Trisodium dihydrogen -N,N-[bis[2-[bis(carboxylatomethyl)amino]ethyl]]glycinate

Endpoint summary

Description of key information

Using a read-across extrapolation approach from OECD 401 and 402 guideline limit studies on the structural analogue DTPA pentapotassium salt, DTPA trisodium salt is predicted to be of low acute oral and dermal toxicity with LD50 values in excess of 2,000 mg/kg.bw. The two substances are structurally similar and have the same metal ion, chelating mode of action.

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:

August 1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No data on batch number and composition; basic data given, comparable to guidelines (max reliability score can be 2)

Justification for type of information:

The source substance (DTPA 5K) and the target substance (DTPA 3Na) are the pentapotassium and trisodium salts of the same organic acid and are therefore structurally very similar. The purity/impurity profile for the source material is not characterised in the acute oral toxicity robust summary, but since the target material is > 99.9% pure and contains no detectable impurities, the extrapolation of acute oral toxicological properties from the source material to the target material is considered valid as a ‘worst case' scenario. The source material acute oral toxicity study was conducted according to OECD test guideline 401 and is considered reliable with restrictions (Category 2).

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Principles of method if other than guideline:

Limit test was carried out at 5000 mg/kg bw instead of 2000 mg/kg bw.

GLP compliance:

yes

Remarks:

audited in-house

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HC/CFY (Remote Sprague Dawley)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hacking and Churchill Ltd. Huntingdon, UK
- Age at study initiation: 4-6 weeks
- Weight at study initiation: 114-132 g
- Fasting period before study: overnight prior to exposure
- Housing: in groups by sex in metal cages with wire mesh floors
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: for a minimum of 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 64 (mean)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 3 To: 17 August 1984

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Test material applied as received.
DOSE VOLUME APPLIED: 3.76 ml/kg

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

2/sex in preliminary study
5/sex in main study

Control animals:

no

Details on study design:

- Duration of observation period following administration: 5 days (preliminary study), 14 days (main study)
- Frequency of observations and weighing: frequently on day of dosing, at least twice on following days. Weekly weighing.
- Necropsy of survivors performed: yes (main study)

Statistics:

Not needed because of limit test

Preliminary study:

No mortality (0/4)

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 5 000 mg/kg bw

Mortality:

No mortality (0/10)

Clinical signs:

other: All animals (10/10): piloerection, hunched posture, abnormal gait, lethargy, decreased respiration rate, pallor of extremities, increased salivation, diarrhoea. Recovery was complete on day 5.

Gross pathology:

Terminal autopsy findings were normal.

Other findings:

None.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material is not toxic as the acute lethal dose was > 5000 mg/kg bw

Executive summary:

The study was performed to assess the acute toxicity of the test material following a single oral administration to the Sprague-Dawley strain rat. The procedure permitted identification of the highest dose which could be administered without causing compound related mortality) . The study was performed according to OECD guideline 401. Following a preliminary test, a group of ten animals (five male and five female) was given a single, oral dose of the test material at a dose level of 5000 mg/kg bodyweight. The animals were observed for 14 days after the day of dosing and were then killed for gross pathological examination. There were no deaths. Clinical signs of toxicity noted were piloerection, hunched posture, abnormal gait, lethargy, decreased respiratory rate, pallor of extremities, increased salivation, and diarrhoea; recovery was complete on day 5.

All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy. The acute median lethal dose (LD50) of the test material was found to be greater than 5000 mg/kg bodyweight. The test material was considered not to have significant acute toxicity and does not require classification as harmful, toxic or very toxic according to the GHS scheme.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The source substance (DTPA 5K) and the target substance (DTPA 3Na) are the pentapotassium and trisodium salts of the same organic acid (Diethylenetriaminepentaacetic acid) and are therefore structurally very similar. The two substances have comparable high water solubility and would be rapidly and fully dissociated into a common anion and sodium and potassium cations in the gastro-intestinal tract. The absorption, distribution and metabolism of the two substances would therefore be expected to be essentially identical. The common organic acid moiety has a chelating mode of action and would be expected to exert long-term, secondary adverse effects by the sequestration of essential metal ions, rather than specific acute organ toxicity. Sodium and potassium are normal physiological components of the body and are considered not to have any significant impact on the robustness of the read-across hypothesis.

Reason / purpose for cross-reference:

read-across source

Specific details on test material used for the study:

> 99% pure

Species:

rat

Route of administration:

oral: gavage

Vehicle:

not specified

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Conclusions:

The acute oral toxicty of DTPA trisodium salt is predicted to be in excess of 5,000 mg/Kg.bw.

Executive summary:

The acute oral toxicity of DTPA pentapotassium salt is low with an LD50 value in excess of 5,000 mg/kg (OECD 401 guideline). DTPA pentapotassium salt is structurally similar to DTPA trisodium salt and the analogue has a similar chelating mode of action to the target substance. Based on a read-across approach DTPA trisodium salt is predicted to have similar low acute oral toxicity, with an LD50 in excess of 5,000 mg/kg.bw.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 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 exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Justification for type of information:

According to the specific rules for adaptation in column 2 of section 8.5 (Annex VIII), testing by a third acute route is not required if exposure to humans via inhalation is not likely. DTPN 3Na has a low vapour pressure (2.6 x 10-4 Pa at 25 °C.) and is imported and used as a 45-47% (w/w) solution in water (greater than 500 g/L). The potential for human exposure via the inhalation route is very limited.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No data on batch number and composition; basic data given; comparable to guidelines/standards (max. reliability score can be 2)

Justification for type of information:

The source substance (DTPA 5K) and the target substance (DTPA 3Na) are the pentapotassium and trisodium salts of the same organic acid and are therefore structurally very similar. The purity/impurity profile for the source material is not characterised in the acute dermal toxicity robust summary, but since the target material is > 99.9% pure and contains no detectable impurities, the extrapolation of acute dermal toxicological properties from the source material to the target material is considered valid as a ‘worst case' scenario. The source material acute dermall toxicity study was conducted according to OECD test guideline 402 and is considered reliable with restrictions (Category 2).

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Remarks:

audited in-house

Test type:

standard acute 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: Interfauna UK, Ltd., Huntingon, UK
- Age at study initiation: 7-10 weeks
- Weight at study initiation: 200-249 g
- Fasting period before study: no
- Housing: individually in metal cages with wire mesh floor
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 50 (mean)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 13 To: 27 January 1987

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: ca. 10% of total body surface
- % coverage: 10% of total body surface
- Type of wrap if used: gauze held in place with an impermeable dressing encircled around the trunk


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


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.20 mL/kg bw
- Concentration (if solution): 90% w/v paste in distilled water
- Constant volume or concentration used: 2.20 mL/kg bw
- For solids, paste formed: yes


VEHICLE
- Amount(s) applied (volume or weight with unit): see above (2.20 mL/kg bw)
- Concentration (if solution): 90% w/v

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations twice daily, BW weekly.
- Necropsy of survivors performed: yes

Preliminary study:

Not performed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality

Clinical signs:

other: No clinical signs of systemic reactions present.

Gross pathology:

No macroscopic changes noted.

Other findings:

Dermal responses:
The sites of application showed no general inflammatory responses, but 9 animals developed multiple minute encrustations on the
treated skin. These were first apparent on day 4 and resolved completely by day 9.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal LD50 is > 2000 mg/kg bw.

Executive summary:

The study was performed to assess the acute toxicity of the test material following a single dermal administration to the Sprague-Dawley

strain rat. The procedure permitted identification of the LD50 value. The study was performed according to OECD guideline 402 and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

A group of ten animals (five male and five female) was given a single, dermal dose of the test material (lasting 24 hours) at a dose level of 2000 mg/kg bodyweight. The animals were observed for 14 days after the day of dosing and were then killed for gross pathological examination. There were no deaths. No clinical signs of systemic toxicity were noted. No inflammatory responses were noted, but 9/10 animals showed multiple minute encrustations on the treated skin on days 4 -9. Male animals showed expected gains in bodyweight over the study period, low body weight gains were noted in 4/5 females. No abnormalities were noted at necropsy.

The acute median lethal dose (LD50) of the test material was found to be greater than 2000 mg/kg bodyweight.

The test material was considered not to have significant acute toxicity and does not require classification as harmful, toxic or very toxic according to the EC scheme and GHS scheme.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The source substance (DTPA 5K) and the target substance (DTPA 3Na) are the pentapotassium and trisodium salts of the same organic acid (Diethylenetriaminepentaacetic acid) and are therefore structurally very similar. The two substances have comparable high water solubility and would be dissociated into a common anion and sodium or potassium cations during dermal administration, with consequent low expected absorption. The common organic acid moiety has a chelating mode of action and would be expected to exert potential, long-term, secondary, adverse, systemic effects by the sequestration of essential metal ions, rather than specific acute organ toxicity. The neutral pH of the target substance would ameliorate any potential local dermal, irritant effects of the alkaline source substance

Reason / purpose for cross-reference:

read-across source

Specific details on test material used for the study:

> 99% purity

Species:

rat

Type of coverage:

occlusive

Vehicle:

water

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Limit test dosage

Conclusions:

The acute dermal toxicity of DTPA 3Na was predicted to be > 2,000 mg/kg. bw.

Executive summary:

The acute dermal toxicity of DTPA pentapotassium salt is low with an LD50 valvue in excess of 2,000 mg/kg (OECD 402 test). DTPA pentapotassium salt is structurally similar to DTPA trisodium salt and the analogue has a similar chelating mode of action to the target substance. Based on a read-across approach DTPA trisodium salt is predicted to have similar low acute dermal,toxicity, with an LD50 in excess of 2,000 mg/kg.bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

The acute oral and dermal toxicities of DTPA pentapotassium salt are low, with LD50 values in excess of 5,000 mg/kg and 2,000 mg/kg, respectively (OECD 401 and 402 limit tests). DTPA pentapotassium salt is structurally similar to DTPA trisodium salt and the analogue has the same metal sequestering mode of action as the target substance. The counter ions are not considered to have any significant effect on the toxicities of the two substances. Based on a read-across approach, DTPA trisodium salt is predicted to have similarly low acute oral and dermal toxicity.

 

 

 

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Justification for classification or non-classification

DTPA trisodium salt is considered not to meet the CLP criteria for classification for acute oral or dermal toxicity.