N-methyl-P,P-bis(2-methylaziridin-1-yl)phosphinamide

Endpoint summary

Description of key information

Rat Oral LD50: >50 - <300 mg/kg bw (OECD 423, GLP, Rel. 1, K).

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:

key study

Study period:

08 November - 05 December 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study performed according to OECD Guideline 423 with a minor deviation: temperature was occasionally lower than the optimum value

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

dated 17 December, 2001

Deviations:

yes

Remarks:

temperature was occasionally lower than the optimum value

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

temperature was occasionally lower than the optimum value

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

27 April 2017

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 1000010405
- Date received: 19 October 2017
- Manufacturing date: 10 November 2016
- Expiration date: 15 June 2018
- Purity test date: 20 December 2016

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Fridge (6±3°C), darkness

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Used as supplied

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage JANVIER LABS, France
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8 or 9 weeks
- Weight at study initiation: 191-219 g
- Fasting period before study: 1 day
- Housing: Animals were housed by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid.
- Diet (e.g. ad libitum): Foodstuff (ENVIGO - 2016), ad libitum
- Water (e.g. ad libitum): Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18-25°C
- Humidity: 30-70%
- Air changes: 10/hour
- Photoperiod: 12 hours dark / 12 hours light

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Distilled water was chosen as it produced the most suitable formulation at the requested concentration.

DOSAGE PREPARATION: In the first step of the study, 0.3028 g of the test item was weighed in a flask and distilled water was added to obtain 10.0900 g. The preparation was stirred by vortex to obtain colourless solution just before administration. In the second step of the study, 0.0511 g of the test item was weighed in a flask and distilled water was added to obtain 10.2200 g. The preparation was stirred by vortex to obtain a colourless solution just before administration. In the third step of the study, 0.0528 g of the test item was weighed in a flask and distilled water was added to obtain 10.5646 g. The preparation was stirred by vortex to obtain a colourless solution just before administration. Each preparation was administered under a volume of 10 mL/kg bw using a suitable syringe graduated fitted with an oesophageal metal cannula.

Doses:

50 and 300 mg/kg bw

No. of animals per sex per dose:

3 and 6 female rats in 300 and 50 mg/kg bw, respectively

Control animals:

other: historical data

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality were recorded at 30 minutes, 1 hour, 3 hours, 4 hours, 24 hours, and then once daily for 14 days. Animals were weighed on day D0 (just before administering the test item) and then on D2, D7, and D14.
- Necropsy of survivors performed: Yes; animals were euthanized with sodium pentobarbital (Dolethal®) on D14 and macroscopic observations were noted.

Statistics:

No data

Preliminary study:

Not applicable

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Based on:

test mat.

Mortality:

All animals treated at the dose of 300 mg/kg bw (3/3) were found dead on Day 5. Two mortalities were noted in animals treated at the dose of 50 mg/kg bw on Day 9.

Clinical signs:

other: In 300 mg/kg bw group, no clinical signs related to the administration of the test item were observed before the death. Rigor mortis (3/3) and soiled urogenital zone (3/3) were noted before the necropsy. In 50 mg/kg bw group, the mortalities were precede

Gross pathology:

- In 300 mg/kg bw group, the macroscopic examination of the dead animals revealed a thinning of forestomach and corpus (3/3) with black spots (3/3), partially red stomach contents (2/3) and dark red liquid in thoracic cavity (2/3).
- In 50 mg/kg bw group, the macroscopic examination of the dead animals revealed red spots in the corpus (2/2) and red spots in a thinning of forestomach (1/2).
- The macroscopic examination of the surviving animals at the end of the study did not reveal treatment related changes.

Other findings:

None

None

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Under the test conditions, the oral LD50 of the test item is higher than 50 mg/kg bw and lower than 300 mg/kg bw by oral route in the rat. In accordance with the OECD Test Guideline No. 423, the LD50 cut-off of the test item may be considered as 200 mg/kg bw by oral route in the rat.
According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation (EC) No. 1272/2008, and according to the Globally Harmonized System of classification and labelling of chemicals (GHS), the test item has to be classified in category 3. The signal word "Danger", symbol “skull and bones” and hazard statement H301 "Toxic if swallowed” are required.

Executive summary:

In an acute oral toxicity study performed according to the OECD Guideline 423 and in compliance with GLP, the test item was administered to a group of 3 female Sprague Dawley rats at the dose of 300 mg/kg bw and then to a group of 6 female Sprague Dawley rats at the dose of 50 mg/kg bw. Animals were then observed for mortality, clinical signs and body weight changes for 14 days, and were all sacrificed for macroscopic examinations.

All animals treated at the dose of 300 mg/kg bw (3/3) were found dead on Day 5. No clinical signs related to the administration of the test item were observed before the death. Rigor mortis (3/3) and soiled urogenital zone (3/3) were noted before the necropsy. The macroscopic examination of the animals revealed a thinning of forestomach and corpus (3/3) with black spots (3/3), partially red stomach contents (2/3) and dark red liquid in thoracic cavity (2/3).

Two mortalities were noted in animals treated at the dose of 50 mg/kg bw on Day 9. The mortalities were preceded on Day 8 by a decrease in spontaneous activity (2/2), muscle tones (2/2), myosis (1/2), piloerection (2/6) and an increase of lachrymation (1/6). Rigor mortis (1/2) and weight loss (1/2) were noted before the necropsy. The macroscopic examination of the animals revealed red spots in the corpus (2/2) and red spots in a thinning of forestomach (1/2).

In the surviving animals (4/6), no clinical signs related to the administration of the test item were observed during the study. The body weight evolution of the animals remained normal during the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

Rat Oral LD50 >50 - <300 mg/kg bw.

Under the test conditions, the oral LD50 of the test item is higher than 50 mg/kg bw and lower than 300 mg/kg bw by oral route in the rat. In accordance with the OECD Test Guideline No. 423, the LD50 cut-off of the test item may be considered as 200 mg/kg bw by oral route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation (EC) No. 1272/2008, and according to the Globally Harmonized System of classification and labelling of chemicals (GHS), the test item has to be classified in category 3. The signal word "Danger", symbol “skull and bones” and hazard statement H301 "Toxic if swallowed” are required.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

200 mg/kg bw

Quality of whole database:

GLP guideline study

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In an acute oral toxicity study performed according to the OECD Guideline 423 and in compliance with GLP, the test item was administered to a group of 3 female Sprague Dawley rats at the dose of 300 mg/kg bw and then to a group of 6 female Sprague Dawley rats at the dose of 50 mg/kg bw. Animals were then observed for mortality, clinical signs and body weight changes for 14 days, and were all sacrificed for macroscopic examinations.

All animals treated at the dose of 300 mg/kg bw (3/3) were found dead on Day 5. No clinical signs related to the administration of the test item were observed before the death. Rigor mortis (3/3) and soiled urogenital zone (3/3) were noted before the necropsy. The macroscopic examination of the animals revealed a thinning of forestomach and corpus (3/3) with black spots (3/3), partially red stomach contents (2/3) and dark red liquid in thoracic cavity (2/3).

Two mortalities were noted in animals treated at the dose of 50 mg/kg bw on Day 9. The mortalities were preceded on Day 8 by a decrease in spontaneous activity (2/2), muscle tones (2/2), myosis (1/2), piloerection (2/6) and an increase of lachrymation (1/6). Rigor mortis (1/2) and weight loss (1/2) were noted before the necropsy. The macroscopic examination of the animals revealed red spots in the corpus (2/2) and red spots in a thinning of forestomach (1/2).

In the surviving animals (4/6), no clinical signs related to the administration of the test item were observed during the study. The body weight evolution of the animals remained normal during the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

Under the test conditions, the oral LD50 of the test item is higher than 50 mg/kg bw and lower than 300 mg/kg bw by oral route in the rat. In accordance with the OECD Test Guideline No. 423, the LD50 cut-off of the test item may be considered as 200 mg/kg bw by oral route in the rat.

Justification for classification or non-classification

The oral LD50 of the registered substance is higher than 50 mg/kg bw and lower than 300 mg/kg bw by oral route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation (EC) No. 1272/2008, and according to the Globally Harmonized System of classification and labelling of chemicals (GHS), the registered substance has to be classified in category 3. The signal word "Danger", symbol “skull and bones” and hazard statement H301 "Toxic if swallowed” are required.