Triphenylphosphine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable test method based on scientific principles with detailed documentation, only 2 animals per dose group

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Principles of method if other than guideline:

This study was conducted to assess the inhalation toxicity of the test substance when administered as a respirable aerosol in a xylene vehicle to male and female beagle dogs. Four atmospheric concentration levels and two different durations of treatment were used in the study; the specific test regimes were as follows: two dogs (1 male, 1 female) per group received twenty 6-hour exposures over four weeks at exposure levels of 0.5, 3.2. 9.7 and 28 milligrams test substance per meter cubed (mg/m3); two 6-hour exposures were administered to two dogs (1 male, l female) per group at concentrations of 0.3, 3.6 and 24 mg/m3 test substance. These shorter duration treatments were followed by a four week recovery period. A concurrent vehicle control group (1 male, 1 female dog) received twenty 6-hour exposures to150 parts per million (v/v in air) of xylene, a level of solvent which was comparable to that in each test exposure chamber. Chambers were monitored analytically for test substance levels at least 3 times/chamber/day. Particle size distribution were determined periodically throughout the study. Body weight measurements, physical observations and neurological examinations were performed pre-test and weekly throughout the study. Complete gross postmortem examinations were performed and selected sections of nervous system tissue were preserved from all test animals for histopathological evaluation.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triphenylphosphine

EC Number:

210-036-0

EC Name:

Triphenylphosphine

Cas Number:

603-35-0

Molecular formula:

C18H15P

IUPAC Name:

triphenylphosphine

Test material form:

solid

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

body weight 9.6-13.2 kg in males and 8.2-10.4 kg in females

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Details on inhalation exposure:

- Analytical concentrations of 0, 0.5, 3.2, 9.7, 28 mg/m3 (as aerosol in xylene, aerosol particles 0.5 um) or for only 2 times to 0.5, 3.2 or 28 mg/m3 (post exposure observation period 30 days).
- Whole-body exposure using chambers of 10 m3 which received an aerosol produced from the test substance dissolved in xylene (complete air change in the chamber every 3.3 minutes).
- The concentration of xylene was 150 ppm or less in all chambers (solvent not specified, isomer mixture??).
- Chambers were monitored analytically for test substance levels 3x/d per chamber and particle-size distribution periodically.
- The count medium diameter of the aerosol particles was found to be 0.5 um or less, i.e. respirable.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

5 weeks

Frequency of treatment:

3 - 5 days/week, 6 hours/day (20 exposures)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.5 mg/m³ air (nominal)

Remarks:

as aerosol in xylene

Doses / concentrations 2

Dose / conc.:

3.2 mg/m³ air (nominal)

Remarks:

as aerosol in xylene

Doses / concentrations 3

Dose / conc.:

9.7 mg/m³ air (nominal)

Remarks:

as aerosol in xylene

Doses / concentrations 4

Dose / conc.:

28 mg/m³ air (nominal)

Remarks:

as aerosol in xylene

No. of animals per sex per dose:

1

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Body weight determined once weekly. Animal observation twice daily, full physical and neurological assessment once weekly.

Sacrifice and pathology:

Dogs were sacrificed and necropsy performed. Histopathologic examination was focussed on the spinal cord and sciatic nerve.

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 28 mg/m3 (20 exposures), both dogs showed indications of neurological impairment: failure in the extensor postural thrust reflex with tendency to knuckle over, unsteadiness and weakness in the hind limbs. (This effect was already noted in one male dog having received only two exposures.) The locomotor reflex in the male dog appeared also unsteady and uncoordinated (ataxia).
At 10 mg/m3 erratic placement of limbs on week 1 and 4 was observed in one male dog.
In one male receiving only 2 exposures of 3 mg/m3 some limb placement incoordination throughout the study was seen.
Only the effects at the highest dose were considered by the authors to be treatment-related (in other dose groups effects not persistent, no severe signs, animals were only exposed twice).

Mortality:

no mortality observed

Description (incidence):

All animals survived.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight development was normal.

Neuropathological findings:

effects observed, treatment-related

Description (incidence and severity):

The sections prepared from the high-dosed dogs revealed moderate generalised vacuolative degeneration of axons in the ventral and lateral funicule of both the cervical and lumbar spinal cord. No such findings in the sciatic nerve. No such lesions were noted in the control animals having received xylene alone.
The above mentioned neuronal lesions were seen in the longitudinal sections, recognised with both H&E and luxol fast blue stains, characterised by multiple dilated or vacuolated axon sheaths with accumulations of scattered eosinophilic debris and occasional dark rounded bits of what appeared to have been nuclear chromatin.
Similar damages in the lower dose groups, but marginal in nature, were not considered to correlate with test substance exposure since in a histopathological reevaluation also historical control animals showed some axonal lesions. Sporadic degeneration is an expected finding in the spinal cord of "normal" animals.

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

10 mg/m³ air

Sex:

male/female

Basis for effect level:

other: no adverse effects at this dose

2

Dose descriptor:

LOAEC

Effect level:

28 mg/m³ air

Sex:

male/female

Basis for effect level:

clinical signs

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

This study was conducted to assess the inhalation toxicity of the test substance when administered as a respirable aerosol in a xylene vehicle to male and female beagle dogs.

 

Four atmospheric concentration levels and two different durations of treatment were used in the study; the specific test regimes were as follows: two dogs (1 male, 1 female) per group received twenty 6-hour exposures over four weeks at exposure levels of 0.5, 3.2. 9.7 and 28 milligrams test substance per meter cubed (mg/m³); two 6-hour exposures were administered to two dogs (1 male, 1 female) per group at concentrations of 0.3, 3.6 and 24 mg/m³ test substance. These shorter duration treatments were followed by a four week recovery period. A concurrent vehicle control group (1 male, 1 female dog) received twenty 6-hour exposures to 150 parts per million (v/v in air) of xylene, a level of solvent which was comparable to that in each test exposure chamber.

Chambers were monitored analytically for test substance levels at least 3 times/chamber/day. Particle size distribution were determined periodically throughout the study. Body weight measurements, physical observations and neurological examinations were performed pre-test and weekly throughout the study. Complete gross postmortem examinations were performed and selected sections of nervous system tissue were preserved from all test animals for histopathological evaluation.

 

All animals survived the duration of the study. Signs of neurological impairment were noted during the study in male dogs receiving 2 exposures at 24 mg/m³ test substance or 20 exposures at 28 mg/m³ test substance and in the female dogs receiving 20 exposures at 28 mg/m³test substance.

Histopathological examinations"(H&E, and luxol fast blue stains) revealed moderate generalized vacuolative degeneration of the ventral and lateral funicle of the cervical and lumbar spinal cord of the dogs which received twenty exposures to 28 mg/m³ test substance. Similar lesions, although minimal and focal in nature were noted in spinal cord sections of dogs receiving 0.5 or 3.2 mg/m³test substance. In the lowest treatment group animals, this lesion was observed in one male following 20 exposures and in·one female following only two exposures. These lesions were not seen in any vehicle control dog. Evaluations of body weight, general physical observations (non-neurological) and gross postmortem results were considered unremarkable.