Ammonium 2-amino-4-(hydroxymethylphosphinyl)butyrate

Endpoint summary

Description of key information

After acute oral administration by gavage, the rat is the less sensitive species with an LD50 between 1500 to 2000 mg/kg bw. The acute oral LD50 in mice is between 416 to 460 mg/kg bw and a dose of 400 mg/kg bw killed both dogs whereas no mortality was observed at 200 mg/kg bw. In rodents deaths were noted up to 8 days after administration. The major clinical signs were neurological effects such as decreased motility, uncoordinated gait, hunched posture, piloerection, exophthalmus, convulsions, diarrhea. Mice exposed to glufosinate ammonium through the dietary route showed mortality starting at 300 mg/kg bw.The calculated LD50 values are consistent between two different mouse strains and lie between 416 and 464 mg/kg bw. Clinical signs including clonic convulsions, abdominal position, squatting, uncoordinated gait, piloerection, poor general condition. Surviving animals showed recovery from day 2 or at the latest day 6, depending on dose, severity and strain.   

Table 1: acute oral toxicity data

Species	Strain	Sex	LD50 (mg/kg bw)
Mouse	NMRI	Female	416
		Male	431
	ICR	Female	464
		Male	436
Rat	F344	Female	1510
		Male	1660
	Wistar	Female	1620
		Male	2000
Dog	Beagle	Male/Female	200 - 400

 

Neurological effects were also observed after dermal application. The clinical signs observed in rats include hyperactivity or passiveness, convulsions or convulsive jumping, disequilibrium, squatting, high legged posture, retracted abdomen or flanks, increased salivation and aggressivity. In rabbits, pilo-erection, unsteady gait, lethargy and ataxia were observed.The LD50 was above 4000 mg/kg bw in rats, above 2000 mg/kg bw in male rabbits and between 1500and 2000 mg/kg bw in female rabbits.  

Table 2: acute dermal toxicity data

Species	Strain	Sex	LD50 (mg/kg bw)
Rabbit	New Zealand White	Male/Female	2000
Rat	Wistar	Male	> 4000
		Female	> 4000

 

 

The LC50 obtained in rats after acute exposure via inhalation was 1.26 mg/L in males and 2.60 mg/L in females. The deaths occurred between days 4 and 9 after inhalation. The major clinical signs were narrowed eye openings, periodic tremors and clonic convulsions, hyperactivity, piloerection, increased salivation and passivity.  

Table 3: acute inhalation toxicity data

Species	Strain	Sex	LD50 (mg/L)
Rat	Wistar	Male	1.26
		Female	2.6

 

 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23 Sep. - 14 Oct. 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

NMRI

Remarks:

HoE: NMRKf (SPF71)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst
- Weight at study initiation: 22 - 26 g
- Fasting period before study: not specified
- Housing: group
- Diet: produced by Altromin GmbH, ad libitum
- Water: tap water; ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

Route of administration:

oral: gavage

Vehicle:

water

Doses:

315, 500, 800 mg/kg bw

No. of animals per sex per dose:

10 (females only)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighing weekly, observations of intoxication and mortality rate performed
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

LD50 determined by probit analysis (Lindner/Weber method)
Confidence limits calculated: Fieller

Sex:

female

Dose descriptor:

LD50

Effect level:

416 mg/kg bw

Based on:

act. ingr.

95% CL:

>= 345 - <= 498

Mortality:

1/10 animals / 315 mg/kg bw
8/10 animals / 500 mg/kg bw
10/10 animals / 800 mg/kg bw
Animals died within day 1 and 8 after treatment

Clinical signs:

Following symptoms were registered 24h after dosing: Ataxy, bizarre movements, squatting, abdominal position, clonic convulsions, convulsive jumping, rolling spasms, "Straub" phenomenon, increased salivation, irregular, jerky respiration, hyperactivity in the dosage group 315 mg/kg bw and benumbedness in the remaining groups.
Surviving animals recovered from day 2 after the treatment onwards whilst the animals that died later showed squatting, lateral posiion, bristled hair, poor general condition and in some instances barely perceptible respiratory movements which decreased respiratory rate until exitus

Body weight:

Before exitus marked decrease in body weight
Body weight gains of surviving animals were normal

Gross pathology:

Animals that died during the first days after the treatment showed translucent livers with hepatic marking at the edge in some instances and pulmonary plethora.
no abnormal findings for animals that died during the further course of the experiment or were killed after study termination

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23 Sep. - 14. Oct 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

NMRI

Remarks:

HoE: NMRKf (SPF71)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst
- Weight at study initiation: 22 - 26 g
- Fasting period before study: not specified
- Housing: group
- Diet: produced by Altromin GmbH, ad libitum
- Water: tap water; ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

Route of administration:

oral: gavage

Vehicle:

water

Doses:

315, 500, 800 mg/kg bw

No. of animals per sex per dose:

10 (males only)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighing weekly, observations of intoxication and mortality rate performed
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

LD50 determined by probit analysis (Lindner/Weber method)
Confidence limits calculated: Fieller

Sex:

male

Dose descriptor:

LD50

Effect level:

431 mg/kg bw

Based on:

act. ingr.

95% CL:

>= 337 - <= 533

Mortality:

2/10 animals / 315 mg/kg bw
6/10 animals / 500 mg/kg bw
10/10 animals / 800 mg/kg bw
Animals died within day 1 and 7 after treatment

Clinical signs:

Following symptoms were registered 24h after dosing: Ataxy, bizarre movements, squatting, abdominal position, clonic convulsions, convulsive jumping, rolling spasms, "Straub" phenomenon and irregular, jerky respiration
Improvement of general condition of the surviving animals from day 2 after treatment onwards, whilst the mice that had died later showed abdominal position, bristled hair and poor general condition until exitus.

Body weight:

Before exitus marked decrease in body weight
Body weight gains of surviving animals were normal

Gross pathology:

Dead animals until day 2: Translucent and in some instances marked livers and blood-congested lungs
no abnormal findings for animals that died from day 2 onwards until the end of observation period

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

416 mg/kg bw

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

GLP compliance:

yes

Test type:

traditional method

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund, SPF breeding colony
- Age at study initiation: 8-10 weeks
- Weight at study initiation: males 163-193 g, females 174-193 g
- Housing: in fully air-conditioned rooms in Makrolon cages (Type 4) on softwood granulate in groups of 5 animals
- Diet (e.g. ad libitum): rat diet Altromin 1324 (Altromin GmbH, Lage/Lippe), ad libitum
- Water (e.g. ad libitum): tap water in plastic bottles, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 0.6 - <= 10.3 µm

Details on inhalation exposure:

The rats were placed individually in cylindrical plastic tubes and exposed to specified dust concentrations for 4 hours. The plastic tubes leading into the exposure cylinder are so arranged that only the noses of the animals are inside the cylinder. The inhalation chamber itself consists of a stainless steel and glass cylinder with a volume of 60 L, standing in a vent pipe with a volume of ca. 4 m3. Particles of test substance escaping from the exposure
chamber into the vent pipe are drawn off and neutralized by gas-cleaning equipment.
The dust was produced with the aid of a "Wright Dust Feed" generator manufactured by L. Adams Ltd., London. The different concentrations were achieved by adjusting the gear transmission ratios. The dust produced by the scraper head was drawn from above into the exposure chamber by a current of air flowing at a rate of 1000 L/h at 4 bar.
A suction device at the bottom of the inhalation chamber drew off the dust at a rate of 1000 L/h through a cotton-wool filter and a washing bottle filled with water.

Remarks on duration:

4 hours

Concentrations:

0.12, 0.19, 0.38, 2.0 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighing took place on days 2, 3, 4, 7 and 14 after exposure
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic examination, behavioural tests

Statistics:

The LC 50, the 95 % range of confidence and the equation of the probit lines were assessed on the basis of the actual death rates by probit analysis (according to the method of UNDER and WEBER); the limits of confidence were calculated according to the method of FIELLER or SIDAK (program supplied by the Department Praktische Mathematik of HOECHST A6)

Sex:

male

Dose descriptor:

LC50

Effect level:

1.26 mg/L air

Sex:

female

Dose descriptor:

LC50

Effect level:

2.6 mg/L air

Mortality:

0.12 mg/L: 0/10
0.19 mg/L: 1/10
0.38 mg/L: 2/10
2.0 mg/L: 5/10

Clinical signs:

other: The following clinical signs of intoxication were observed: narrowed eye openings, periodic tremors and clonic convulsions, hyperactivity, pilo-erection, increased salivation and passivity.

Body weight:

A reduction of bodyweights was recorded in the male and female animals during the days immediately after inhalation, to a greater extent with increasing concentrations. All surviving animals had regained their initial weight on day 14 after inhalation.

Gross pathology:

Autopsy of the animals which died during and of those killed at the end of the study revealed no macroscopically visible changes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 260 mg/m³

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Remarks:

The study was subjected to Quality Assurance inspections and is of acceptable quality.

Test type:

standard acute method

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Froxfield Rabbits, Petersfield, Hampshire, England
- Age at study initiation: 9-13 weeks
- Weight at study initiation: 2.1-2.8 kg
- Housing: individually in metal cages with perforated floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: min. 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-21
- Humidity (%): 46-76%
- Air changes (per hr): 19
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

water

Remarks:

distilled

Details on dermal exposure:

TEST SITE
- % coverage: 10%
- Type of wrap if used: gauze fastened with an impermeable dressing encircled firmly around the trunk

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm (30-40°C) water
- Time after start of exposure: 24 hours

Duration of exposure:

24 hours

Doses:

1500, 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: observations: 30 min after dosing, then hourly for 6 hours and at least twice per day on the subsequent days. Bodyweights were recorded on day 1 (dosing), 8, 15 (or at death)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic examination

Preliminary study:

Preliminary study indicated that the LD50 was above 2000 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 2 000 mg/kg bw

Mortality:

2000 mg/kg bw: 2/5 males and 3/5 females died
1500 mg/kg bw: no mortalities

Clinical signs:

There were no dermal reactions at the site of application in any of the treated animals.
Animals treated at 2000 mg/kg bodyweight appeared normal on the day of dosing. Signs of intoxication to treatment were first observed on
Day 2 of the study. These signs were pilo-erection, unsteady gait, lethargy and ataxia. The rabbits were in a collapsed state at this time. Reactions seen shortly after dosing in rabbits treated at 1500 mg/kg were pilo-erection, unsteady gait and lethargy.
Recovery of survivors as judged by external appearance and behaviour was generally complete in animals treated at 1500 mg/kg bodyweight by Day 3 and in animals treated at 2000 mg/kg bodyweight between Days 5 and 7. One male rabbit 736 (2000 mg/kg bodyweight) still showed
pilo-erection on Day 7 and was still thin in appearance on Day 14. A further male rabbit 1410 (1500 mg/kg bodyweight) was not eating on
Days 5 and 6.

Body weight:

A bodyweight loss was recorded on Day 8 for one male (2000 mg/kg bodyweight) and one male (1500 mg/kg bodyweight) and on
Day 15 for one male and one female (2000 mg/kg bodyweight).
Bodyweight gains were recorded for all other surviving rabbits on Days 8 and 15.

Gross pathology:

Autopsy amongst rabbits dosed at 2000 mg/kg bodyweight revealed pale areas on liver lobes containing purulent material in one male and areas of consolidation in the left lung of one male.
All other autopsy findings were normal.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

For additional information, please also refer to the chapter "Specific investigations - neurotoxicity".

Justification for classification or non-classification

Following oral administration, the most sensitive species are mouse and dog. The data available on dog is considered of limited value for classification since only 2 animals were tested per dose level. Therefore, classification is based on the effects observed in mouse. In accordance with Regulation (EC) 1272/2008, classification for acute toxicity oral Cat. 4 (H302) is warranted.  

Based on the data available data on acute inhalation toxicity and in accordance with Regulation (EC) 1272/2008, classification for acute toxicity inhalation Cat. 4 (H332) is warranted. 

Following single dermal administration, the most sensitive species is the rabbit. Based on the data available and in accordance with Regulation (EC) 1272/2008, classification for acute toxicity dermal Cat. 4 (H312) is warranted.  

Based on evaluation of the whole database, including human data, and in accordance with Regulation (EC) 1272/2008, an additional classification for target organ toxicity (STOT SE Cat.1; H372) is warranted to account for the effects on the nervous system after acute exposure.