[ethane-1,2-diylbis[nitrilobis(methylene)]]tetrakisphosphonic acid

Endpoint summary

Description of key information

An acute oral toxicity LD50 of 6900 mg/kg is reported in a report which was carried out according to a protocol similar to guideline but which pre-dated GLP (Younger Laboratories 1968). The sample was fed as a 25% solution-suspension in corn oil at 5010, 6310, 7940 and 10000 mg/kg, with necropsy findings of inflammation of the gastric mucosa and liver hyperemia.

A reliable acute inhalation study conducted according to a protocol equivalent to current guideline reports an LC50 value of 4.60 mg/l (3.78-5.17 mg/l) of dust (Biodynamics 1980). The study was not compliant with GLP.

An acute dermal LD50 value of >5010 mg/kg was reported in a study which was conducted according to an appropriate test protocol, but which pre-dated GLP. No real symptoms of acute toxicity were noted (Younger Laboratories 1968). The test material was administered as a 25% solution in corn oil at 501, 794, 1260, 2000, 3160, 5010 mg/kg.

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

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

Principles of method if other than guideline:

After the approximate Minimum Lethal Dose was determined, groups of male and female rats were fed in increasing doses at increments of 0.1 fractional log intervals at four levels designed to blanket the toxicity range thereby supplying data for calculation of the LD50. The length of the observation period was not specified.

GLP compliance:

no

Test type:

other:

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Sample fed as a 25% solution-suspension in corn oil

Doses:

5010, 6310, 7940, 10000 mg/kg

No. of animals per sex per dose:

3+2 M/F per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: not specified

- Frequency of observations and weighing: no data

- Necropsy of survivors performed: not specified
.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 6 900 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 6070-7865 mg/kg

Mortality:

See table 1. Survival time was 4 hours to approximately 24 hours.

Clinical signs:

other: Toxic symptoms included diarrhea, loss of appetite and increasing weakness.

Gross pathology:

At autopsy, there was inflammation of the gastric mucosa in addition to liver hyperemia.

Other findings:

None reported.

Table 1: Number of animals dead and time range within which mortality occurred

Dose (mg/kg bw)	Mortality (# dead/total)			Time range of deaths (hours)
	Male	Female	Combined
5010	0/2	0/3	0/5
6310	1/3	1/2	3/5	4-24h
7940	2/3	2/2	4/5	4-24h
10000	3/3	2/2	5/5	4-24h

 

Interpretation of results:

GHS criteria not met

Conclusions:

An acute oral toxicity LD50 of 6900 mg/kg is reported in a report which was carried out according to a protocol similar to guideline but not in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

6 900 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:

supporting study

Study period:

1980

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: River Breeding Laboratories, Wilmington, Massachusetts

- Animal weight: 239-263g (males), 218-240g (females)

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Wright Dust Feed cylinders using a carver hydraulic press
- Exposure chamber volume: 26.5 litre chamber
- Source and rate of air: 15 litres / minute
- System of generating particulates/aerosols: The test material was sieved through a #60 mesh sieve and packed into the Wright Dust cylinders using the Carver hydraulic press operating at 200 pounds per square inch. Dry air was passed through a modified Wright Dust Feed generator with a specially machined cutting blade to generate a dust laden atmosphere.


TEST ATMOSPHERE
- Brief description of analytical method used: The cylinders, cutting blade and nozzle were weighed before and after the exposure. The difference in weight represented the total amount of test material delievered into the test chamber; this divided by the total volume of air delivered yielded the nominal exposure concentration. Air samples were withdrawn each hour for gravimetric determination of the airborne concentration; these samples were withdrawn for determination of the particle size distribution using castella Cascade Impactor.
- Samples taken from breathing zone: yes

- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.7 microns / 2-2.7

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

4.60 mg/l (3.78-5.17 mg/l) i.e. approximately 30% of the nominal value which was 15.5 mg/l

No. of animals per sex per dose:

5M, 5F

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for abnormal signs before exposure, every 15 minutes for first hour, hourly thereafter, upon removal from the chamber hourly for four hours post-exposure and daily thereafter for 14 days. Individual body weights for all rats were recorded on day 0 (prior to exposure) and on days 1,2,4,7 and 14.

- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.6 mg/L air (analytical)

Based on:

test mat.

Remarks on result:

other: dust

Mortality:

There were no mortalities.

Clinical signs:

other: Beginning ca. 15 minutes after initiation of exposure: hypoactivity, salivation, red nasal discharge, swollen eyelids, lacrimation, rapid or laboured respiration and soft stool were observed. Due to the density of the dust cloud visibility of the animals

Body weight:

Transient body weight losses were seen in most rats but in most cases these had recovered to the starting weights by day 4 or 7. Weight gains in the second week were within the range of normal expectation.

Gross pathology:

At necropsy lung discolouration was seen in all males and two females. These are common macropathological entities in this strain of rat but the incidence in males may reflect a slight response to treatment, especially if viewed in conjunction with the in vivo evidence of irritant effects on the ocular, buccal, nasal and respiratory mucosae on the day of exposure.

Other findings:

None reported.

Interpretation of results:

GHS criteria not met

Conclusions:

An LC50 value of 4.60 mg/l (3.78-5.17 mg/l) i.e. approximately 30% of the nominal value which was 15.5 mg/l is reported in a reliable study conducted according to a protocol equivalent to current guideline. The study was not compliant with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

4 600 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1968

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

The number of animals tested per dose was one.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

Similar to version adopted in 1987

Principles of method if other than guideline:

The diluted compound was applied in increasing doses at increments of 0.2 fractional log intervals to the skin of the rabbits. Only one rabbit was tested per dose.

GLP compliance:

no

Test type:

other:

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Housing: individual cages

Type of coverage:

occlusive

Vehicle:

corn oil

Details on dermal exposure:

No data.

Duration of exposure:

24 hours

Doses:

25% solution in corn oil at 501, 794, 1260, 2000, 3160, 5010 mg/kg

No. of animals per sex per dose:

1 animal per dose, either male or female.

Control animals:

no

Details on study design:

- Duration of observation period following administration: no data

- Necropsy of survivors performed: no

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 010 mg/kg bw

Based on:

test mat.

Mortality:

There were no mortalities.

Clinical signs:

other: No real symptoms of acute toxicity were noted. Weakness was at a minimum and there was no nervousness.

Gross pathology:

No necropsy.

Other findings:

None reported.

The compound was not absorbed to any great extent.

Interpretation of results:

study cannot be used for classification

Conclusions:

An acute dermal LD50 value of >5010 mg/kg was reported in a study which was conducted according to an appropriate test protocol, but not in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 010 mg/kg bw

Additional information

The most recent and reliable studies were selected as key. The available supporting studies are concurrent with the key studies,

and support the low acute toxicity of EDTMP-H (CAS 1429-50-1).

Although the final LC50 of the acute inhalation toxicity study to dust exposure is determined to be >4.6 mg/l which is below the threshold value for classification, the range (3.78-5.17 mg/l) from which the mean was derived, the lack of mortalities and the overall results of the acute toxicity endpoints indicate low acute toxicity of the test material.

Justification for classification or non-classification

Based on the available information, no classification is required for acute toxicity for EDTMP acid according to Regulation (EC) No. 1272/2008.