(2S)-2-amino-3-(4-{[bis(sodiooxy)phosphoryl]oxy}phenyl)propanoic acid

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2020-04-16 to 2020-06-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Version / remarks:

adopted 2001-12-17

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Version / remarks:

2008-05-30

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-amino-3-(4-{[bis(sodiooxy)phosphoryl]oxy}phenyl)propanoic acid

EC Number:

860-352-3

Cas Number:

1610350-91-8

Molecular formula:

C9H10NO6PNa2

IUPAC Name:

(2S)-2-amino-3-(4-{[bis(sodiooxy)phosphoryl]oxy}phenyl)propanoic acid

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS B.V., Inc, Postbus 6174, 5960 AD Horst / The Netherlands
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 193.6 g - 229.9 g
- Fasting period before study: Overnight
- Housing: Groups of one to five rats (of the same sex and dose group) were housed in akrolon Type IV cages with wire mesh top and granulated soft wood bedding.
- Diet: Ad libitum (except for overnight fasting prior to dosing; diet was returned immediately after dosing was complete)
- Water: Ad libitum
- Acclimation period: At least 5 days prior to the start of dosing under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 45-65 (22-65 for several hours)
- Air changes (per hr): 8
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From day 0 to day 14

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL in sterile water
- Amount of vehicle: 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

Pre-experiment: 300 mg/kg bw (1 animal) and 2000 mg/kg bw (1 animal);

Main experiment: 2000 mg/kg bw (4 animals)

No. of animals per sex per dose:

Pre-experiment: 300 mg/kg bw (1 female) and 2000 mg/kg bw (1 female);

Main experiment: 2000 mg/kg bw (4 females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Morbidity / Mortality: At least three times within the first six hours after application, thereafter at least once daily for 14 days.
Body weight: On Day 0 (prior to dosing), Day 7, and 14, or (if applicable) at death (unscheduled).
- Necropsy of survivors performed: Yes
- Clinical signs including body weight: Clinical signs and body weight development were monitored in all animals during the study.
- Other examinations performed: Clinical signs, body weight,organ weights, histopathology

Statistics:

Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was made.

Results and discussion

Preliminary study:

Doses of 300 mg/kg bw (1 animal) and 2000 mg/kg bw (1 animal) were tested in a preliminary study. Following results were obtained:
Mortality: There were no deaths during the study.
Clinical Signs: There were no clinical signs of reaction to treatment throughout the study.
Body Weights: The animal showed expected gains in body weight over the observation period.
Necropsy: Macroscopic examination at study termination on Day 14 revealed an empty stomach (both animals).

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no deaths during the study.

Clinical signs:

other: There were no clinical signs of reaction to treatment throughout the study.

Gross pathology:

Macroscopic examination at study termination on Day 14 revealed unspecific results, i.e., an empty stomach in one animal, a slightly enlarged heart in one animal, and a slight hypotrophy of the kidney in one animal. No abnormalities were noted in any other animal at the macroscopic examination.

Any other information on results incl. tables

 

Table 1: Individual Clinical Observations and Mortality Data – 300 mg/kg Dose Level mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	5-6	1	2	3	4	5	6	7	8	9	10	11	12	13	14
300	Female 1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0= No signs of systemic toxicity

 

Table 2: Individual Body Weights and Body Weight Changes – 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week		Body Weight Gain (g) During Week
		0	7	14	1	2	1	2
300	Female 1	193.6	215.1	232.0	21.5	16.9	11.1	7.9

 

Table 3: Individual Necropsy Findings – 300 mg/kg b.w.

Dose Level mg/kg	Animal Number and Sex	Time of Death	MacroscopicObservations
300	Female 1	Euthanatized Day 14	Empty stomach

 

Table 4: Individual Clinical Observations and Mortality Data – 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	5-6	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	Female 1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Female 2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Female 3	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Female 4	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Female 5	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0= No signs of systemic toxicity

 

Table 5: Individual Body Weights and Body Weight Changes – 2000 mg/kg b.w.

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week		Body Weight Gain (g) During Week
		0	7	14	1	2	1	2
2000	Female 1	208.3	232.9	248.8	24.6	15.9	11.8	6.8
	Female 2	215.7	248.0	254.8	32.3	6.8	15.0	2.7
	Female 3	222.7	246.5	258.6	23.8	12.1	10.7	4.9
	Female 4	217.5	231.6	249.1	14.1	17.5	6.5	7.6
	Female 5	229.9	260.0	271.8	30.1	11.8	13.1	4.5

 

Table 6: Individual Necropsy Findings – 2000 mg/kg b.w.

Dose Level mg/kg	Animal Number and Sex	Time of Death	MacroscopicObservations
2000	Female 1	Euthanatized Day 14	Empty stomach
	Female 2	Euthanatized Day 14	No abnormalities detected
	Female 3	Euthanatized Day 14	Slight hypotrophy of left kidney
	Female 4	Euthanatized Day 14	No abnormalities detected
	Female 5	Euthanatized Day 14	Slightly enlarged heart

 

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The acute median lethal oral dose (LD50) to rats of the test item was demonstrated to be greater than 2000 mg/kg body weight.

Executive summary:

The study was performed to assess the acute oral toxicity of the test item to the rat.

Following a sighting test at dose levels of 300 mg/kg b.w. and 2000 mg/kg b.w. in one female rat per dose group, a further group of four fasted females was given a single oral dose of the test item, as a solution in sterile water, at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored in all animals during the study. All animals were subjected to gross necropsy.

Mortality: There were no deaths.

Clinical Observations: There were no signs of systemic toxicity noted.

Body Weight: All animals showed expected gains in body weight.

Necropsy: Only unspecific results, i.e., a slightly enlarged heart and minor hypotrophy of the kidney were observed in one animal each (both treated with a dose level of 2000 mg/kg b.w.). Two animals (the animal treated with 300 mg/kg b.w. and one animal treated with 2000 mg/kg b.w.) showed an empty stomach.