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

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of four male and four female rabbits were dosed via stomach tube once daily, five days a week for three weeks. Animals dying, moribund or surviving to the end of the three week period were subjected to a detailed gross post mortem and histopathological examination.

GLP compliance:

no

Remarks:

Study predates GLP

Limit test:

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

Details on test material:

- Name of test material (as cited in study report): RM17
- Substance type: No data
- Physical state: White waxy solid at room temperature, somewhat resembling candle wax
- Analytical purity: 89.2%
- Impurities (identity and concentrations):
Light ends 0.2%
RC 78H 0.2%
1-eicosene <0.1%
RC 716 <0.1%
RC 716 oxide 0.1%
Unknown (3) 2.7%
Unknown (6) 2.8%
RM 17 oxide 4.7%
- Composition of test material, percentage of components: No data
- Isomers composition: No data
- Purity test date: 89.2%
- Lot/batch No.: Unable to define samples in terms of batch number
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Other: The sample actually used to dose the animals was not analysed at the time of dosing. Subsequent analysis of the test material stored in an unsealed drum, however, showed that approximately 40% of the tertiary phosphines had been converted to oxides during several months storage. It is therefore likely that a significant amount of the test material used in the study may have been converted to the oxide during heating of the sample in preparation for dosing.

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ranch Rabbits, Crawley, Sussex
- Weight at study initiation: 2.5 -3.8 kg
- Fasting period before study: No
- Housing: Animals were individually housed
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Duration of treatment / exposure:

Three weeks

Frequency of treatment:

Once daily, five days a week

Doses / concentrations

Remarks:

Doses / Concentrations:
1 or 2 g/kg
Basis:

No. of animals per sex per dose:

4

Control animals:

yes, concurrent no treatment

Examinations

Sacrifice and pathology:

Animals dying, moribund or surviving to the end of the three week period were subjected to a detailed gross post mortem and histopathological examination.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

See table 1

Details on results:

CLINICAL SIGNS AND MORTALITY
Several of the animals died during the second week of dosing following a period of prostration and respiratory distress; death would seem to be due to respiratory depression, either central or peripheral in origin.


GROSS PATHOLOGY
Approximately 20 to 30% of the fibres in both the sciatic and posterior tibial nerves of some rabbits showed degenerative changes, which in general reflected the severity of the clinical signs. There was no peripheral distribution of the lesions, the total fibre length of both nerves showed the changes. Both myelin and axonal damage was indicated by the observation that degeneration was seen with both the special stains employed, and the observation in rabbits dying after five to nine doses that the lesion was most sever in the Glees and Marsland stained material indicated that the axonal damage may have preceeded the myelin damage.

In the spinal cord foci of vascular cuffing by round cells and loss of anterior horn cells with collections of round cells in the grey matter were present in some rabbits. Occasional areas of mucoid degeneration in the anterior horn were also seen.

No lesions were observed in the brain, but some of the sections of spinal cord showed ganglion cell degeneration and fibre degeneration in the nerve roots.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1

Dose level	Rabbit number	Number of doses	Clinical signs	Pathological lesions
				Sciatic	Post-tibial nerve	Spinal cord	Dorsal root ganglia
Females     Controls	1 2 3 4	15 15 15 10	0 0 0 0	0 0 0 -	0 0 0 -	0 0 0 -	- Normal - -
1 g/kg/day	1* 2 3 4	10 14 9 14	0 ++ ++ ++	++ +++ ++++ ++++	+ ++ ++ +++	0 + + +	- Degeneration Degeneration -
2 g/kg/day	1 2 3  4*	9 5 13 7	++ 0 ++ 0	++++ + ++++ -	++ + ++ -	+++ + + -	- - Degeneration -
Males   Controls	1 2 3 4	15 15 15 15	0 0 0 0	0 + 0 0	+ 0 0 0	0 0 0 0	- - - -
1 g/kg/day	1* 2 3 4	15 15 15 15	0 0 0 0	++ + + 0	++ 0 0 0	+ - - -	Degeneration - - -
2 g/kg/day	1 2  3*  4*	9 9 6 6	+++ + 0 +	++ ++ ++ ++++	++ ++ + ++	+ 0 0 0	Degeneration - - -

* Death due to misdose

- Not examined

Applicant's summary and conclusion

Conclusions:

Groups of four male and four female rabbits were dosed via stomach tube once daily, five days a week for three weeks. Animals dying, moribund or surviving to the end of the three week period were subjected to a detailed gross post mortem and histopathological examination.

Several of the animals died during the second week of dosing following a period of prostration and respiratory distress; death would seem to be due to respiratory depression, either central or peripheral in origin.

Approximately 20 to 30% of the fibres in both the sciatic and posterior tibial nerves of some rabbits showed degenerative changes, which in general reflected the severity of the clinical signs. There was no peripheral distribution of the lesions, the total fibre length of both nerves showed the changes. Both myelin and axonal damage was indicated by the observation that degeneration was seen with both the special stains employed, and the observation in rabbits dying after five to nine doses that the lesion was most sever in the Glees and Marsland stained material indicated that the axonal damage may have preceeded the myelin damage.

In the spinal cord foci of vascular cuffing by round cells and loss of anterior horn cells with collections of round cells in the grey matter were present in some rabbits. Occasional areas of mucoid degeneration in the anterior horn were also seen.

No lesions were observed in the brain, but some of the sections of spinal cord showed ganglion cell degeneration and fibre degeneration in the nerve roots.