Reaction mass of Dimethyl [3-[(hydroxymethyl) amino]-3-oxopropyl] phosphonate and Dimethyl (3-amino-3-oxopropyl)phosphonate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30.01.1992 - 01.07.1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

Date of draft report delayed; New Managing Director: Dr. M. Thouin

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl [3-[(hydroxymethyl)amino]-3-oxopropyl]phosphonate

EC Number:

243-528-9

EC Name:

Dimethyl [3-[(hydroxymethyl)amino]-3-oxopropyl]phosphonate

Cas Number:

20120-33-6

Molecular formula:

C6H14NO5P

IUPAC Name:

dimethyl [3-[(hydroxymethyl)amino]-3-oxopropyl]phosphonate

Constituent 2

Reference substance name:

Dimethyl (3-amino-3-oxopropyl)phosphonate

EC Number:

219-765-9

EC Name:

Dimethyl (3-amino-3-oxopropyl)phosphonate

Cas Number:

2526-69-4

Molecular formula:

C5H12NO4P

IUPAC Name:

dimethyl (3-amino-3-oxopropyl)phosphonate

Test material form:

liquid: viscous

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: EN 746916/1991
- Expiration date of the lot/batch: September 1996

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature, in the original container, protected from light.
- Stability under test conditions: Stable for 4 years under storage conditions

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Ibm-Han, (outbred)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. CH-4414 Fuellinsdorf / Switzerland
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: Males 8 weeks; females : 10 weeks
- Weight at study initiation: Males : 182.4 - 200.0 g; Females : 180.6 - 199.3 g
- Fasting period before study:
- Housing: Animals were housed in groups of five in Makrolon type-4 cages (dimensions in mm : 590 x 385 x 200 ht)
- Diet: ad libitum, Pelleted standard Kliba 343, Batch No. 78/91 rat maintenance diet ("Kliba",Klingentalmuehle AG, CH-4303 Kaiseraugst / Switzerland)
- Water: ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours dark period

IN-LIFE DATES: January 16, 1992 to January 30, 1992

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

other: Distilled water

Mass median aerodynamic diameter (MMAD):

3 µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: GLASS CHAMBER DILUTION SYSTEM NEBULIZER (Hospitak No. 95)
- Exposure chamber volume: 1 litre
- Method of holding animals in test chamber: constructed of anodised aluminium and readily accepts a variety of different sized Makrolon animal restraint tubes
- Method of particle size determination: Mercer 7 stage cascade impactor (Model 02-1300, In-Tox Inc., Albuquerque, New Mexico, U.S.A)
- Temperature, humidity, pressure in air chamber: 20.0 to 37.1 for 9 h 45 min sampling time and 20.0 & 42.3 for 11 h 25 min sampling time respectively

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 94.3 % of particles found on the 3 ym stage or less of the impactor
- GSD (Geometric st. dev.): 2.71 ± 1.44 mg/l air

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

4.83 mg/L air

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Body weights were recorded prior to exposure and weekly thereafter
- Mortality, clinical signs and necropsy were performed
- Additionally, following data were recorded on data sheets and transcribed for compilation and analysis:

- relative humidity
- oxygen concentration
- temperature
- test article concentration (nominal, gravimetric)
- particle size distribution (gravimetric)

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

discriminating conc.

Effect level:

> 4.83 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No deaths occurred during exposure nor during the 15-day observation period.

Clinical signs:

other: No clinical signs were observed.

Body weight:

No effects on body weights were noted.

Gross pathology:

Isolated dark red foci were noted on the left or right caudal lung lobe of 2 males and 2 females.

Other findings:

None

Any other information on results incl. tables

Physical Measurements

Exposure date: January 16, 1992

Exposure start time: 09h.00

Exposure completion time: 13h.00

Exposure airflow rate: 1.3 l/min/animal

Sampling time           Temperature               Relative Humidity           Oxygen Concentration

(hh.min)                      (°C)                             (% rh)                          (0₂vol%)

9h.45                          20.0                             37.1                             20.9

11h.25                        20.0                             42.3                             20.9

NOMINAL DETERMINATION OF CONCENTRATION

Consumption: 48.68 g

Duration of exposure: 240 min

Exposure airflow rate: 21 l/min

Dilution: 1/1

Concentration: 4.83 mg/l air

GRAVIMETRIC DETERMINATION OF THE AEROSOL CONCENTRATION

Mean sampling airflow rate : 1.57 l/min

Sampling Time                                  Aerosol Concentration

(hh.min)                                              (mg/l air)

 09.20 - 09.28                                      2 14

10.20 - 10.28                                       1 30

11.15 - 11.23                                       4 68

12.15 - 12.23                                       2 73

MEAN + S.D. 2.71 + 1.44 mg/l air

PARTICLE SIZE IN CUMULATIVE %

Sampling Time            (um, effective cutoff diameter)

(hh.mm.sec)                >4.6    3 0             2.13    1.6      1.06    0.715     0.325    <0.325

9.^40.00.9.^40.30              100     94.33         77.6    62.3    52.8    29.1 1     7.4        6.9

94.3 % of particles found on the 3 ym stage or less of the impactor

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

An acute inhalation toxicity of DMPPA_701-402-5 has been carried out with only one concentration (4.83 mg/L air), where no effects has been observed concluding LC50 >4.83 mg/L air.

Executive summary:

In an acute inhalation toxicity study (OECD 403), Wistar rats (5 males, 5 females) were exposed during a single, continuous 4-hour period to DMPPA_701-402-5 via the inhalation route to a mean nominal concentration of 4.83 mg/l air (highest achievable concentration). Clinical signs and mortality were observed during and following exposure over a 15-day observation period. Body weights were recorded prior to exposure and weekly thereafter. All animals were necropsied and subjected to gross macroscopic examination.

No deaths occurred during exposure nor during the 15-day observation period. The LC₅₀ of DMPPA_701-402-5, as assessed in this 4-hour acute inhalation toxicity study (Limit Test) in rats of both sexes, observed over a period of 15 days was estimated to be >4.83 mg/l air (nominal concentration).