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

Endpoint summary

Description of key information

DMPPA_701-402-5 was found to be not toxic on acute exposure as seen in the oral (LD50 >2000 mg/kg bw), dermal (LD50 >2000 mg/kg bw) and inhalation (LC50 >4.83 mg/L air) toxicity studies.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

24.01.1992 - 20.03.1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

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: In the original container, protected from light at room temperature (approx. 20°C)
- Stability under test conditions: stable for at least 48 hours

Species:

rat

Strain:

Wistar

Remarks:

Hanlbm

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wölferstrasse 4
CH-4414, Füllinsdorf
- Females (if applicable) nulliparous and non-pregnant: Not Specified
- Age at study initiation: males: 8 weeks; females: 10 weeks
- Weight at study initiation: males: 202 - 211 g; females: 176 - 181 g
- Fasting period before study: overnight for approximately 17 hours
- Housing: Groups of five in Makrolon type-3 cages (size: 22 x 37.5 x 15 cm) with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz)
- Diet: ad libitum (Pelleted standard Kliba 343, Batch 87/91 rat maintenance diet ("Kliba",Klingentalmuehle AG, CH-4303 Kaiseraugst))
- Water: ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light (approx. 100 Lux) / 12 hours dark

IN-LIFE DATES: From: January 7 to 21, 1992

Route of administration:

oral: gavage

Vehicle:

water

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Test days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, mortality, body weight,organ weights, necropsy

Statistics:

The toxicity was estimated without use of a statistical model

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No intercurrent deaths occurred during the course of the study.

Clinical signs:

other: No clinical signs were noted.

Gross pathology:

No macroscopical organ findings were noted.

Other findings:

None

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose (LD50) of DMPPA_701-402-5 after single oral administration is greater than 2000 mg/kg body weight.

Executive summary:

The test article DMPPA_701-402-5 was administered to Wistar rats of both sexes by oral gavage, at a single dose of 2000 mg/kg as per OECD 401 guideline. During this study clinical signs, mortality, body weight,organ weights, necropsy parameters were observed.

There was no mortality found in either of sex during the study period. There were no adverse effects were seen for clinical signs, body weight,organ weights and necropsy.

The LOGIT-Model could not be applied to these data. So, LD₅₀ median lethal dose of FAT 80'001/I in male and female Wistar rats is greater than 2000 mg/kg body weight.

Based upon the classification criteria according to „Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008“  the test item is not classified with respect to the acute oral toxicity study in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

GLP-compliant and OECD guideline study

Acute toxicity: via inhalation route

Link to relevant study records

Reference

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

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

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

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

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

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)

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

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

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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

4 830 mg/m³ air

Quality of whole database:

GLP-compliant and OECD guideline study

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31.12.1991 till 27.01.1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Remarks:

Swiss Principles of Good Laboratory Practice (Good Laboratory Practice (GLP) in Switzerland, Procedures and Principles, March 1986)

Test type:

standard acute method

Limit test:

yes

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: In the original container, protected from light at room temperature (approx. 20 °C)
- Stability under test conditions: stable ; expiration date: September, 1996

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wölferstrasse 4
CH-4414 Füllinsdorf
- Females (if applicable) nulliparous and non-pregnant: Not specified
- Age at study initiation: males: 10 weeks; females: 12 weeks
- Weight at study initiation: males: 237 - 248 g; females: 205 - 216 g
- Housing: Individually in Makrolon type-2 cages ( size: 16.5 x 22 x 14 cm) with standard softwood bedding
- Diet: ad libitum; Pelleted standard K l i b a 343, Batch 87/91 rat maintenance diet (" Kliba",Klingentalmuehle AG, CH-4303 Kaiseraugst)
- Water: ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 2 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light (approx. 100 Lux) /12 hours dark

IN-LIFE DATES: From January 7 to 21, 1992

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Approximately 24 hours before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10 % of the total body surface. The test article was applied undiluted. Only those animals with no injury or irritation on the skin were used in the test . On test day 1, the test article was applied evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.
Twenty-four hours after the application , the dressing was removed. The treated skin was washed with lukewarm tap water, dried with disposable paper towels and the skin reaction was assessed according to the method of Noakes and Sanderson.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Test days 1 ( pre-administration) , 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, mortality, body weight,organ weights, necropsy

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No intercurrent deaths occurred during the course of the study.

Clinical signs:

other: The following local signs were observed: 2000 mg/kg: males/females - scales (back) ( 9 ) ; skin yellow (back) (10). The animals had recovered from local symptoms within 11 to 14 days of observation. No systemic symptoms were observed.

Gross pathology:

no macroscopical organ findings noted

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 (median lethal dose) of DMPPA_701-402-5 after single dermal administration to rats of both sexes, observed over a period of 14 days, is >2000 mg/kg body weight

Executive summary:

In an acute dermal toxicity study carried out according to OECD 402 guideline, the test article DMPPA_701-402-5 was applied to the skin of rats of both sexes for 24 hours at a single dose of 2000 mg/kg. No death was observed during the study. No adverse effects were seen except local signs such as scales (back) ( 9 ); skin yellow (back) (10). The animals were recovered from local symptoms within 11 to 14 days of observation. No systemic symptoms were observed.

Based on these observations, the LOGIT-Model could not be applied to the observed rate of death. Therefore, the LD₅₀ (median lethal dose) of DMPPA_701-402-5 after single dermal administration to rats of both sexes, observed over a period of 14 days, is >2000 mg/kg body weight. Based on the classification criteria according to the Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008, DMPPA_701-402-5

does not have to be classified for acute dermal toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

GLP-compliant and OECD guideline study

Additional information

Acute oral toxicity:

A LD50 oral (gavage, Hanlbm: WIST (SPF) rats and ) of >2000 mg/kg in female rats is reported for DMPPA_701-402-5 in two acute oral studies (Mukherjee, A. 2004 and Hoff, N. 1992) conducted according to OECD 423 and 401 respectively. In these studies, no fatalities occurred, body weight development was normal. No clinical signs were noted.

 

Acute inhalation toxicity:

An acute inhalation toxicity study in the rat with DMPPA_701-402-5 has been carried out with only one concentration (4.83 mg/L air), where no effects has been observed concluding LD50 >4.83 mg/L air.

Acute dermal toxicity:

A LD50 dermal (semiocclusive application for 24 h,Hanlbm: WIST (SPF)rats) of >2000 mg/kg in male and female rats is reported for DMPPA_701-402-5. No fatalities occurred, the body weight gain of the animals was not affected throughout the study by test article treatment. No other test item related effects were noted. Following local signs were observed: scales on the back of one animal; skin yellow on the back of an other animal. These animals had recovered from local symptoms within 11 to 14 days of observation .

Justification for classification or non-classification

Acute oral toxicity:

Based on the above stated assessment of the acute oral toxicity of DMPPA_701-402-5 (absence of toxicity up to 2000 mg/kg) the substance does not need to be classified according to CLP.

 

Acute dermal toxicity:

Based on the above stated assessment of the acute dermal toxicity of DMPPA_701-402-5 (absence of toxicity up to 2000 mg/kg) the substance does not need to be classified according to CLP.

 

Acute inhalation toxicity:

Based on the above stated assessment of the acute inhalation toxicity of DMPPA_701-402-5 (absence of toxicity up to 4.83 mg/L air), no classification for acute inhalation toxicity is deemed necessary according to CLP.