Sodium salts of [[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid (1-3 Na:1)

Administrative data

Description of key information

There are no acute toxicity data for DTPMP (1-3Na), therefore key data for DTPMP (5-7Na) have been used. Reliable data are available for both the oral and dermal routes from studies conducted with aqueous solutions of DTPMP (5-7Na). See Section 13 for the read-across justification.

 

In the key acute oral toxicity study with DTPMP (5-7Na), conducted according to a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP (5-7Na) was ≥10 ml/kg bw in rats (equivalent to ≥5838 mg active salt/kg bw and ≥4612 mg active acid/kg bw based on an aqueous solution containing 33% active acid) (SafePharm Laboratories, 1982a, reliability score 1).

 

In the key acute dermal toxicity study with DTPMP (5-7Na), conducted according to a protocol comparable to OECD Test Guideline 402 and according to GLP, the LD50 for DTPMP (5-7Na) was ≥10 ml/kg bw (equivalent to 5838 mg active salt/kg bw and 4612 mg active acid/kg bw based on an aqueous solution containing 33% active acid) in rats (SafePharm Laboratories, 1982c, reliability score 1).

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:

19.08.1982 to 02.09.1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Method: Safepharm protocol (number GM 11/80/21A). Broadly compatible with the now-deleted OECD Test Guideline 401.

GLP compliance:

yes

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: A. Tuck and Sons Ltd., Battlesbridge, Essex, UK.
- Age at study initiation: 4-6 weeks
- Weight at study initiation: Males: 98-120 g; Females: 90-115 g
- Fasting period before study: Overnight prior to dosing
- Housing: Groups of five in polypropylene cages
- Diet (e.g. ad libitum): "Standard laboratory rodent diet", ad libitum
- Water (e.g. ad libitum): Mains tap water, ad libitum
- Acclimation period: Minimum of five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 2
- Humidity (%): 65-72
- Air changes (per hr): Approx. 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 19.08.1982 to 02.09.1982

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

Doses:

3 and 10 ml/kg bw

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily observations and weighing on days 0, 7 and 14.
-Further observations were made 0.5, 1, 2, 3, 4, and 5 hours following dosing for mortalities and signs of overt toxicity.
-All surviving animals were killed on day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic examination of abnormal organs.

Statistics:

Not required as no deaths occurred.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 10 mL/kg bw

Based on:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 5 838 mg/kg bw

Based on:

act. ingr.

Remarks:

active salt

Remarks on result:

other: equivalent to 4612 mg active acid/kg bw/day

Mortality:

No deaths occurred.

Clinical signs:

irregular respiration

lethargy (hypoactivity)

other:  

Body weight:

other body weight observations

Remarks:

Bodyweight gains of all rats were considered to be within normal limits, apart from one male dosed at 3.0 ml/kg. This decrease in weight gains was not seen in the higher dosage group, and therefore cannot be considered to be test substance related.

Gross pathology:

No abnormal findings.

Other findings:

None reported.

Calculation of equivalent dose:

1) average specific gravity of DTPMP (5-7Na) = 1.39 (email, I. Bartlett to R. Wildey, 09.04.2003), 

2) DTPMP (5-7Na) composed of 42% active salt including minor components, remainder presumed to be water (derived from online data sheet).

For purposes of comparison with other Group 3 results, >5838 mg active salt/kg bw is equivalent to >4612 mg parent acid (DTPMP, CAS 15827-60-8)/kg bw.

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute oral toxicity study, conducted using a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP (5-7Na) was ≥10 ml/kg bw in rats (equivalent to ≥5838 mg active salt/kg bw and ≥4612 mg active acid/kg bw based on an aqueous solution containing 33% active acid).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 838 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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

Study period:

03.08.1982 to 17.08.1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

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: A. Tuck and Sons Limited, Battlesbridge, Essex, UK.
- Age at study initiation: 6 to 8 weeks
- Weight at study initiation: Males: 221-235 g; Females: 202-234 g.
- Fasting period before study: No
- Housing: Individually (during exposure) or in groups of five in polypropylene cages.
- Diet (e.g. ad libitum): Standard laboratory rodent diet (Rat diet provided by University of Nottingham), ad libitum
- Water (e.g. ad libitum): Mains tap water, ad libitum
- Acclimation period: Minimum of five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 65-75
- Air changes (per hr): Approximately 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 03.08.1982 to 17.08.1982

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal, lateral and ventral regions.
- % coverage: No data
- Type of wrap if used: Elastic adhesive bandage backed with aluminium foil.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 ml/kg bw

Duration of exposure:

24 hours

Doses:

10 ml/kg bw

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Skin responses were evaluated 0.5, 1, 2, 3, 4, and 5 hours after removal of the patch and residual test substance, and each day for 14 days.  Body weight was measured on days 0, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: Macroscopic examination.

Statistics:

Not required as no deaths occurred.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 10 mL/kg bw

Based on:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 5 838 mg/kg bw

Based on:

act. ingr.

Remarks:

active salt

Remarks on result:

other: equivalent to 4612 mg active acid/kg bw

Mortality:

No deaths.

Clinical signs:

lethargy (hypoactivity)

Body weight:

other body weight observations

Remarks:

Body weight gains appeared to be within normal limits throughout the two week observation period.

Gross pathology:

No abnormal findings.

Other findings:

None

Calculation of equivalent dose: Based on 

1) average specific gravity of DTPMP (5-7Na) = 1.39 (email, I. Bartlett to R. Wildey, 09.04.2003), 

2) DTPMP(5-7Na) composed of 42% active salt including minor components, remainder presumed to be water (derived from online data sheet).

An error in the study report: the clinical observations section reports that lethargy was observed in one male animal only.  Appendix I (Individual clinical observations) shows that this symptom was also observed in one female animal.

For purposes of comparison with other Group 3 results, ≥5838 mg active salt/kg bw is equivalent to ≥4612 mg active acid (DTPMP, CAS 15827-60-8)/kg bw.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute dermal toxicity study, conducted according to a protocol comparable to OECD Test Guideline 402 and according to GLP, the LD50 for DTPMP (5-7Na) was ≥10 ml/kg bw (equivalent to 5838 mg active salt/kg bw and 4612 mg active acid/kg bw based on an aqueous solution containing 33% active acid) in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 838 mg/kg bw

Additional information

Acute toxicity studies were conducted using aqueous solutions of DTPMP (5-7Na) and LD50 values are reported on the basis of test material as well as the equivalent doses expressed as active acid and active salt.

 

In the key acute oral toxicity study with DTPMP (5-7Na) (aqueous solution containing 33% w/w active acid; composed of 42% w/w active salt), conducted according to a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP (5-7Na) was ≥10 ml/kg bw in rats (equivalent to ≥5838 mg active salt/kg bw and ≥4612 mg active acid/kg bw; calculated as 5838 mg DTPMP (5-7Na)/kg * 0.79 = 4612 mg DTPMP-H/kg body weight) (SafePharm Laboratories, 1982a). In the study 5 male and 5 female rats were given a single oral gavage dose of 3 or 10 ml DTPMP (5-7Na)/kg bw. Following administration, the animals were observed daily for clinical signs of toxicity and the animals were weighed on study days 0, 7 and 14. At the end of the 14-day observation period, the animals were sacrificed and subject to gross pathological examination. No deaths occurred during the study. At 3 ml/kg bw the general signs of toxicity in all animals included piloerection, hunched posture and lethargy for the first day after dosing. On day 2 after dosing, all animals appeared normal. At 10 ml/kg bw the general signs of toxicity in all animals included piloerection, hunched posture, lethargy and decreased respiratory rate shortly after dosing.  All male and two female test animals also suffered ptosis.  From day 4 after dosing, no abnormal symptoms were observed in any animal. No macroscopic abnormalities observed at necropsy.

 

In the first supporting acute oral toxicity study with DTPMP (5-7Na) (aqueous solution containing 33% w/w active acid; composed of 42% w/w active salt), conducted according to a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP (5-7Na) was <15 ml/kg bw (equivalent to <8757 mg active salt/kg and 6918 mg active acid/kg bw; calculated as 8757 mg DTPMP (5-7Na)/kg * 0.79 = 6918 mg DTPMP-H/kg body weight) in the rat (SafePharm Laboratories, 1982b). In the study 5 male and 5 female rats were given a single oral gavage dose of 15 ml DTPMP (5-7Na)/kg bw. The animals were observed at 0.5, 1, 2, 3, 4, and 5 hours after dosing, and each day for 14 days. Body weight was measured on days 0, 7, and 14. At the end of the 14-day observation period, the animals were sacrificed and subject to gross pathological examination. Nine animals died within two days after dosing. General signs of toxicity in all animals included piloerection, abnormal body carriage hunched posture), lethargy, decreased respiratory rate and ptosis shortly after dosing.  Also, diarrhoea and ataxia in three males and two females, and convulsions in one male were observed. From day 8 after dosing, no abnormal symptoms were observed in the surviving animal (a female). Macroscopic abnormalities in all animals that died during the study included congestion and/or haemorrhage of the lungs were observed. Also haemorrhage of the glandular region of the stomach and/or small intestine in 8 animals, pallor of organs (spleen, kidneys, liver) in 6 animals, injection of the blood vessels (no further explanation given in the report) of the small intestine in 1 animal, testicles very swollen in 1 animal were observed.  No macroscopic abnormalities were observed at necropsy of surviving animal.

 

In a supporting acute oral toxicity study reported with DTPMP (5-7Na) (composed of 43% w/w active salt including minor components, 57% w/w water; active acid content not specified), conducted prior to the adoption of OECD Test Guidelines and pre-dating GLP,  the LD50 was ≥9000 mg/kg  bw (equivalent to >3870 mg active salt/kg bw and 2979 mg active acid/kg bw; calculation based on 3870 mg DTPMP (5-7Na)/kg * 0.77 = 2979 mg DTPMP-H/kg body weight) in rat (Monsanto, 1979). In the study, 5 male and 5 female rats were given a single oral doses of 5000, 6000, 7000, 8000 and 9000 mg DTPMP (5-7Na)/kg bw (doses presumed equivalent to 2150, 2580, 3010, 3440 and 3870 mg active salt/kg bw respectively). Body weight was measured on days 0, 7 and 14 and 20 animals were necropsied. No deaths occurred during the study. Diarrhoea was observed in one animal. Many animals exhibited urine-stained fur one day after dosing. There were generally no findings upon gross examination of the internal organs except for unilateral hydronephrosis in one animal and haemorrhagic thymus in one other.

 

In another supporting acute oral toxicity study with DTPMP (5-7Na) (the test material was hand-labelled with a trade name corresponding to DTPMP (5-7Na); aqueous solution containing 33% w/w active salt; active acid content was not specified), conducted prior to the adoption of OECD Test Guidelines and pre-dating GLP, the LD50 was ≥5000 mg/kg bw (equivalent to ≥1650 mg active salt/kg bw and ≥1303 mg active acid/kg bw; calculated as 1650 mg DTPMP (5-7Na)/kg * 0.79 = 1303 mg DTPMP-H/kg body weight) in the rat (Hazleton Laboratories, 1979). In the study, two male and two female rats were given a single oral doses of 250, 500, 1000, 2000 mg DTPMP (5-7Na)/kg bw not diluted solution, therefore presumed equivalent to 82.5, 165, 330, 660, and 1650 mg active salt/kg bw, respectively, after correction for purity. Body weights were recorded before and after dosing, and clinical signs recorded for 14 days after dosing. No deaths or clinical signs of toxicity occurred during the study period. The body weights appeared normal throughout the study period. No abnormalities were noted during necropsy.

 

In the key acute dermal toxicity study with DTPMP (5-7Na) (aqueous solution containing 33% w/w active acid; composed of 42% w/w active salt), conducted according to a protocol comparable to OECD Test Guideline 402 and in compliance with GLP, the LD50 for DTPMP (5-7Na) was ≥10 ml/kg bw (equivalent to 5838 mg active salt/kg bw and 4612 mg active acid/kg bw; calculated as 5838 mg DTPMP (5-7Na)/kg * 0.79 = 4612 mg DTPMP-H/kg body weight ) in rats (SafePharm Laboratories, 1982c). In the study, 5 male and 5 female rats were subject to a single 24-hour occlusive dermal application of 10 ml DTPMP (5-7Na)/kg bw (aqueous solution containing 33% v/v active acid). Skin responses were evaluated at 0.5, 1, 2, 3, 4, and 5 hours after removal of the test patch and residual test substance, and on each day for 14 days.  Body weight was measured on days 0, 7, and 14. At the end of the 14-day observation period, the animals were sacrificed and subject to gross pathological examination. No deaths occurred during the study. Lethargy was observed in two animals (one male and one female) on the day of dosing.  From 4 hours after dosing, no abnormal symptoms were observed in any animal. Body weight were within normal limits throughout the test period. No abnormal findings were noted during necropsy.

 

In a supporting acute dermal toxicity study with DTPMP (5-7Na) (composed of 43% w/w active salt including minor components, 57% w/w water), conducted prior to the adoption of OECD Test Guidelines and pre-dating GLP, available only as a summary, the LD50 was ≥2000 mg/kg bw in rabbits (equivalent to 860 mg active salt/kg bw and 662 mg active acid/kg bw; calculated as 860 mg DTPMP (5-7Na)/kg * 0.77 = 662 mg DTPMP-H/kg body weight) (Monsanto, 1979). Details of the study were not available.

 

In a supporting acute dermal toxicity study with DTPMP (5-7Na) (the test material was hand-labelled with a trade name corresponding to DTPMP (5-7Na); aqueous solution containing 33% w/w active salt; active acid content was not specified), conducted prior to the adoption of OECD Test Guidelines and pre-dating GLP, the LD50 was ≥5ml/kg bw (equivalent to 2145 mg active salt/kg bw and 1695 mg active acid/kg bw; calculated as 2145 mg DTPMP (5-7Na)/kg * 0.79 = 1695 mg DTPMP-H/kg body weight) in the rat (Hazleton Laboratories, 1979). In the study, 5 male and 5 female rats were subject to a single 24-hour occlusive dermal application of 5 ml DTPMP (5-7Na)/kg bw. Animals were observed for overt signs of toxicity or behavioural change at 15 minutes, 1, 2, and 4 hours after treatment, and subsequently once daily for 14 days. Body weights were recorded on the day of treatment and 14 days after treatment. Gross pathology was planned only for the animals that died before the end of the observation period. No deaths or clinical signs of toxicity occurred during the study period. The body weights appeared normal throughout the study period. Necropsy was not performed as no animals died during the study.

Justification for classification or non-classification

Based on the available data for DTPMP (5-7Na), no classification for acute toxicity is required for DTPMP (1-3Na) according to Regulation (EC) No 1272/2008.