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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
publication
Title:
Age-Related Percutaneous Penetration of 2-sec-Butyl-4,6-dinitrophenol (Dinoseb) in Rats
Author:
Hall, L.L. et al.
Year:
1992
Bibliographic source:
FUNDAMENTAL AND APPLIED TOXICOLOGY 19, 258-267

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The effect of age and dosage on the percutaneous absorption and disposition of dinoseb was investigated in female rats. The results were compared with the aid of a preliminary physiological compartmental model. In addition, the dermal absorption determined using two in vitro methods was compared to the in vivo results.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
[14C]dinoseb (uniformly ring labelled, specific activity 4.29 mCi/mmol) was purchased from Pathfinder Labs Inc. Radiochemical purity was greater than 98% as determined by HPLC. Unlabelled dinoseb was obtained from the US EPA Repository for Toxic and Hazardous Material.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
female
Details on test animals and environmental conditions:
Guaranteed time-pregnant Fischer 344 rats were purchased from the Charles River Breeding Farm (Kingston, NY). Male pups were culled from the litters because of the dorsal skin thickening that occurs at sexual maturity. The female pups were randomized and replaced with the dams (eight pups/ dam). At weaning, the females were again randomized and divided into two groups, using rank ordered weights. The first group was used for the studies in young animals and the second group was used for the adult studies. Thirty-three-day-old (DO) animals were used for the young group because the restraints used to protect the application site did not retard growth significantly as they did in younger animals and vaginal opening, a hormone-dependent event, starts at approximately 40 days of age. This provided a 7- day period to perform the studies before puberty began. Eighty-two-DO adult female rats were chosen for logistical reasons. The animals were maintained according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Food (Purina Rat Chow, No. 5001, St. Louis, MO) and water were available ad libitum. The animals were maintained on a 12-hr light/dark cycle at constant temperature and humidity. Twenty-four hr prior to in vivo and in vitro experiments, animals were lightly anesthetized with ethyl ether and hair on the backs of the animals was removed with electric clippers using a size 40 blade. The clipped area was then washed with acetone to remove dirt and sebaceous gland secretions.

Administration / exposure

Type of coverage:
other: protected by perforated plastic beaker/bubble
Vehicle:
acetone
Duration of exposure:
The dose-effect animals were terminated at 72 hr and the serially terminated animals at 1, 6, 24, 48, 72, and 120 hr.
Doses:
250(60), 536 (129), and 2680 nmol/cm2 (644 µg/cm2) in the young rat and 210 (52), 536 (129), and 2680 nmol/cm2 (644 µg/cm2). The serial termination studies were performed at 285 nmol/cm2(68 µg/cm2)
No. of animals per group:
3 females per dose and age group
Control animals:
no

Results and discussion

Total recovery:
Mean recoveries ranged from 87.5 to 105.9% in young and 87.9 to 102% in adult rats.

Any other information on results incl. tables

Mean recoveries ranged from 87.5 to 105.9% in young and 87.9 to 102% in adult rats. Dermal absorption of dinoseb appeared to be biphasic. After 6 hrs, the skin penetration was about 44% in both young and adults, while after 120 hr 75.9% was absorbed in young and 92.5% in adults. The maximum body burden of dinoseb-derived radioactivity observed in young was 41% and occurred at 6 hr, but by 120 hr the body burden had dropped to 5.8%. In adults a maximum observed body burden of 52% occurred at 24 hr and subsequently the body burden declined to 6.8% at 120 hr

 

Time (hr)

Dose level

 

Dose level

 

%Absorbed

 

%Absorbed

 

 

 

 

Young

Adults

1

285 nmol/cm2

68µg/cm2

11.8 ± 2.2

21.1 ± 6.6

6

285 nmol/cm2

68µg/cm2

43.0 ± 6.0

44.2 ± 10.1

24

285 nmol/cm2

68µg/cm2

67.6 ± 3.4

86.6 ± 0.8

48

285 nmol/cm2

68µg/cm2

61.1 ± 10.5

88.1 ± 0.4

72

285 nmol/cm2

68µg/cm2

55.6 ± 1.5

82.7 ± 1.4

120

285 nmol/cm2

68µg/cm2

75.9 ± 1.7

92.5 ± 0.8

 

 

Dose (nmol/cm2)

 

Dose (µg/cm2)

 

Time (hr)

%Absorbed

Young

 

 

 

250

60

72

77.7 ± 5.9

535

129

72

81.5 ± 2.8

2680

2680

72

82.9 ± 1.0

Adult

 

 

 

210

52

72

86.4± 1.14

535

129

72

90.5 ± 1.11

2680

2680

72

93.2 ± 0.6

 

The primary route of excretion of dinoseb-derived radioactivity was urinary. By 120 hrs the young excreted about 4.6 and the adult 4.3 times as much in urine as in faeces. Urinary excretion was 57.7 and 69.5% of the recovered dose in young and adults, respectively.

HPLC analysis of 24-h urine samples collected from adults treated with dinoseb showed extensive metabolism. The metabolite profile of radioactivity excreted in urine was similar for the i.v. and dermal treated animals. Detection of parent in the urine samples from the i.v.- and dermal-treated animals was minimal.

Applicant's summary and conclusion

Conclusions:
In vivo dermal absorption in both young and adults appeared biphasic with 55.6 and 82.7% of the recovered dose, respectively, penetrating in 72 hr. The primary route of excretion was urinary and by 120 hrs accounted to 57.7 and 69.5%, respectively, in young and adult rats. HPLC analysis of 24-h urine samples showed extensive metabolism, with a similar metabolite profile for the i.v. and dermal treated animals. In vitro measurements of skin absorption at 72 hr with static cells showed higher values in young and lower values in the adult compared to in vivo dermal absorption values. In vitro flow-through measurements at 72 hr gave lower dermal absorption values for both young and adult rats, compared to in vivo values.


Executive summary:

In a series of studies, the effects of age, dosage, and method of determination on skin absorption, distribution, retention and excretion of dinoseb were examined in female rats.

[14C]dinoseb was applied to previously clipped back skin of 33- and 82-day-old female Fischer 344 rats at a dosage range of 210-2680 nmol/cm2. Radioactivity in the treated skin, tissues, urine, and faeces was determined at 1, 6, 24, 48, 72, and 120 hr following dermal application. In vitro dermal absorption of [14C]dinoseb was also measured in rats of the same age by static and flow-through methods. The metabolic profile in 24-h sample of urine was determined following dermal application and i.v. administration of an equivalent dose.

Dermal absorption was shown to be dependent on age, with skin of adults being more permeable to dinoseb than that of young, and independent of dose. In vivo dermal absorption in both young and adults appeared biphasic with 55.6 and 82.7% of the recovered dose, respectively, penetrating in 72 hr.

The primary route of excretion was urinary, with 57.7 and 69.5% of dose recovered in urine by 120 hrs. HPLC analysis of 24-h urine samples showed extensive metabolism, with similar metabolite profile for i.v. and dermal-treated animals. Detection of parent in the urine samples from the i.v. and dermal-treated animals was minimal.

In vitro measurements of skin absorption at 72 hr with static cells showed higher values in young and lower values in the adult compared to in vivo dermal absorption values. In vitro flow-through measurements at 72 hr gave lower dermal absorption values for both young and adult rats, compared to in vivo values.