.72	3.01
Bridge rinse	0.10	0.13	0.38	1.00
Soap rinse	56.97	53.50	48.52	33.96
Water rinse	5.27	5.54	4.82	5.37
Gauze A	3.92	2.72	3.39	2.44
Gauze B	0.18	0.12	0.08	0.44
Paper	0.04	0.06	0.08	0.07
Paper rinse	1.77	1.45	2.93	0.40
Cage wash	0.08	0.06	0.07	0.36
Recovery	99.98	93.05	93.86	63.67#
Total absorbed	31.25	28.62	32.94	16.98
			Average	30.9
			SD	2.2
			k-factor	1.6
			Absorp%	34.4

# data not taken into account, outside the acceptable recovery range

 

Table X. High Dose (9.2 mg/Rat): Summary of absorption

10 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.02	0.08	0.08	0.08
Carcass	2.75	3.76	3.73	4.74
Skin I	28.42	16.85	21.09	21.01
Skin II	3.24	2.39	2.38	2.56
Urine	0.60	0.91	1.19	1.15
Faeces	0.01	0.05	0.03	0.00
Bandage rinse	3.22	0.13	0.17	0.59
Bridge rinse	0.88	4.96	6.12	3.20
Soap rinse	26.89	32.84	37.88	29.05
Water rinse	3.59	4.00	3.34	5.29
Gauze A	2.41	1.96	2.38	3.08
Gauze B	0.10	0.16	0.08	0.15
Paper	9.51	7.91	0.14	0.34
Paper rinse	5.83	6.48	8.93	17.22
Cage wash	0.07	0.07	0.12	0.11
Recovery	87.54#	82.55#	87.66#	88.57#
Total absorbed	35.11	24.11	28.62	29.65

# data not taken into account, outside the acceptable recovery range

 

 

Table XVI. High Dose (8.7 mg/Rat): Summary of absorption

24 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.03	0.03	0.03	0.02
Carcass	1.51	1.13	1.43	1.21
Skin I	24.47	22.13	23.70	33.82
Skin II	2.51	3.05	2.85	2.17
Urine	0.10	0.00	0.00	0.03
Faeces	0.00	0.00	0.00	0.00
Bandage rinse	0.80	0.26	0.15	0.12
Bridge rinse	0.89	2.32	1.66	2.66
Soap rinse	69.27	57.94	58.93	51.09
Water rinse	5.97	4.92	6.80	5.82
Gauze A	1.08	1.99	3.40	4.83
Gauze B	0.09	1.08	0.14	0.10
Paper	0.03	0.08	0.01	0.03
Paper rinse	1.45	5.65	0.73	0.97
Cage wash	0.05	0.00	0.07	0.12
Recovery	108.25	100.58	99.90	102.99
Total absorbed	28.67	26.34	28.08	37.37
			Average	30.12
			SD	4.94
			k-factor	1.60
			Absorp%	38.0

 

 

Table XVII. High Dose (8.9 mg/Rat): Animal data

82 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.02	0.03	0.03	0.03
Carcass	1.26	2.02	2.01	2.04
Skin I	0.70	2.96	2.32	2.54
Skin II	4.06	4.44	3.39	3.77
Urine 10	1.19	0.74	0.81	0.62
Urine 34	9.53	6.14	8.97	7.26
Urine 58	4.28	6.69	7.89	6.58
Urine 82	1.74	3.54	2.74	2.57
Faeces 10	0.04	0.01	0.00	0.00
Faeces 34	5.77	3.13	2.83	2.65
Faeces 58	3.33	5.11	6.46	5.83
Faeces 82	1.40	3.24	3.14	2.12
Bandage Rinse	0.47	0.54	0.31	0.17
Bridge Rinse	2.20	0.34	0.28	0.68
Soap Rinse I	40.79	41.54	41.65	41.15
Water Rinse I	7.05	4.72	3.78	4.05
Soap Rinse II	0.28	1.46	1.52	0.70
Water Rinse II	0.22	0.52	0.61	0.45
Paper Rinse	7.07	5.61	3.52	6.66
Gauze A	2.11	2.08	1.96	3.44
Gauze B	0.12	0.12	0.12	0.09
Gauze C	0.01	0.02	0.04	0.02
Gauze D	0.02	0.02	0.01	0.01
Cage Wash I	0.13	0.09	0.06	0.18
Cage Wash II	0.88	0.89	0.89	1.02
Paper	0.21	0.16	0.21	0.12
Recovery	94.88	96.16	95.55	94.75
Total absorbed	34.33	39.03	41.54	37.21
			Average	38.03
			SD	3.04
			k-factor	1.60
			Absorp%	42.9

 

 

Table XVIII. High Dose (9.6 mg/Rat): Animal data

96 hour dosing	Percentage of Dose
ANIMAL:	#1	#2	#3	#4
Blood	0.02	0.02	0.02	0.02
Carcass	1.70	1.62	1.97	1.35
Skin I	8.53	14.31	5.25	5.76
Skin II	1.29	7.49	4.26	3.35
Urine 24	2.75	16.43	5.04	3.77
Urine 48	5.53	6.72	7.60	6.56
Urine 72	3.77	3.10	4.83	4.45
Urine 96	1.45	1.19	1.55	1.96
Faeces 24	0.91	1.52	0.87	1.10
Faeces 48	3.54	3.91	4.04	3.45
Faeces 72	2.76	2.52	3.45	3.58
Faeces 96	1.24	0.77	0.98	1.19
Bandage Rinse	0.56	0.62	0.12	1.15
Bridge Rinse	3 .31	3.36	4.38	2.36
Soap Rinse I	14.85	10.58	19.04	11.70
Water Rinse I	10.67	2.98	2.59	2.90
Soap Rinse II	0.39	0.49	0.30	0.59
Water Rinse II	0.25	0.55	0.16	0.43
Paper Rinse	24.16	18.32	0.56	0.42
Gauze A	6.41	1.52	3.49	3.36
Gauze B	0.07	0.08	0.78	0.21
Gauze C	0.01	0.03	0.04	0.02
Gauze D	0.01	0.05	0.01	0.03
Cage Wash I	0.21	0.28	0.15	0.16
Cage Wash II	0.44	0.35	0.23	0.47
Paper	3.47	3.83	15.42	14.96
Recovery	94.99	102.64	87.13#	75.30#
Total absorbed	34.14	60.23	40.24	37.17
			Average	47.19
			SD	18.45
			k-factor	1.60
			Absorp%	76.7

# data not taken into account, outside the acceptable recovery range

 

 

 

 

 

Applicant's summary and conclusion

Conclusions:

The rate of absorption of 14C-test substance is inversely related to the dosage level for 0.01, 0.1 and 1.0mg/sq.cm dose. After a 10-hour period, the total amount absorbed (blood + carcass + skin + urine + faeces + cage wash) was 71.0 % and 42.0 % for the low and mid dose levels respectively, while the high dose level at this time point did not show acceptable recovery levels for further assessment. Within each dose level, the dermal absorption results varied enormously between the individual animals. At the low dose level, the dermal absorption ranged from 25.17 to 64.61 %, with an average and standard deviation of respectively 52.86 % and 9.96. At the mid dose level, the dermal absorption ranged from 24.97 to 44.28 %, with an average and standard deviation of respectively 33.64 % and 6.30. And at the high dose level, the dermal absorption ranged from 26.34 to 60.23 %, with an average and standard deviation of respectively 34.20 % and 8.16. The dermal absorption calculations were in line with EFSA guidance.

Executive summary:

A dermal absorption study was conducted utilising a simulated 3.6EC formulation of 14C-test substance on male rats over a 2, 4 and 10-hour test period at three dosage levels (0.1, 1.0 and 10.0 mg/rat). The test area was 10 sq. cm (2.5 cm by 4.0 cm) located on the upper back portion of the rat. Resulting doses were based on areas of 0.01, 0.10, 1.0 mg/sq. cm for the low, mid and high dosage levels. This study was conducted according to the Biochemistry Protocol 68-861 and did not follow GLP criteria.
The range of total 14C recovery mean values for the three dosage levels and sacrifice times was from 63.67 % to 119.92 %. As per the EFSA guidance on dermal absorption (2017) only the recoveries between 90 and 110% were used for further assessment.
The rate of absorption of 14C-test substance is inversely related to the dosage level (as the dosage level increases, the total percent absorbed decreases). After a 10-hour period, the total amount absorbed was 71.0 % and 42.0 % for the low and mid dose levels respectively, while the high dose level at this time point did not show acceptable recovery levels for further assessment. Within each dose level, the dermal absorption results varied enormously between the individual animals. At the low dose level, the dermal absorption ranged from 25.17 to 64.61 %, with an average and standard deviation of respectively 52.86 % and 9.96. At the mid dose level, the dermal absorption ranged from 24.97 to 44.28 %, with an average and standard deviation of respectively 33.64 % and 6.30. And at the high dose level, the dermal absorption ranged from 26.34 to 60.23 %, with an average and standard deviation of respectively 34.20 % and 8.16.
For all dose levels less than 20 % of the dose was excreted in a 10-hour period. The main route of excretion was in the urine.
The dermal absorption calculations were in line with EFSA guidance.