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Description of key information

In the key acute oral toxicity study, conducted according to the now deleted OECD 401 but in compliance with GLP, the LD50 for the undiluted ammonium salt of ATMP was greater than 2000 mg/kg bw in rats (Safepharm Laboratories Ltd., 1995).

In the key acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP, the LD50 for ATMP-xNa (aqueous solution containing 41% w/w active salt) was concluded to be >10 ml/kg (equivalent to 5740 mg active salt/kg bw and 4437 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
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27.03.1995 to 18.04.1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
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: Charles River (UK) Ltd., Margate, Kent, UK
- Age at study initiation: 5 to 8 weeks
- Weight at study initiation: Males: 148-165 g; Females: 132-157 g.
- Fasting period before study: Overnight
- Housing: Groups of five in solid-floor polypropylene cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 47-54
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 27.03.1995 To: 18.04.1995
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED:1.63 ml/kg bw
Doses:
2000 mg/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: The animals were observed for deaths or overt signs of toxicity at 30 minutes, one, two and four hours after dosing, and then once daily for 14 days. Body weights were recorded prior to dosing and on Day7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: gross pathology.
Statistics:
Not required.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths.
Clinical signs:
other: There were no clinical signs of toxicity.
Gross pathology:
No abnormal findings.
Other findings:
None
Interpretation of results:
GHS criteria not met
Conclusions:
In a GLP, acute oral toxicity (limit) study (reliability score 1) conducted according to the now deleted OECD 401, the LD50 for undiluted ammonium salt of ATMP was greater than 2000 mg/kg bw in rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 2 000 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:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
Method: SafePharm protocol (number GM 08/82/53A)
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 & Sons Limited, Essex, UK.
- Age at study initiation: 6-8 weeks
- Weight at study initiation: Males: 219-242 g: Females: 210-232 g.
- Fasting period before study: None
- Housing: Five per polypropylene cage
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Minimum 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.
- % coverage: No data
- Type of wrap if used: The trunks of the rats were encircled with a strip of elastic adhesive bandage, backed with aluminium foil. The bandage was tightened sufficiently to prevent the animal from wriggling free and wrapped round to form a double layer.


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
- Constant volume or concentration used: yes
Duration of exposure:
24 hours
Doses:
10 ml/kg
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: Animals were observed 0.5, 1, 2, 3, 4 and 5 hours following dosing. On subsequent days the animals were observed at least once. Body weights were recorded on days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: none
Statistics:
None required.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 10 mL/kg bw
Based on:
test mat.
Remarks on result:
other: equivalent to >5740 mg active salt/kg bw and >4437 mg active acid/kg bw
Mortality:
No animals died.
Clinical signs:
other: Lethargy and increased red coloured lacrimation in one rat on the day of dosing.
Gross pathology:
No abnormal findings.
Other findings:
None

The dermal LD50 in the rat was determined to be >10 ml/kg bw (reviewer comment: presumed equivalent to >5740 mg active
salt/kg bw).

Interpretation of results:
GHS criteria not met
Conclusions:
In the acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP, the LD50 for ATMP-xNa (aqueous solution containing 41% w/w active salt) was concluded to be >10 ml/kg (equivalent to 5740 mg active salt/kg bw and 4437 mg active acid/kg bw) in rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 437 mg/kg bw

Additional information

In the key acute oral toxicity study, conducted according to the now deleted OECD 401 but in compliance with GLP, five Sprague-Dawley male and female rats were administered 2000 mg/kg bw/day ATMP-xNH4 by oral gavage. No clinical signs of toxicity and no changes in body weight were observed. No deaths occurred throughout the study. It was concluded that the LD50 for the undiluted ammonium salt of ATMP was greater than 2000 mg/kg bw in rats (Safepharm Laboratories Ltd., 1995).

In a supporting acute oral limit study, conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, 5 male and 5 female rats were subject to a single oral gavage administration of 10 ml/kg ATMP-xNa (aqueous solution containing 41% w/w active salt) (SafePharm Laboratories, 1982a). The animals were observed for 14 days following dosing. Body weights were recorded on days 0, 7 and 14. Necropsy was performed at the end of the study period. Two females died within 3-4 hours of dosing. No other deaths occurred. Pilo-erection, abnormal body carriage (hunched posture), lethargy and decreased respiratory rate were seen in the animals. These signs were accompanied by ptosis in two males and one female and pallor of the extremities in one female. Recovery of survivors occurred by Day 2. At necropsy, congestion of the lungs in both animals that died and haemorrhage of the small intestine in one animal were observed. There were no abnormal findings in surviving animals. The LD50 for ATMP-xNa was concluded to be ≥10 ml/kg (equivalent to 5740 mg active salt/kg bw and 4437 mg active acid/kg bw) in rats.

 

In a supporting acute oral toxicity study conducted according to a protocol similar to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 for ATMP-xNa was approximately 15 ml/kg (calculated to be equivalent to 6654 mg active acid/kg bw) in rats (SafePharm Laboratories, 1982b).

In another supporting acute oral toxicity study, conducted prior to OECD test guidelines and GLP, the LD50 value for ATMP-xNa (active acid content not specified) was concluded to be 7130 mg/kg (Younger Laboratories, 1971).

 

In a supporting acute oral study toxicity study, conducted prior to OECD test guidelines and GLP but according to a protocol similar to the now-deleted OECD Test Guideline 401, aqueous solution of ATMP-5Na (40 % w/w active salt content) was administered to Sprague-Dawley rats (two or three per sex depending on dose; five total) as aqueous solutions at doses of 12600, 15800, 20000, 25100 mg/ kg bw (equivalent to 5040, 6320, 8000 and 10040 mg active salt/kg respectively). Observations were made for clinical signs and the viscera of the animals that died were examined macroscopically. There were 0, 1, 4 and 5 deaths at 12600, 15800, 20000, 25100 mg/kg bw, respectively. Survival time was several hours to three days with most deaths occurring overnight. Toxic symptoms included severe diarrhoea, loss of appetite, lethargy, and increasing weakness. At macroscopic examination, there were renal, liver and pulmonary hyperaemia. The LD50 for ATMP-xNa was concluded to be 17800 mg/kg bw in rats (presumed equivalent to 7120 mg active salt/kg bw and 5204 mg active acid/kg bw) (Younger Laboratories, 1962).

In a supporting acute oral study toxicity study, conducted prior to OECD test guidelines and GLP, an LD50 of 2700 mg active acid/kg bw was determined for ATMP-H (aqueous solution containing 50% active acid) in the rat (Gloxhuber, 1969).

In a supporting acute oral study toxicity study, conducted prior to OECD test guidelines and GLP but according to a protocol similar to the now-deleted OECD Test Guideline 401, ATMP-H (aqueous solution containing 25% w/w active acid) was administered to Sprague-Dawley rats (two or three per sex depending on dose; five total) at doses of 2000, 2510, 3160 and 3980 mg active acid/kg bw (the doses were corrected for purity), by a single oral gavage administration. Observations for clinical signs were made and the viscera of the animals that died were examined macroscopically. There were 0, 1, 2 and 5 deaths, respectively. Survival time was several hours to four days with most deaths occurring "overnight". Toxic symptoms included weakness in one to two hours with diarrhoea, salivation and tremors. At macroscopic examination inflammation of the gastrointestinal mucosa as well as renal and liver hyperaemia were observed. The LD50 for the test substance was calculated to be 2910 mg active acid/kg bw (Younger Laboratories, 1967).

 

In the key acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP, 5 male and 5 female rats were subject to a single 24 hour dermal occlusive application of 10 ml/kg ATMP-xNa (aqueous solution containing 41% w/w active salt) (SafePharm Laboratories, 1982c). The animals were observed for 14 days following dosing. Body weights were recorded on days 0, 7 and 14. Necropsy was performed at the end of the 14day observation period. No animals died during the 14-day study period. Lethargy and increased red coloured lacrimation were seen in one rat on the day of dosing. No abnormal findings were observed at necropsy. The LD50 for ATMP-xNa was concluded to be >10 ml/kg (equivalent to 5740 mg active salt/ kg bw and 4437 mg active acid/kg bw) in rats (Safepharm Labs Inc., 1982c).

In a supporting acute dermal toxicity study, conducted prior to the adoption of OECD test guidelines and GLP, but according to a protocol similar to OECD Test Guideline 402, ATMP-H (aqueous solution containing 25% w/w active acid) was applied to the clipped, intact skin, under an occlusive dressing, for up to 24 hours, at doses of 1000, 1580, 2510, 3980 and 6310 mg active acid/kg bw (the doses were corrected for purity) to one New Zealand white rabbit per dose. There were no deaths, so no macroscopic examination was conducted. Activity and appetite were temporarily reduced in the two highest-dose group animals. The LD50 was concluded to be >6310 mg active acid/ kg bw (Younger Laboratories, 1967).

In the supporting acute dermal toxicity study, conducted prior to OECD test guideline and GLP, the LD50 value for ATMP-xNa (active acid content not specified) was concluded to be greater than 7940 mg/kg bw (Younger Laboratories, 1971).

 

In another supporting acute dermal toxicity study conducted prior to the adoption of OECD Test Guidelines and GLP, aqueous solution of ATMP-5Na (40 % w/w active salt) was applied to the clipped, intact skin of albino rabbits (one female per dose) under occlusive dressing for 24 hours. The doses used were 1580, 2510, 3980, 6310, 10000 and 15800 mg/kg bw (equivalent to 632, 1004, 1592, 2524, 4000 and 6320 mg active salt/kg, respectively). Animals were then observed for clinical signs of toxicity and mortality (duration not specified). No deaths and no clinical signs were observed. The LD50 was therefore concluded to be greater than the highest dose tested, 15800 mg/kg bw (equivalent to 6320 mg active salt/kg and 4620 mg active acid/kg bw) (Younger Laboratories, 1962).

Justification for classification or non-classification

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