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Diss Factsheets

Toxicological information

Endpoint summary

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Administrative data

Description of key information

In the key acute oral toxicity study, conducted prior to OECD test guidelines and GLP but according to a protocol similar to the now-deleted OECD Test Guideline 401, an LD50 of 2910 mg active acid/kg bw (the doses were corrected for purity) was determined for ATMP-H (CAS 6419-19-8; EC No., 229-146-5 aqueous solution containing 25% active acid) in the rat (Younger Laboratories, 1967, Reliability 2).

In the key 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, the LD50 for ATMP-H (aqueous solution containing 25% w/w active acid) was concluded to be >6310 mg active acid/kg bw (Younger Laboratories, 1967, Reliability 2). 

Key acute oral and dermal toxicity studies on ATMP-xNa are included in support of read-across of the reproductive toxicity study on DTPMP (5-7Na) only.

Key acute toxicity studies on DTPMP acid and sodium salts are included in support of read-across of the reproductive toxicity study on DTPMP (5-7Na) only.

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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
Conducted prior to the adoption of OECD test guidelines.
Deviations:
yes
Remarks:
Limited detail on test substance, and methodology.
GLP compliance:
no
Test type:
standard acute 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: No data
- Age at study initiation: No data
- Weight at study initiation: Males: 230 - 250 g. Females: 210 - 225 g.
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data


IN-LIFE DATES: No data
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: No data.
Doses:
2000, 2510, 3160 and 3980 mg/kg bw (as a 25 % aqueous solution).
No. of animals per sex per dose:
Two or three depending on dose (five in total/dose).
Control animals:
no
Details on study design:
- Duration of observation period following administration: No data, but at least four days.
- Frequency of observations and weighing: Not stated
- Necropsy of survivors performed: No
- Other examinations performed: clinical signs, and gross pathology.
Statistics:
LD50 calculated by a modification of the method of E. J. de Beer (no further detail, calculation not presented).
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 910 mg/kg bw
Based on:
act. ingr.
Remarks:
active acid
95% CL:
>= 2 530 - <= 3 345
Mortality:
No deaths at the lowest dose of 2000 mg/kg bw. There were one, two and five deaths in the 2510, 3160 and 3980 mg/kg bw groups, respectively. Survival time was several hours to four days, with most death occurring "overnight" (it is not clear if this means the night after the dosing).
Clinical signs:
other: Weakness in one to two hours with diarrhoea, salivation and tremors.
Gross pathology:
Inflammation of the gastrointestinal mucosa as well as liver and renal hyperaemia.
Other findings:
None
Interpretation of results:
GHS criteria not met
Conclusions:
In the acute oral toxicity study, conducted according to a protocol similar to the now-deleted OECD Test Guideline 401 and prior to GLP, an LD50 of 2910 mg active acid/kg bw (the doses were corrected for purity) was determined for ATMP-H (aqueous solution containing 25% active acid) in the rat.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 910 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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
Conducted prior to adoption of OECD test guidelines.
Deviations:
yes
Remarks:
Limited details on methods and animal conditions.
Principles of method if other than guideline:
Method: other: Not stated. Insufficient detail to fully assess comparability with OECD guideline.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: Males: 2.3-2.5 kg. Females: 2.0 and 2.1 kg.
- Fasting period before study: No data
- Housing: Individually (cage type to stated)
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data


IN-LIFE DATES: No data
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: No data
- % coverage: No data
- Type of wrap if used: "plastic strips"


REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): No data
- Concentration (if solution): 25% aqueous solution
- Constant volume or concentration used: yes


VEHICLE
- Amount(s) applied (volume or weight with unit): No data
- Concentration (if solution): 25% solution
Duration of exposure:
24 hours
Doses:
1000, 1580, 2510, 3980 and 6310 mg/kg bw
No. of animals per sex per dose:
One
Control animals:
no
Details on study design:
- Duration of observation period following administration: Not clear, but at least five days.
- Frequency of observations and weighing: Body weights appear to have been measured prior to dosing and five days after dosing.
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs and gross pathology of animals that die.
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 6 310 mg/kg bw
Based on:
act. ingr.
Remarks:
active acid
Mortality:
No deaths occurred at any dose.
Clinical signs:
other: Activity and appetite were temporarily reduced after doses of 3980 and 6310 mg/kg bw.
Gross pathology:
No deaths so not conducted.
Other findings:
None
Interpretation of results:
GHS criteria not met
Conclusions:
In the key 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, the LD50 for ATMP-H (aqueous solution containing 25% w/w active acid) was concluded to be >6310 mg active acid/kg bw.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 6 310 mg/kg bw

Additional information

In the key acute oral 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 (CAS 6419-19-8; EC No., 229-146-5; 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, Reliability 2).

In a supporting acute oral 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, Reliability 4).

In another supporting acute oral 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 (active acid content unspecified) was administered to Sprague-Dawley rats (two or three per sex depending on dose; five total) as aqueous solutions at doses of 5010, 6310, 7940 and 10000 mg/kg bw, by oral gavage. Observations were made for clinical signs and the viscera of the animals that died were examined macroscopically. There were 0, 1, 3 and 5 deaths, respectively. Survival time was several hours to two days with most deaths occurring "overnight". Toxic symptoms included severe diarrhoea, increasing weakness and tremors. At macroscopic examination, there was liver hyperaemia and inflammation of the gastric mucosa. The LD50 for the test substance was calculated to be 7300 mg/kg bw (Younger Laboratories, 1962, Reliability 2).

In the key 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, Reliability 2). 

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 was applied to the clipped, intact skin, under an occlusive dressing, for at least 24 hours, at doses of 1580, 2510, 3980, 10000 and 15800 mg/kg bw (one female New Zealand white rabbit per dose). The animals were then observed for clinical signs of toxicity (no further details). There were no deaths and no macroscopic examination was conducted. Discomfort was shown at the higher doses, but there were no significant signs of systemic toxicity. The LD50 was concluded to be >15800 mg/kg bw (Younger Laboratories, 1962, Reliability 2).

Discussion of classification conclusion

The classification decision is based on data for the substance itself ATMP-H. In the absence of detailed information of the impurities in the test material used in the key data, these are considered separately for completeness. The known impurities, phosphonic acid, orthophosphoric acid, hydrogen chloride and ammonium chloride are present at concentrations above 1% in the registered substance and have classifications listed in Annex VI of Regulation (EC) No 1272/2008. (Hydroxymethyl)phosphonic acid is also present at above 1% concentration, but it is not listed in Annex VI of Regulation (EC) No 1272/2008. Therefore, it has not been considered in this assessment.

The registered substance is typically manufactured as aqueous solutions containing about 50% w/w solids hence about 50% w/w water. However, in accordance with the definition in REACH of a substance, water (as a solvent that may be separated) is not considered to be a constituent. The SIP concentration ranges are based on the substance as registered (without water); therefore, concentration ranges in the substance as sold are approximately half of the values quoted here.

Phosphonic acid, (CAS 13598-36-2, EC No. 237-066-7) is present at the concentration range of 0-≤12 % w/w in the registered substance ATMP-H (equivalent to 0-6% of a 50% aqueous solution; no solids products are on the market). It is classified for acute oral toxicity Category 4 according to Annex VI of CLP Regulation (EC) No 1272/2008.

Ammonium chloride (CAS 12125-02-9, EC No. 235-186-4) is present at the concentration range of 0-≤3 % w/w (equivalent to 0-1.5% of a 50% aqueous solution; no solids products are on the market). It is classified for acute oral toxicity Category 4 according to Annex VI of CLP Regulation (EC) No 1272/2008.

These two impurities do not contribute to the acute toxicity of the substance and do not affect the classification conclusion for ATMP-H based on the additivity approach.

Hydrogen chloride (CAS 7647-01-0, EC No. 231-595-7) is present at the concentration range of 0-≤2 % w/w (equivalent to 0-1% of a 50% aqueous solution; no solids products are on the market). It is classified for specific target organ toxicity (respiratory tract) following single exposure (STOT SE) Category 3, H355 "May cause respiratory irritation" according to Annex VI of CLP Regulation (EC) No 1272/2008. Since, the STOT SE classification is Category 3, hydrogen chloride does not affect the classification conclusion for ATMP-H.

Orthophosphoric acid is not classified for acute toxicity according to Annex VI of CLP Regulation (EC) No 1272/2008.

Overall, the impurities present in ATMP-H do not affect the classification conclusion for the substance.

Justification for classification or non-classification

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