Registration Dossier

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31.10.1978 to 03.11.1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
To provide preliminary information about the absorption, distribution and excretion of a compound after its administration to animals.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dequest 2060, neutralised to pH 7.0 with sodium hydroxide.
- Substance type: Phosphonic acid
- Physical state: Slightly yellow liquid
- Radiochemical purity (if radiolabelling): 98% (according to a letter dated 19th Sept 1978 from D.B. Hines to G. Hassins)
- Specific activity (if radiolabelling): 8 microCi/mg (according to a letter dated 19th Sept 1978 from D.B. Hines to G. Hassins)
- Locations of the label (if radiolabelling): C
- Expiration date of radiochemical substance (if radiolabelling): None noted
- Stability under test conditions: No data
- Storage condition of test material: No special precautions noted
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: No data
- Weight at study initiation: 175 to 225 g
- Fasting period before study: yes, overnight and four hours after dosing
- Housing: Metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): No data
- Acclimation period: At least four days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: 31.10.1978 to 03.11.1978

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Duration of exposure:
72 hours
Doses:
- Concentration: 6.1 mg/ml
- Dose volume: 0.1 ml, which contained 2.31 microCi.
- Rationale for dose selection: None given
No. of animals per group:
Three male animals in total
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: No data
- Method of storage: No data

APPLICATION OF DOSE: Using Eastman 910 adhesive, a contoured glass ring was glued to the middle of the back of each animal. The ring was 3.6 cm diameter.

TEST SITE
- Preparation of test site: Shaved
- Area of exposure: back
- % coverage: No data
- Time intervals for shavings or clipplings: No data

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes: A porous glass disk was fitted over the skin inside the glass ring. This permited air circulation over the test site, but prevented loss of the test substance by flaking or ingestion.

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: After 72 hours
- Washing procedures and type of cleansing agent: No

For 72 hours after dosing the animals were housed in metabolism cages designed to seperate urine, feces and expired CO2. The rats were fitted with fecal cups. Accumulated urine and feces was collected at 24, 48 and 72 hours after application of the test substance. CO2 was collected from the rats at 8 hour intervals for 72 hours (3 samples/day/rat).

SAMPLE COLLECTION
- Collection of blood: Blood samples taken at terminal sacrifice at 72 hours.
- Collection of urine and faeces: metabolism cages and fecal cups.
- Collection of expired air: metabolism cages
- Terminal procedure: Ether
- Analysis of organs: All organs and tissues removed for analysis.

SAMPLE PREPARATION
- Storage procedure: Samples frozen until analysis.
- Preparation details: Organs and tissues rinsed with water and blotted with paper towel. Fat or connective tissue from the organs removed and placed in sample jars. Organs that have internal cavities (heart, gall and urinary bladders) cut open and rinsed with water. If the urinary bladder contained urine, this urine was rinsed into the urine 48-72 hour collection. Skin samples were taken from the back of the animals. Bone samples were taken from the femur after the bone marrow had been removed. Muscle samples were taken from the hind limb. Adipose tissue samples were taken from the area of the psoas muscle. Carcasses were then frozen with dry ice before grinding in a Wiley mill.

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting
- Liquid scintillation counting results (cpm) converted to dpm as follows: No details
- Validation of analytical procedure: No details
- Limits of detection and quantification: No details

Results and discussion

Signs and symptoms of toxicity:
no effects
Dermal irritation:
no effects
Absorption in different matrices:
- Non-occlusive cover + enclosure rinse: None reported
- Skin wash: None reported
- SKin adjacent to test site: 0.007 ± 0.002 (mean and SD)
- Skin test site: 89 ± 2% (mean and SD)
- Blood: 0.01 ± 0.01µg/g (mean and SD)
- Carcass: 0.5 ± 0.5% (mean and SD)
- Urine: 0.02 to 2% (mean 0.8%)
- Cage wash + cage wipe: 0.1 ±0.1 (mean and SD)
- Faeces: <=0.01%
- Expired air (if applicable): None reported
- Serial non-detects in excreta at termination: No

- Liver: none detected
- Kidneys: 0.01 ± 0.01% (mean SD)
- Gonads: none detected
- Plasma: none detected
- Muscle: 0.01 ±0.01 µg/g
Total recovery:
- Total recovery: 90%
- Recovery of applied dose acceptable: Accepted as low, but reasonable
- Results adjusted for incomplete recovery of the applied dose: Apparently not
- Limit of detection (LOD): No details
- Quantification of values below LOD or LOQ: No details
Percutaneous absorption
Dose:
0.1 ml
Parameter:
percentage
Absorption:
< 1 %
Remarks on result:
other: 72 hours
Conversion factor human vs. animal skin:
None

Any other information on results incl. tables

Table 1 Average excretion (% of dose ± SD)

  0 -24 h  24 -48 h  48 -72 h  Total 
Urine  0.7 ± 0.6   0.02  ± 0.01  0.01 ±0.01  0.8  ± 0.7
Feces   0.003  ± 0.003  None detected  None detected  0.0 ± 0.0

Total recovery: 90 ± 3%

Applicant's summary and conclusion

Conclusions:
In a dermal metabolism study that predated GLP (reliability score 2) less than 1% of a dermally applied dose (0.1 ml) of neutralised DTPMP was absorbed over a 72 hour exposure period. Most (89 %) of the applied dose was recovered from test site. Total recovery was 90%.