Reaction mass of 9-icosyl-9-phosphabicyclo[3.3.1]nonane and 9-icosyl-9-phosphabicyclo[4.2.1]nonane

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: No data

Principles of method if other than guideline:

Molten (50°C) RM-17 was applied to rabbit skin and removed 15 minutes later by scraping with a spatula, or by vigorously swabbing with organic solvents, hot water or hot water plus surfactant. The efficiency of removal was estimated either by visual examination or by analysis of the skin.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 9-icosyl-9-phosphabicyclo[3.3.1]nonane and 9-icosyl-9-phosphabicyclo[4.2.1]nonane

EC Number:

915-206-4

Molecular formula:

C28H55P

IUPAC Name:

Reaction mass of 9-icosyl-9-phosphabicyclo[3.3.1]nonane and 9-icosyl-9-phosphabicyclo[4.2.1]nonane

Test material form:

other: Solid at room temperature, but liquified by heat

Details on test material:

- Name of test material (as cited in study report): RM-17
- Physical state: Solid at room temperature, but is liquified by heat
- Other: RM-17 was from batches received from SCUK Stanlow on 5th May 1978, and the 13th February 1979. Samples were withdrawn from a sealed container, melted at 50°C in a water bath, drawn into disposable syringes and allowed to cool to room temperature. Before use the syringes were re-heated to 50°C in a water bath and the material was applied molten at this temperature.

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Groups of male and female New Zealand white rabbits from the Shell Toxicology Laboratory (Tunstall) Breeding Unit were used. They ranged from 6 to 12 months in age and 3 to 5 kg in weight.

The animals were singly housed in stainless steel cages with sawdust filled trays for excreta. Food was provided by means of a top loading food hopper and water by means of an automatic drinking line and valves. The rabbit food (SG1 with Vitamin C supplement) was replenished daily, and the water (filtered but untreated water from the public supply) was automatically replenished.

Animal preparation:
The dorsal hair was removed from the shoulders to the hind quarters using fine electric clippers the day before experimentation. The skin was carefully examined and any animals showing damage to the stratum corneum was discarded. A 5 cm x 5 cm area of dorsal/flank skin was marked out using a template to ensure that each area was similar in size and position.

Administration / exposure

Type of coverage:

open

Vehicle:

other: The test material was molten

Duration of exposure:

The molten (50°C) RM-17 was gently applied to the standard area of skin over a period of 3 - 4 minutes.

Doses:

Care was taken to ensure that as much RM-17 as possible was retained on the marked area as it solidifed, but there was an inevitable overspill down the flanks and into the fur. Consequently, the standard dose of 4 ml/kg applied in some of the experiments was reduced to a more practical dose of 10 ml/rabbit, thus ensuring that the dose was only just in excess of that needed to cover completely the application site.

It was difficult to estimate the amount applied to the standard area of skin in view of the varying amounts of overspill, but observation would indicate that with a 20% overspill the dose was approximately 300 mg/sq cm of skin, or approximately 800 mg/g of skin.

No. of animals per group:

Decontamination studies:
RM-17 was applied to the skin of groups of 1 male and 1 female conscious rabbits.

Skin penetration studies:
No data.

Results and discussion

Signs and symptoms of toxicity:

yes

Dermal irritation:

yes

Any other information on results incl. tables

RM-17 was applied to the skin of groups of 1 male and 1 female conscious rabbits and the skin decontamination 1 h later using a variety of techniques. The results of the visual assessment of the efficiency of the decontamination procedures are presented in Table 1.

Table 1 – Visual assessment of skin decontamination

Decontamination technique	Temp (°C)	Comments
Scraping with spatula	20	Ineffective despite vigorous scraping
Water	20	Ineffective
	50	Some decontamination
	60	Effective, but some pain
	70
Corn oil	20	Some decontamination
	50
	60	Fairly effective
PEG 400/IMS (2:1 v/v)	20	Ineffective, immediate erythema
	65	Some decontamination, immediate erythema
Liquid soap (undiluted)	20	Ineffective, some erythema
	60	Fairly effective, some erythema
TEEPOL (10% in water)	20	Ineffective, immediate erythema
	60	Fairly effective, immediate erythema
Toluene	20	Effective, but stressful
n-butanol	20	Fairly effective, but caused severe erythema leading to necrosis

 

On the basis of these results hot water, TEEPOL and liquid soap were selected for further study as they met the criteria for effective decontaminating agents of being readily available and innocuous, and appear to remove RM-17 from the surface of the skin. Corn oil was not studied further, despite being effective, since a source of coin oil at 60° would not be readily available in an industrial environment.

Although visual assessment was a good indicator of the removal of RM-17 from the skin, the possibility of the material remaining in the stratum corneum or in the hair follicles was checked using chemical analysis of the skin. Groups of anaesthetised rabbits were dosed with RM-17 and the skin decontaminated 15 min later using water, TEEPOL or liquid soap. The animals were killed 6 h after application and the skin from the site of application analysed for total RM-17 and its oxide (Table 2). Because of the prolonged anaesthesia needed, only one animal was dosed and decontaminated on each experimental day.

Although there are differences between the values for the skin analyses - which could reflect either the vigor of the decontamination process of the delays between sampling and analysis - the results show clearly that all three methods are effective.

Although the decontamination procedures employed in the preceding experiment were effective in removing RM-17 from the skin, there remained the possibility of enhanced penetration through the skin as a result of the decontamination procedure. Some preliminary experiments were therefore undertaken to evaluate this risk by comparing the blood and fat levels of RM-17 following skin application with and without decontamination.

RM-17 was applied to the skin of anaethetised rabbits and left in place for 6 h. Blood samples were taken from the carotid artery after 10 min, 30 min, 1 h, 2 h, 4 h and 6 h. After 6 h the rabbits were killed and samples of the fat taken for analysis. A further group of anaethetised rabbits was dosed with RM-17, but after dosing they were allowed to regain consciousness. Samples of venous blood were taken after 24, 48 and 72 h, and fat samples after death at 72 h. The analysis results, presented in Table 3, show no detectable levels of RM-17 in the blood up to 6 h after application. Residues above the limit of detection (0.10 µg/g) were found in the blood of some rabbits 24 h after dosing, increasing up to 72 h after dosing.

The effects of solvent decontamination on penetration were then assessed by comparing the results of the non-decontaminated skin experiment with the results from similar experiments, but with decontamination after 15 min. The results of the decontamination experiment are presented in Table 4.

Applicant's summary and conclusion

Conclusions:

Hot water, hot soap solution and hot TEEPOL solution removed RM-17 from the skin and did not appear to enhance skin penetration.

Hot water and soap is recommended as an effective decontamination procedure.

Preliminary experiments indicate that RM-17 only slowly penetrated intat rabbit skin.