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Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Percutaneous and Oral Absorption of Chlorinated Paraffins in the Rat
Author:
Yang JJ et al.
Year:
1987
Bibliographic source:
Toxicology and Industrial Health, Vol 3, No. 3, pg 405-412

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
This report describes the results obtained in parallel percutaneous absorption studies of 14C-labelled C l 8 (50-53% chlorine) and C28 chlorinated paraffins (47% chlorine) in male and female Sprague-Dawley rats at a dose (66 mg / cm2 surf ace area) which is equivalent to a dose of 2.0 g/kg of body weight. Additionally, results of an oral absorption study of t he [14C]C18 chlorinated paraffin at a dose of 0.5 g/ kg in rats are presented for comparison. These studies were designed to compare the relative absorption of chlorinated paraffins in the rat by dermal and oral routes of administration and to provide information concerning the effect of carbon chain length on percutaneous absorption.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
[1,-14C]polychlorooctadecane
IUPAC Name:
[1,-14C]polychlorooctadecane
Constituent 2
Reference substance name:
[14,15-14C]polychlorooctacosane
IUPAC Name:
[14,15-14C]polychlorooctacosane
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): [1,-14C]polychlorooctadecane and [14,15-14C]polychlorooctacosane
- Radiochemical purity (if radiolabelling): > 96% by thin-layer chromatography
- Specific activity (if radiolabelling): C l 8 (27.6, 22.8 µCi/ mmol) and C28 chlorinated paraffins (7.2
µCi/ mmol)
- Locations of the label (if radiolabelling): [1,-14C]polychlorooctadecane and [14,15-14C]polychlorooctacosane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Lakeview, N.Y.
- Age at study initiation: 3-6 months old
- Housing: housed in wire mesh cages prior to treatmen t.
- Individual metabolism cages: yes, following treatment, animals were housed in metabolic cages designed for CO2 trapping studies. A Harvey carbon 14 cocktail was used as a trapping medium for the exhaled 14CO.
- Diet (e.g. ad libitum): Lab Chows, Ralston Purina Co., St. Louis, Mo., ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70° F
- Humidity (%): 50% relative humidity
- Air changes (per hr): The metabolism cages were configured to maintain an air flow rate of 1-2 liters/ min.
- Photoperiod (hrs dark / hrs light): 12 hr light-dark cycle

Administration / exposure

Type of coverage:
other: not occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
percutaneous study: 4 days
oral study: single dose
Doses:
percutaneous study: approximately 2.0 g/kg
oral study: 0.5 g/ kg
No. of animals per group:
percutaneous study: five to seven rats per sex
oral study: Three female rats
Control animals:
no
Details on study design:
The C18 or C28 chlorinated paraffin (68 ul) was applied evenly to the skin surface area encircled by a 1.25 cm diameter teflon cell (Crown Glass Co., Somerville, N.J.). The cell was securely attached to the shaved dorsal skin on each rat with adhesives. After dosing, a wire mesh cell cover was attached and the rat was wrapped with Elastoplast tape (Beiersdorf Inc., Norwalk, Conn.) to further secure the cell. An opening was cut out over the mesh cover so that the application site was not occluded. The rats were fitted with cardboard collars during the course of the study to minimize oral ingestion of test material.

Urine and feces from the rats and trapping fluids were collected at 24, 48, 72 and 96 hr. Four days after initial treatment, the rats were anesthetized by exposure to 100% C02 and blood was collected by cardiac puncture. The following were removed and stored for analysis: liver, kidneys, stomach, small intestine, large intestine, urinary bladder, brain, heart, lung. spleen, muscle, bone (femur), gonads, retroperitoneal fat and residual carcass. Percutaneous absorption was determined directly by summing 14C activity found in urine, feces, expired air and tissues.

Sample collection for the oral study was carried out using the same procedures described above for the percutaneous absorption study.

The 14C radioactivity in the trapping fluids was determined without further sample processing by counting in a Beckman LS 9000 liquid scintillation counter (Fullerton, Calif.). The 14C in the urine samples was counted directly after addition of scintillation fluid. Fecal and most tissue samples were homogenized and combusted in a Harvey OX300 biological oxidizer (Hillsdale, N.J.) before being counted. However, samples of urinary bladder, muscle, bone, gonads, fat and blood were combusted without prior homogenization to generate 14CO, which was then trapped in scintillation fluid and counted. The limit or the detection of chlorinated paraffin (and metabolites) in various samples obtained from the study was at or below 0.01% of the applied dose.

The homogenate of feces collected each day from the orally-dosed animals were extracted with n-penta ne ( 150 ml); the extraction efficiency was > 99% for the C18 chlorinated paraffin. The extracts were subjected to silica gel (toluene) and reversed-phase (methanol) thin-layer chromatography on 5 x 20 cm plates. After removal of the plates from the development chamber, a series of 0.5 cm bands were scraped from each plate from the origin to the solvent front ( 10 cm) and the radioactivity present in each band was determined by liquid scintillation counting.

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Percutaneous Absorption. The applied C18 chlorinated paraffin was absorbed over 96 hr in male and female rats to the extent of 0.70% (SD = 0.15%) and 0.61% (SD = 0.19%), respectively. A large percentage of the absorbed radioactivity was exhaled as 14C02 (0.28% of the dose). At study termination, about 0.12% of the absorbed C18 chlorinated paraffin was found in tissues, primarily intestines, liver and fat. Rat skin was observed to be an almost impenetrable barrier to absorption of the C28 chlorinated paraffin with less than 0.1% of the applied topical dose being absorbed over 96 hr.
Oral Absorption. A total of 24.7% of the applied dose was recovered in the first 24 hr excreta followed by more gradual increases to reach an averaged total of 86.2% (SD = 5.6%) by 96 hr. Significantly higher radioactivity was present in the feces (76.4% of the dose) than in expired air (3.3%) and urine (l.9%). Approximately 20% of the 14C found in the feces (approximately 16% of the dose) was extractable with n-pentane and identified as the parent chlorinated pa raffin. Radioactivity in the tissues (96 hr) was found primarily in liver, intestines and fat.

Applicant's summary and conclusion

Conclusions:
The experimental results show that very little of either chlorinated paraffin tested was absorbed dermally over 96 hr. Despite the low permeability of both chlorinated paraffins, the C18 paraffin was absorbed at a significantly higher rate than the C28 paraffin, indicating that increasing chain length (and perhaps increasing viscosity) con tributes to decreased permeability.

Excretion of 14CO, resulting from the metabolism of the C18 chlorinated paraffin, was observed in rats following both topical and oral administration.

Absorption was markedly higher when the rats were treated with C18 chlorinated paraffin orally rather than dermally. The absorbed and partially metabolized chlorinated paraffin was primarily eliminated through the feces, where it was found along with a small portion of the unabsorbed parent material.

In conclusion, the results indicate that rat skin acts as an effective barrier to chlorinated paraffins containing eighteen or more carbons and more than 40% chlorine by weight. The oral absorption of the Cl8 chlorinated paraffin was estimated to be nearly 100 times greater than the dermal absorption.