Dimethyl phosphonate

Endpoint summary

Description of key information

-Acute toxicity oral (rat) LD50 (female) = 3040 mg/kg bw; LD50 (male) = 3283 mg/kg bw, method similar to OECD TG 401;
-Acute toxicity oral (mouse) LD50 (male) = 2815 mg/kg bw; method similar to OECD TG 401
-Acute toxicity: dermal : waiver
-Acute toxicity: inhalation (rat, mouse, guinea pig) LC50 > 7100 mg/m³, limit test, no guideline followed.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (no GLP study, no environmental conditions reported, body weights not recorded, fasting period too short). However, according to OECD SIDS a reliability of 1 was given.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

(no GLP study, no environmental conditions reported, body weights not recorded).

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 6 weeks.
- Fasting period before study: yes. Rats were fasted overnight before dosing.
- Housing: 5 animals per cage. Cage: Polycarbonate (Lab Products, Inc., Garfield, NJ, USA).
- Diet (e.g. ad libitum): Purina Lab Chow meal (St. Louis, MO, USA); available ad libitum (except during fasting period).
- Water (e.g. ad libitum): Acidified with HCl (pH 2.6) tap water; available ad libitum.
- Acclimation period: 2 weeks.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 259.03, 378.85, 556.82, 817.62, 1200.00 mg/mL
- Justification for choice of vehicle: the vehicle was chosen because of the potential of the test substance for chemical hydrolysis in water.
- Amount of vehicle (if gavage): 5.675 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 5.675 mL/kg bw

DOSAGE PREPARATION: Appropriate amounts of dimethyl hydrogen phosphite and corn oil were added by pipette to test tube; mixture was shaken for 1 min; mixtures were resuspended before dosing.

Doses:

1470, 2150, 3160, 4640, 6810 mg/kg bw.

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: observed immediately after dosing, 1 h and 4 h later, and 1 X d thereafter for 14 d.
- Necropsy of survivors performed: yes.
- Other examinations performed: clinical signs, necropsy.

Statistics:

The LD50 values as determined by the Spearman-Karber method (Finney, 1978. Statistical Method in Biological Assay, 3rd ed. New York: MacMillan
Publishing Co, pp. 394-401).

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

3 283 mg/kg bw

Based on:

test mat.

95% CL:

2 729 - 3 949

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

3 040 mg/kg bw

Based on:

test mat.

95% CL:

2 527 - 3 656

Mortality:

Number of deaths among male animals at each dose:
- 1470 mg/kg bw: 0/5
- 2150 mg/kg bw: 0/5
- 3160 mg/kg bw : 2/5
- 4640 mg/kg bw : 5/5
- 6810 mg/kg bw : 5/5

Number of deaths among female animals at each dose:
- 1470 mg/kg bw: 0/5
- 2150 mg/kg bw: 0/5
- 3160 mg/kg bw: 3/5
- 4640 mg/kg bw: 5/5
- 6810 mg/kg bw: 5/5

Clinical signs:

other: At dose >= 3160 mg/kg bw the following symtomps were observed: inactivity, weakness, shallow breathing.

Gross pathology:

No data

Other findings:

- Other observations: at a dose >= 3160 mg/kg bw: gas was found in the stomach and/or intestine.

Table 1. Survival of rats in the single-administration gavage studies of dimethyl hydrogen phosphite (a)

	Dose (mg/kg)	Survival (b)
MALE
	1470	5/5
	2150	5/5
	3160	3/5
	4640	0/5
	6810	0/5
FEMALE
	1470	5/5
	2170	5/5
	3160	2/5
	4640	0/5
	6810	0/5

(a) Body weights were not recorded.

(b) Number surviving/number initially in the group; all deaths occurred on day 1.

Based on the study results and according to DSD-DPD and CLP classification criteria, the test substance is not to be classified.

Interpretation of results:

GHS criteria not met

Executive summary:

The oral LD50 of dimethyl phosphonate was determined by acute oral toxicity study conducted with a method similar to OECD guideline 401 with deviations (no GLP study, environmental conditions not reported; body weights not recorded; fasting period too short). The LD50 of dimethyl phosphonate was calculated to be 3040 mg/kg bw in female Fischer 344 rats (95% confidence limits of 2627-3656 mg/kg) and 3283 mg/kg bw in male rats (95% confidence limits of 2729-3949 mg/kg). Clinical signs of toxicity, which have been observed after oral administration of dimethyl phosphonate, were inactivity, weakness, prostration and shallow breathing in rats. Based on the study results, the test substance is not to be classified.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 040 mg/kg bw

Quality of whole database:

Comparable to guideline study with acceptable restrictions (no GLP study, no environmental conditions reported, body weights not recorded, fasting period too short). However, according to OECD SIDS a reliability of 1 was given.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating conc.

Value:

7 100 mg/m³ air

Quality of whole database:

Basic data given. Adopted from OECD SIDS. The original source is available and has been reviewed.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral

The oral LD50 of dimethyl phosphonate was 3040 mg/kg bw in female Fischer 344 rats and 3283 mg/kg bw in Fischer 344 male rats (NTP 1985). In B6C3F1 mice the LD50 value was 2815 mg/kg bw for males (NTP, 1985). Clinical signs of toxicity were inactivity, weakness, prostration and shallow breathing in rats and mice at dose groups of > or = 3160 mg/kg bw and > or = 2150 mg/kg bw, respectively (NTP, 1985). In male mice white opaque eyes were occasionally observed (NTP, 1985). Necropsy findings included gas in stomach and/or intestine (rats at dose groups > or = 3160 mg/kg bw) (NTP, 1985).

Inhalation

The only study of good quality was performed on ten male rats, mice and guinea pigs per test group exposed to 7100 mg/m³ dimethyl phophonate (calculated exposure concentration from air flow and net loss of material) for 6 hours. No deaths occurred. Clinical signs like occasionally labored respiration after approximately 2 hours of exposure and ptosis after 5 hours were observed in mice only. At necropsy, congestion and hemorrhage in the lungs were observed in rats.

Dermal

An old dermal study cited in OECD SIDS, 2004 reported that the dermal LD50 in male and female rabbits was calculated to be 681 mg/kg bw. This value is lower than the oral LD50s in rats and mice, and may point to the fact that the rabbit may be a more sensitive species. Signs of intoxication were depression, ptosis, labored respiration, ataxia and placidity at doses of > or = 1000 mg/kg bw. At necropsy (concentrations of > or = 1000 mg/kg bw) hemorrhagic lungs, red-tinged fluid in the pleural cavity, congestion of the thymus and kidneys, edema or thickening of the mucosa of the stomach, and inflammation of a portion of the intestines were observed. The study is not reliable because of several methodological deficiencies: number of the animal tested per sex is too low (2 animals per sex); the test was performed on animals of both sexes; weight of the animals dosed is lower in comparison to that recommended in OECD TG 402; the doses used were not spaced accurately; observation period was too short, microscopic analysis was not performed; individual weights of the animals were determined just at the end of the observation period; the size of the skin area treated was not reported; the test material was applied to the closely clipped intact abdominal skin under a dental damming binder placed around the trunk of the animal. Therefore this data source is not considered acceptable for assessment.

However, as stated in the Annex VIII of REACH legislation, testing by the dermal route is only appropriate if: (1) inhalation of the substance is unlikely; and (2) skin contact in production and/or use is likely; and (3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. According to physico-chemical parameters, an inhalative exposure is likely. Thus, a dermal study must not be conducted.

Justification for classification or non-classification

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.