Registration Dossier

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 March 1994 - April 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was not conducted according to an OECD guideline, but performed under GLP conditions. The design seems proper and results are described extensively in the report.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Preliminary dermal absorption study was performed in 5 rats that were exposed dermally to a 14C-RDP formulation in PEG 400 or a neat 14C-RDP solution for <15 minutes or 6 hours. Urine and faeces were collected and were analysed for radioactivity as well as the excised skin test site and the residual carcass. A post-dose period of 24 hours was chosen for two of the rats.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
EC Number:
701-337-2
Cas Number:
not available
Molecular formula:
C30H24O8P2
IUPAC Name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
Details on test material:
- Name of test material (as cited in study report):
1. 14C-resorcinol bis-(diphenyl phosphate)
2. Fyrolflex RDP (resorcinol bis-(diphenyl phosphate))
- Physical state:
1. Solid
2. Liquid
- Analytical purity: No data
- Impurities (identity and concentrations): Confidential information
- Composition of test material, percentage of components: Confidential information
- Lot/batch No.: Confidential information
- Expiration date of the lot/batch: No data
- Storage condition of test material:
1. In the dark at approx. -20 degrees Celsius
2. In the dark at room temperature
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (Portage, MI)
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: 220-246 g
- Housing: Standard
- Individual (metabolism) cages: yes
- Diet (e.g. ad libitum): Ad libitum, rodent chow
- Water (e.g. ad libitum): Ad libitum, public water supply
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.8-24.4
- Humidity (%): 24-37
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
polyethylene glycol
Duration of exposure:
Animal #1 and #4: <15 min
Animal #2, #3 and #5: 6 hrs
Doses:
- Nominal doses: 100 mg/kg bw (50uCi/animal)
- Actual doses:
Animal #1: 97.74 mg/kg bw
Animal #2: 81.14 mg/kg bw
Animal #3: 86.41 mg/kg bw
Animal #4: 110.4 mg/kg bw
Animal #5: 108.4 mg/kg bw
- Actual doses calculated as follows: Amount RDP administered determined gravimetrically
- Dose volume:
Animal #1-3 (14C-RDP formulation): <200 uL
Animal #4-5 (neat 14C-RDP): approx. 20 uL
No. of animals per group:
1
Control animals:
no
Details on study design:
DOSE PREPARATION
14C-RDP formulation (in PEG 400, administered to animal #1-3)
- Method for preparation of dose suspensions: 14C-RDP and nonradiolabeled RDP were mixed in PEG 400 to a final concentration of 121.1 mg/g or 112 mg/mL

Neat 14C-RDP (administered to animal #4 and #5)
- Method for preparation of dose suspensions: 14C-RDP was dissolved in ethanol and the appropriate amount was weighed. Ethanol was removed and the 14C-RDP was mixed with non-radiolabeled RDP to a final concentration of 872.8 mg/g.

APPLICATION OF DOSE:
Dermally administered using a pipette to achieve targetdose level of 100 mg/kg bw. Solution was spread evenly on test site.

TEST SITE
- Preparation of test site: clipping without abrading skin (24 hours prior to dosing, under anesthesis). Skin wiped clean with acetone (O-rings used to mark test site)
- Area of exposure: dorso-thoracic region
- Coverage: approx. 4.9 cm2
- Type of cover / wrap if used: a piece of fine nylon mesh on the O-rings

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (covering of test site)

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: Nylon mesh stored in ethanol
- Washing procedures and type of cleansing agent: two imes wash with cotton balls dipped in neat soap solution and then rinsed three times using contton balls moistened with lukewarm municipal water. Finally, area was wiped dry using an additional cotton ball. All cotton balls stored in ethanol.
- Time after start of exposure:
Animal #1 and #4: 10 min post-dose
Animal #2, #3 and #5: 6 hours post-dose

SAMPLE COLLECTION
Animal #1 and #4:
- Terminal procedure: CO2 asphyxiation (after washing)
- Analysis of organs: Levels of radioactivity determined in excised dose site (skin) and residual carcass

Animal #2:
- Collection of urine and faeces: Over the period of exposure (6 hours)
- Terminal procedure: CO2 asphyxiation (after washing)
- Analysis of organs: Levels of radioactivity determined in excised dose site (skin) and residual carcass

Animals #3 and #5:
- Collection of urine and faeces: Over the period of exposure (6 hours) and then at 8, 12, 18 and 30 hrs post-dose
- Terminal procedure: CO2 asphyxiation (after post-dose period)
- Analysis of organs: Levels of radioactivity determined in excised dose site (skin) and residual carcass

SAMPLE PREPARATION
- Storage procedure: Urine, faeces, excised dose site and residual carcass were stored at approx. -20 degrees Celsius. Cage washes and extractions of the dose site washes and protective were stored in the refrigerator at 2-8 degrees Celsius.
- Preparation details:
Total weights of urine, feces, and cage washes recorded on collection
Feces homogenized in ethanol:water
Cotton balls extracted in absolute ethanol
Protective coverings extracted in ethanol
Excised dose site solubilized in Soluene 350
Residual carcass solubilized in 4% methanolic potassium hydroxide

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting
- Liquid scintillation counting results (cpm) converted to dpm as follows: by use of an Automatic External Standard (AES) vs. efficiency curve
- Validation of analytical procedure: by external standard
- Limits of detection: mean background values for oxidized or direct samples as appropriate
Details on in vitro test system (if applicable):
Not relevant

Results and discussion

Signs and symptoms of toxicity:
no effects
Dermal irritation:
no effects
Absorption in different matrices:
14C-RDP in PEG 400
Animal #1 (termination: <30 min. post-dose)
- Non-occlusive cover: 4.64%
- Skin wash: 85.69%
- Skin test site: 10.89%
- Carcass: 0.14%

Animal #2 (termination: 6 hrs. post-dose)
- Non-occlusive cover: 10.42%
- Skin wash: 45.47%
- Skin test site: 21.21%
- Carcass: 16.85%
- Urine: 0.03%
- Faeces: 0%
- Cage wash: 0.10%

Animal #3 (termination: 30 hrs. post-dose)
After 6 hours:
- Non-occlusive cover: 6.99%
- Skin wash: 63.77%
After 30 hours:
- Skin test site: 14.13%
- Carcass: 3%
- Urine: 0.43%
- Faeces: 0.35%
- Cage wash: 0.80%

Neat 14C-RDP
Animal #4 (termination: <30 min. post-dose)
- Non-occlusive cover: 1.61%
- Skin wash: 88.46%
- Skin test site: 4.26%
- Carcass: 0.11%

Animal #5 (termination: 30 hrs. post-dose)
After 6 hours:
- Non-occlusive cover: 4.44%
- Skin wash: 45.74%
After 30 hours:
- Skin test site: 25.06%
- Carcass: 8.72%
- Urine: 1.47%
- Faeces: 4.42%
- Cage wash: 1.73%
Total recovery:
14C-RDP in PEG 400
- Total recovery:
Animal #1: 101.36%
Animal #2: 94.08%
Animal #3: 89.47%
- Recovery of applied dose acceptable: Yes (requirement: 100 +/- 10%)
- Quantification of values below LOD or LOQ: No

Neat 14C-RDP
- Total recovery:
Animal #4: 94.44%
Animal #5: 91.58%
- Recovery of applied dose acceptable: Yes (requirement: 100 +/- 10%)
- Quantification of values below LOD or LOQ: No
Percutaneous absorptionopen allclose all
Dose:
97.74 mg/kg bw
Parameter:
percentage
Absorption:
0.1 %
Remarks on result:
other: 15 min
Remarks:
Animal #1: 14C-RDP in PEG 400
Dose:
81.14 mg/kg bw
Parameter:
percentage
Absorption:
17 %
Remarks on result:
other: 6 hrs
Remarks:
Animal #2: 14C-RDP in PEG 400
Dose:
86.41 mg/kg bw
Parameter:
percentage
Absorption:
4.6 %
Remarks on result:
other: 30 hrs
Remarks:
Animal #3: 14C-RDP in PEG 400
Dose:
110.4 mg/kg bw
Parameter:
percentage
Absorption:
0.1 %
Remarks on result:
other: 15 min
Remarks:
Animal #4: Neat 14C-RDP
Dose:
108.4 mg/kg bw
Parameter:
percentage
Absorption:
16.3 %
Remarks on result:
other: 30 hrs
Remarks:
Animal #5: Neat 14C-RDP
Conversion factor human vs. animal skin:
Not relevant

Any other information on results incl. tables

Not relevant

Applicant's summary and conclusion

Conclusions:
Relative dermal absorption of RDP into the systemic circulation is similar, whether administered as neat material or as a formulation in PEG 400. Within 6 hours, a maximum of 17% of the dermally applied dose is absorbed in the systemic circulation. After 30 hours, excretion by urine and faeces is apparent, but the largest amount of substance is still present in the body.
Executive summary:

Preliminary dermal absorption study was performed in 5 rats that were exposed dermally to a 14C-RDP formulation in PEG 400 or a neat 14C-RDP solution for <15 minutes or 6 hours. Urine and faeces were collected and were analysed for radioactivity as well as the excised skin test site and the residual carcass. A post-dose period of 24 hours was chosen for two of the rats.

Total recovery was within 100 +/- 10% of the applied dose for all animals. Relative dermal absorption of RDP into the systemic circulation is similar, whether administered as neat material or as a formulation in PEG 400. Within 6 hours, approximately 17% of the dermally applied dose is absorbed in the systemic circulation. After 30 hours excretion by urine and faeces is apparent, but the largest amount of the dose is still present in the body.