Methylphosphonic acid

Endpoint summary

Description of key information

Acute oral toxicity: LD50 (male/female) rat: 1888 mg/kg bw; LD50 (female) rat:1760 mg/kg bw;  LD50 (male) rat: 2005 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:

2007

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Charles River Laboratories, Wilmington, MA
- Age at study initiation: about 7 weeks
- Weight at study initiation: 150 to 225 g
- Fasting period before study: over night
- Housing: individually, steel wire mesh cages
- Diet ad libitum
- Water ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Doses:

2000, 1750, 1500, 1000 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: prior to dosing
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 888 mg/kg bw

95% CL:

1 462 - 2 438

Sex:

male

Dose descriptor:

LD50

Effect level:

2 005 mg/kg bw

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 760 mg/kg bw

Mortality:

At 2000 mg/kg bw all deaths occurred on day 1 of the study. At 1750 mg/kg bw, one female died on day 3, one male on day 2.
No adverse clinical signs were seen in any other dose groups.

2000 mg/kg bw: 4/5 males, 5/5 females (9/10)
1750 mg/kg bw: 1/5 males, 1/5 females (2/10)
1500 mg/kg bw 0/5 males, 0/5 females (0/10)
1000 mg/kg bw 0/5 males, 0/5 females (0/10)
0 mg/kg bw 0/5 males, 0/5 females (0/10)

Clinical signs:

other: At 2000 mg/kg bw, four males and five females were hypoactive and cold to touch with laboured breathing. In addition, three males and two females were observed with convulsions and one male was observed with tremors and redness around nose/eyes.

Gross pathology:

Upon necropsy, all animals treated with 2000 mg/kg bw had at lease one gross lesion noted, including a dilated stomach, (4 m/ 2 f), a dilated small and large intestine (3 m/ 3 f) kidney foci (1 m/ 1 f) and enlarged stomach (3 f). At 1750 mg/kg bw 4 m and 2 f had no gross lesions, 1 m had dilated stomach and dilated intestine filled with yellow liquid. Two females had pigmented ovaries and 1 f had a dilated thin-walled stomach filled with fluid and mucosa. as well as a tan liver focus. Ovary pigmentation was observed in 2 f that had not died and in the male that died the stomach was dilated and fluid-filled, with a thin wall , mucus covering and black pigment. The small intestine was dilated and filled with yellow fluid and the liver exhibited a tan lateral lobe focus. At 1500 mg/kg, one female had bilateral red ovary pigmentation. At 1000 mg/kg no gross lesions were observed.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

LD50 was determined to be 1888 mg/kg bw (females: 1760 mg/kg bw; males: 2005 mg/kg bw).

Executive summary:

The acute oral toxicity of methylphosphonic acid was evaluated in a study conducted according to guideline EPA.OPPTS 870. 1100. For each treatment group 5 males and five females were randomly assigned to treatment and control groups. Animals were administered the test article or vehicle control via oral gavage following an overnight fasting period. The following doses were used: 2000, 1750, 1500, 1000 mg/kg bw. At 2000 mg/kg bw all deaths occurred on day 1 of the study. At 1750 mg/kg bw, one female died on day 3, one male on day 2. No deaths occurred in any other dose groups. Based on the findings of the study, the LD50 was determined to be 1888 mg/kg bw (females: 1760 mg/kg bw; males: 2005 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 888 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

Acute oral toxicity of MPA has been investigated by a number of laboratories, since MPA is used as a tracer for the use of chemical warfare agents (CWAs). Unfortunately, a number of study reports done by the U.S. Army are not public available, but the results of the studies have been reviewed by a number of authors discussing the problems associated with CWAs. The study report chosen as key study is the only one dealing with MPA and providing sufficient information to assess the acute toxicity of the chemical. The study identified an overall lethal dose (LD50) in the rat of 1888 mg/kg bw. Clinical signs observed and lesions noted at necropsy are in line with signs of toxicity and lesions observed frequently after acute toxic ingestion of chemicals in the rat. Most lesions are associated with digestive organs the stomach, the intestine and the liver as the primary organ of detoxification. Additionally to these study reports two results of acute oral toxicity studies have been cited in literature, one demonstrating an acute oral toxicity to the rat of >2000 mg/kg bw (Finlay 2004) and one demonstrating an LD50 value of >5000 mg/kg bw in the rat and the mouse Williams 1987). None of these study reports are currently available and experimental details are not provided by the authors of the review (Munro et al.).

Acute inhalation toxicity:

According to Regulation (EC) No. 1907/2006, Column 2 Adaptation to the Column 1, 8.5, the acute toxicity study is not needed to be conducted if the substance is classified as corrosive to the skin. MPA has been classified as corrosive owing to its pH of 0.9 (70% aqueous solution). Further, MPA is relatively non-volatile substance (MPA melts at 105 °C and vapour pressure 0.000267 Pa), hence exposure via inhalation will be low. Also, MPA is highly soluble in water, hence if inhaled may get cleared by mucociliary mechanism of respiratory tract, thereby further reducing the absorption. Taking into consideration above arguments, low toxicity is expected for inhalation exposure of MPA and the acute inhalation toxicity study is considered to be scientifically not necessary.

Acute dermal toxicity:

According to Regulation (EC) No. 1907/2006, Column 2 Adaptation to the Column 1, 8.5, the acute toxicity study is not needed to be conducted if the substance is classified as corrosive to the skin. Dermal penetration studies with a substance containing about 50 % of MPA demonstrated no significant uptake through the skin. Taking the corrosive properties of the test substance into account, moderate to strong irritating or corrosive effects to the skin would be the major sign of toxicity upon dermal exposure to the test substance. The transdermal uptake of the test substance through exposed skin areas is considered to be not sufficient to reach toxic levels of the chemical in the body. Therefore, testing for acute dermal toxicity is considered to be scientifically not necessary. Appropriate labelling of the test substance for acute dermal effects is not considered since labelling for acute oral toxicity as well as for corrosive effects is sufficient to communicate the toxic effects of the substance.

Justification for classification or non-classification

Based on the data provided by Watson et al. (2007), the substance needs to be classified as slightly toxic upon acute oral ingestion i.e. Acute toxic Class IV (oral) in accordance with CLP Regulation. Since no data for acute dermal and inhalation toxicity are available and the physical chemical properties of the substance demonstrate a very low vapour pressure as well as a negligible low skin penetration rate, the substance will not be classified for acute dermal or inhalation toxicity.