Registration Dossier

Toxicological information

Acute Toxicity: inhalation

Currently viewing:

Administrative data

acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08/10/1993 - 15/04/1994
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study according to international guideline (OECD guideline 403) under GLP. No deviations from guideline reported.
Reason / purpose for cross-reference:
reference to same study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
OECD Guideline 403 (Acute Inhalation Toxicity)
according to guideline
other: TSCA Health Effect Test Guidelines Part 798.1150
Principles of method if other than guideline:
Not relevant
GLP compliance:
Test type:
standard acute method
Limit test:

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:
Cas Number:
not available
Molecular formula:
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): Fyrolflex RDP
- Physical state: Liquid
- Storage condition of test material: In original container at room temperature

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, Portage, MI, USA
- Age at study initiation: 56 - 63 days
- Weight at study initiation: 167 - 196 g 2 weeks before start of experiments
- Housing: Stainless steel cages (15.8 x 15.5 x 17.0 cm). The cages were suspended over excrement pans. Deotized animal cage boards (Shepherd Specialty Papers, Kalamazoo, MI) were provided beneath the suspended cages.
- Diet (e.g. ad libitum): PMI Rodent Diet No. 5002 (Purina Mills, Inc., St. Louis, MO), ad libitum
- Water (e.g. ad libitum): water from an automatic watering system, ad libitum

- Temperature (°C): 23 - 26
- Humidity (%): 25 - 60
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20-10-1993 To: 03-11-1993

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
other: unchanged (no vehicle)
Details on inhalation exposure:
- Exposure apparatus: Cannon 52-port flow-past, nose-only inhalation exposure chamber (Lab Products, Inc., NJ).
- Method of holding animals in test chamber: Study animals are held in clear plastic restraining devices attached to the chamber.
- System of generating particulates/aerosols: The test atmosphere was generated by aerosolization of Fyrolflex® RDP using a pneumatic spray nozzle (Spraying Systems, Inc., Wheaton, IL) supplied by a liquid reservoir and a regulated compressed air source. The resulting mist from the spray nozzle was passed through a cyclone designed to remove large droplets prior to entering the nose-only exposure chamber. Due to the highly viscous nature of Fyrolflex® RDP, the supply reservoir and the feed lines were heated to approximately 50°C in order to provide a consistent flow to the spray nozzle. The airflow rate to the spray nozzle was adjusted to generate an aerosol at the required level in a consistent manner with the particle sizes of < 3um Mass Median Aerodynamic Diameter.
- Method of particle size determination: Aerosol particle size was monitored with a Quartz Crystal Microbalance cascade impactor (California Measurements, Inc., Sierra Madre, CA).

- Brief description of analytical method used: Aerosol mass concentration of Fyrolflexc RDP in the breathing zone of the rats was determined gravimetrically from samples collected at least once each hour during the exposure from one of the exposure ports. The sampling train consisted of a pro-weighed glass fiber filter connected to a constant-flow vacuum pump. The mass of aerosol collected on the filter was determined gravimetrically to determine the amount of Fyrolflex® RDP. A dry-gas meter connected to the positive pressure side of the pump was used to record the corresponding volume of chamber air sampled and the weight to volume ratio was determined. The amount of Fyrolflex® RDP collected on the filters was also determined by using high-performance liquid chromatography. The filters were eluted in acetonitrile and analyzed using a reverse phase (C-18) column and
an acetonitrile/water gradient with UV detection at 254 nm. Calibration was performed using external standards.

In addition to the gravimetric concentration determinations, a realtime sensor was used as a continuous indicator of short-term changes in exposure concentration to guide laboratory personnel in correcting potential concentration excursions. The nominal concentration was calculated by dividing the total mass of test substance consumed during the exposure by the total volume of airflow through the exposure chamber.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.63 - 2.84 um (mean)

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: highest obtainable concentration
Analytical verification of test atmosphere concentrations:
Aerosol mass concentration of Fyrolflexc RDP in the breathing zone of the rats was determined gravimetrically from samples collected at least once each hour during the exposure from one of the exposure ports.
Duration of exposure:
4 h
4.14 mg/l (chemical determination)
No. of animals per sex per dose:
10 males and 10 females.
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: daily; weighing: All test rats were weighed immediately before exposure, on post-exposure day seven, and before necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy, Monocyte Non-Specific Esterase (MNSE) Activity (Blood samples were obtained one week prior to inhalation exposure, as well as one day and two weeks after exposure. Each animal, therefore, served as its own control)
No data

Results and discussion

Preliminary study:
Not relevant
Effect levels
Dose descriptor:
Effect level:
> 4.14 mg/L air (analytical)
None of the rats died during the study.
Clinical signs:
other: Four males and two females showed salivation. Two males and one female showed eye discharge. One male and one female showed red material around the nose. One male and one female showed red material around the eyes. One male displayed ptosis.
Body weight:
All of the rats gained weight during the study males: from 285 to 363 g (mean); females: from 207 to 222 g (mean).
Gross pathology:
Ten males and 9 females did not show gross lesions at necropsy. For one female rat it was reported that the cranial cavity was filled with a clear fluid.
Other findings:
- Other observations: the mono-esterase activity for both males and females was reduced significantly on day 1 of the treatment compared to before the treatment (day -7). After 14 days mono-esterase activity was returned to normal.

Any other information on results incl. tables

Exposure Concentrations: Themean concentrations of Fyrolflex® RDP determined gravimetricallyand chemically from the filter-collected aerosol samples were 4.17and 4.14 mg/l, respectively. The nominal concentrations (ratio of total test substance weight to air volume used during an entire exposure period) calculated according to EPA regulatory requirements was 16 mg/I. It must be noted that the nominal concentration is an accurate indicator of test substance usage only and not of the actual exposure concentration.

Particle Size Distribution: Aerosol Mass Median Aerodynamic Diameter (MMAD) of the chamber atmosphere ranged from 1.33 to 2.13 .um with geometric standard deviations (GSD) in the range of 2.20 to 3.90.

Chamber Conditions: The percent oxygen in the chamber during the exposure was 21%. Airflow rate, temperature and % relative humidity values (means and ranges are also provided ) during the exposure were 33 Ipm (31.1 to 33.7 lpm), 23°C (23 to 24°C), and57% RH (53 to 59%) respectively.

MNSE Activity: There was no statistical difference between sexes and statistical analyses were performed on data from both sexes combined. Mean MNSE activity on Day 1was 70% of control (Day-7) while MNSE activity on Day     14 was 128% of control. MNSE activity was significantly decreased one day following exposure (p < 0.05 as compared to Day -7; Dunnett's test). However, MNSE activity levels 14 days after exposure were comparable to pretest (i.e.,Day   -7) values.

Applicant's summary and conclusion

Interpretation of results:
Migrated information Criteria used for interpretation of results: EU
The acute inhalation toxicity (LC50) of Fyrolflex RDP towards rats is > 4.14 mg/l under the conditions of this study.
Executive summary:

The acute inhalation toxicity of Fyrolflex RDP towards rats was investigated according to OECD guideline 403 under GLP. Ten male and ten female rats were exposed to 4.14 mg/l (measured concentration) of the test substance for 4 hours and observed for 14 days. The LC50 was found to be > 4.14 mg/l. MSNE activity was reduced significantly one day after exposure in both males and females, but had returned to normal after 14 days.