3-((bis(diisopropylamino)phosphanyl)oxy)propanenitrile

Endpoint summary

Description of key information

In an acute oral toxicity study in rats conducted according to OECD 423, the target substance 2-Cyanoethyl-N,N,N’,N’-tetraisopropylphosphordiamidite was associated with signs of toxicity but not mortality at dose level 300 mg/kg bw and with signs of toxicity and mortality at dose level 2000 mg/kg bw. Hence, the LD50 cut-off value was considered to be 500 mg/kg bw.

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:

2017-12-12 to 2018-03-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

adopted 17 December 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8–10 weeks
- Weight at study initiation: Step 1: 154–169, Step 2: 147–167 g, Step 3: 162–166 g
- Fasting period before study: 16-19 h
- Housing: The animals were kept in groups in individually ventilated cages (IVC), type III H, polysulphone cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): Yes, Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum): Yes , free access to tap water, sulphur acidified to a pH value of approximately 2.8
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + / - 3
- Humidity (%): 55 + / - 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

300 mg/kg bw (starting dose) and 2000 mg/kg bw

No. of animals per sex per dose:

3 per step, 3 steps

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Observed for 14 days after dosing for general clinical signs, morbidity and mortality
- Frequency of weighing: Weighed on days 1 (prior to the administration), 8 and 15
- Necropsy of survivors performed: Yes, all animals were subjected to gross necropsy and examined macroscopically for gross pathological changes. In the absence of gross pathological changes no tissues were preserved for a further histopathological evaluation
- Other examinations performed: Clinical examination: A careful clinical examination was made six times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). As soon as symptoms were noticed they were recorded. Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. All abnormalities were recorded.
Cage side observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems as well as somatomotor activity and behavior pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhea, lethargy, sleep and coma.

Statistics:

n.a.

Preliminary study:

n.a.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 cut-off value

Mortality:

See Table 1 in box "Any other information on results incl. tables".

Clinical signs:

other: The most relevant clinical findings in the animals treated with the test item at a dose of 300 mg/kg bw were reduced spontaneous activity, hunched posture, piloerection, half eyelid closure, ataxia, sunken flanks, muscle twitches and tremor. All symptoms

Gross pathology:

No treatment related macroscopic findings were observed in any animal at necropsy.

Table 1: Results on Mortality

Step	Sex / No.	Starting Dose (mg / kg bw)	Number of Animals	Number of Incurrent Deaths
1	Female / 1 - 3	300	3	0
2	Female / 4 - 6	2000	3	3
3	Female / 7 - 9	300	3	0

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In an acute oral toxicity study in rats conducted according to OECD 423, mortality occurred at the dose level 2000 mg/kg bw whereas no signs of toxicity and mortality were observed at the dose level 300 mg/kg bw. Hence, the LD50 cut-off value was determined to be 500 mg/kg bw.

Executive summary:

In an acute oral toxicity study (acute toxic class method, OECD 423), three groups of fasted, 8 -10 weeks old, female Wistar rats (3 rats/group) were given a single oral dose of 2-Cyanoethyl-N,N,N’,N’-tetraisopropylphosphordiamidite (99.6 % purity) at a starting dose of 300 mg/kg bw followed by a dose of 2000 mg/kg bw. Animals were observed for 14 days. All animals treated with the test item at a dose of 2000 mg/kg died on test day 1. All animals treated with the test item at a dose of 300 mg/kg survived until the end of the study showing signs of toxicity. Throughout the 14-day observation period, the body weight gain of the test animals was within the normal range of variation for this strain. At necropsy, no macroscopic findings were observed in any animal of any step. Based on the results from this study, the oral LD50 cut-off value in rats is considered to be 500 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 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 (acute toxic class method, OECD 423), three groups of fasted, 8 -10 weeks old, female Wistar rats (3 rats/group) were given a single oral dose of 2-Cyanoethyl-N,N,N’,N’-tetraisopropylphosphordiamidite (99.6 % purity) at a starting dose of 300 mg/kg bw followed by a dose of 2000 mg/kg bw. Animals were observed for 14 days. All animals treated with the test item at a dose of 2000 mg/kg died on test day 1. All animals treated with the test item at a dose of 300 mg/kg survived until the end of the study showing signs of toxicity. Throughout the 14-day observation period, the body weight gain of the test animals was within the normal range of variation for this strain. At necropsy, no macroscopic findings were observed in any animal of any step. Based on the results from this study, the oral LD50 cut-off value in rats is considered to be 500 mg/kg bw.

Justification for classification or non-classification

Based on the available data, 2-Cyanoethyl-N,N,N’,N’-tetraisopropylphosphordiamidite has to be classified as Acute Tox. 4, H302 according to CLP criteria. The LD50 value for the oral route is 500 mg/kg bw.