Registration Dossier

Administrative data

Description of key information

Reliable data are available for both the oral and dermal routes from studies conducted with aqueous solutions of the registered substance.

In the first acute oral toxicity study with DTPMP-7Na, conducted using a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP-7Na was ≥10 ml/kg bw in rats (equivalent to ≥5838 mg active salt/kg bw and ≥4612 mg active acid/kg bw) (SafePharm Laboratories, 1982a).

In the second acute oral toxicity study with DTPMP-7Na, conducted according to a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP-7Na was <15 ml/kg bw (equivalent to <8757 mg active salt/kg and 6918 mg active acid/kg bw) in the rat (SafePharm Laboratories, 1982b).

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

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
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): Ad libitum
- Water (e.g. ad libitum): 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.
- 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:
At 3.0 ml/kg bw: General signs of toxicity in all animals in this study included piloerection, abnormal body carriage (hunched posture) and lethargy for the first day after dosing. From day 2 after dosing, no abnormal symptoms observed.  No deaths. 
At 10.0 ml/kg bw: General signs of toxicity in all animals in this study included piloerection, abnormal body carriage (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 observed in any animal.  No deaths.  No macroscopic abnormalities observed at necropsy.
Body weight:
Apart from one male in the 3 ml/kg bw groups, all body weights were considered normal.
Gross pathology:
No abnormal findings.
Other findings:
None reported.

Calculation of equivalent dose:

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

2) DTPMP-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-7Na was ≥10 ml/kg bw in rats (equivalent to ≥5838 mg active salt/kg bw and ≥4612 mg active acid/kg bw).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
04.08.1982 to 18.08.1982
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 11/80/21B). Together with SafePharm study 557/8208 (1982a), 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
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Male and female animals (4-6 weeks old, body weight ranges 84-120 and 89-119 g respectively; supplied by A. Tuck and Sons Ltd, Battlesbridge, Essex, UK).
Doses:
15 ml/kg bw (equivalent to 8757 mg active salt/kg)
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
 The test substance was administered by gavage following an overnight fast.  Food was withheld for a further 2 hours after dosing (NB OECD guideline would require food to be withheld for 3-4 hours after dosing). 
Animals were observed 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. POST-MORTEM EXAMINATION (macroscopic only) Animals that died during the test and surviving animals (killed on day 14) were necropsied.  CALCULATION OF LD50 This was in effect a limit test.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
< 15 mL/kg bw
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
< 8 757 mg/kg bw
Based on:
act. ingr.
Remarks:
active salt
Remarks on result:
other: equivalent to 6918 mg active acid/kg bw
Mortality:
Nine animals died within two days after dosing. 
Clinical signs:
General signs of toxicity in all animals included in this study 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. From day 8 after dosing, no abnormal symptoms observed in the surviving animal (a female).  
Gross pathology:
Macroscopic abnormalities in all animals that died during the study included congestion and/or haemorrhage of the lungs.  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.  No macroscopic abnormalities observed at necropsy of surviving animal.

Calculation of equivalent dose: Based on 

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

2) DTPMP-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, <8757 mg active salt/kg bw is equivalent to <
6918 mg parent acid
(DTPMP, CAS 15827-60-8)/kg bw.

Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral toxicity study, conducted according to a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP-7Na was <15 ml/kg bw (requivalent to <8757 mg active salt/kg and 6918 mg active acid/kg bw) in the rat.
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): Ad libitum
- Water (e.g. ad libitum): 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 was observed in two animals (one male and one female) on the day of dosing.  From four hours after dosing, no abnormal symptoms observed in any animal. 
Body weight:
Body weight were within normal limits throughout the test period.
Gross pathology:
No abnormal findings.
Other findings:
None

Calculation of equivalent dose: Based on 

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

2) DTPMP-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-7Na was ≥10 ml/kg bw (equivalent to 5838 mg active salt/kg bw and 4612 mg active acid/kg bw) in rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 838 mg/kg bw

Additional information

Studies were conducted using aqueous solutions of DTPMP-7Na, DTPMP-8Na and DTPMP-xNa (presumed to be DTPMP-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.

The result has been corrected to the equivalent dose of active acid using a using molecular weight conversions:

MW DTPMP-H (573.2 g/mol) / MW DTPMP-7Na (727.07 g/mol) = 0.79

MW DTPMP-H (573.2 g/mol) / MW DTPMP-8Na (749.048 g/mol) = 0.77

MW DTPMP-H (573.2 g/mol) / MW DTPMP-xNa (presumed to be DTPMP-7Na based on trade name) ( 727.07 g/mol) = 0.79

In the first acute oral toxicity study with DTPMP-7Na (aqueous solution containing 33% w/w active acid; composed of 42% w/w active salt), conducted using a protocol comparable to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for DTPMP-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-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 single oral gavage dose of 3 or 10 ml DTPMP-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 second acute oral toxicity study with DTPMP-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-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-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 single oral gavage dose of 15 ml DTPMP-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-8Na (composed of 43% w/w active salt including minor components, 57% w/w water; active acid content not specified), conducted prior to OECD Test Guidelines and 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-8Na/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 single oral doses of 5000, 6000, 7000, 8000 and 9000 mg DTPMP-8Na/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-xNa (the test material was hand-labelled with a trade name corresponding to DTPMP-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 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-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 single oral doses of 250, 500, 1000, 2000 mg DTPMP-xNa/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-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 according to GLP, the LD50 for DTPMP-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-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 single 24-hour occlusive dermal application of 10 ml DTPMP-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-8Na (composed of 43% w/w active salt including minor components, 57% w/w water), conducted prior to the adoption of OECD Test Guidelines and 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-8Na/kg * 0.77 = 662 mg DTPMP-H/kg body weight) (Monsanto, 1979). Details of the study result were not available.

In a supporting acute dermal toxicity study with DTPMP-xNa (the test material was hand-labelled with a trade name corresponding to DTPMP-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 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-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 single 24-hour occlusive dermal application of 5 ml DTPMP-xNa/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 according to Regulation (EC) No 1272/2008.