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EC number: 911-811-2 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
The key acute oral toxicity study, conducted according to OECD Test Guideline 423 and in compliance with GLP, reports an acute oral LD50 value between 500-1000 mg/kg (equivalent to 250-500 mg/kg pure active acid substance as the test material was a 50% aqueous solution, see Note 1) (SafePpharm 2003a).
In the acute dermal toxicity study for HEBMP-xNa, conducted according to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was concluded to be greater than 2246 mg/kg bodyweight (equivalent to 2000 mg active salt/kg bodyweight, equivalent to 1600 1580 mg/kg bw active acid, see Note 2) (Harlan Laboratories, 2012b).
The interpretation of results assumes that the water and the sodium ions do not contribute to toxicity observed in the studies, hence the doses have been adjusted to reinterpret the result in terms of the dose of phosphonate (molecular or anions) only, which is termed the “active acid equivalent”. See Notes 1 and 2 for conversions.
In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2) does not need to be conducted as reliable data via the oral and dermal routes are available.
Note 1: the calculation of results in terms of active acid equivalent was done as follows: LD50 500-1000 mg/kg which already takes into account the specific gravity of the substance, as corrected by the performing laboratory. The test material is said to be a 49% active acid HEBMP, therefore the LD50 500-1000 mg/kg * 49% is equivalent to 250-500 mg HEBMP acid/kg.
Note 2: the calculation of results in terms of active acid equivalent was done as follows: LD50 >2246 mg/kg body weight is equivalent to 2000 mg/ active ingredient/kg body weight due to the presence of 11% water, which was corrected by the performing laboratory. Assuming the study was conducted at neutral pH, this would be equivalent to a predominance of HEBMP-3Na based on pKa values. The result of 2000 mg HEBMP-3Na/kg has been converted into 2000 mg HEBMP acid/kg by using
The result has been corrected to the equivalent dose of active acid using a molecular weight conversions:
MW HEBMP acid (249.1 g/mol) / MW HEBMP-3Na (315.04 g/mol) = 0.79
[when taking the average of the Molecular Weights for the cyclic and linear forms of the substances]
Therefore 2000 mg HEBMP-3Na/kg * 0.79 = 1580 mg HEBMP acid/kg body weight
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 11.09.2003-13.10.2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
- GLP compliance:
- yes (incl. QA statement)
- Test type:
- acute toxic class method
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- 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: 8-12 weeks
- Fasting period before study: overnight and for 4 hours after dosing
- Housing: the animals were housed in groupd of 3 in suspended solid floor polypropylene cages furnished with woodflakes
- Diet: laboratory diet, ad libitum
- Water: ad libitum
- Acclimation period: minimum of 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): minimum 15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- other: undiluted or in distilled water
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 30 mg/ml
MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg - Doses:
- 300 mg/kg, 2000 mg/kg
- No. of animals per sex per dose:
- 3F
- 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 0.5, 1, 2 and 4 hours after dosing and subsequently once daily. individual body weights were reccorded prior to dosing and seven and fourteen days after treatment or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: The gross pathological examination consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. the appearance of any macroscopic abnormalities was recorded. No tissues were retained. - Sex:
- female
- Dose descriptor:
- approximate LD50
- Effect level:
- 500 - 1 000 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- other: An extrapolation to 100% pure substance would give 250 – 500 mg/kg, based on 50% aqueous solution of the multiconstituent (~50:50 linear:cyclic substance).
- Mortality:
- Two animals treated at a dose level of 2000 mg/kg were found dead or killed in extremis two hours or one day after dosing. There were no deaths at a dose level of 300 mg/kg.
- Clinical signs:
- other: Signs of systemic toxicity noted at a dose level of 2000 mg/kg were hunched posture, ataxia, decreased respiratory rate, gasping, laboured and noisy respiration, loss of righting reflex, piloerection, ptosis, pallor of the extremities and red/brown staini
- Gross pathology:
- Abnormalities noted at necropsy of the animal that was found dead two hours after dosing were haemorrhagic lungs, dark liver, dark kidneys, haemorrhage of the non-glandular region of the stomach and severe haemorrhage of the gastric mucosa and small and large intestines. Abnormalities noted at necropsy of the animal that was killed in extremis one day after dosing were haemorrhage of the gastric mucosa and gaseous stomach and small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.
- Other findings:
- None reported.
- Interpretation of results:
- Category 3 based on GHS criteria
- Conclusions:
- An acute oral LD50 value between 500-1000 mg/kg (equivalent to 250-500 mg/kg pure substance) was reported in a study carried out according to an appropriate OECD guideline and in compliance with GLP.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 250 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
- Endpoint:
- acute toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- The study was performed between 16 May 2012 and 30 May 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- 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
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1200 (Acute Dermal Toxicity)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 26 June 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Health and Welfare, 1992
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Test type:
- standard acute method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Five male and five female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200 g, and were eight to twelve weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.
The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24 Hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study. - Type of coverage:
- semiocclusive
- Vehicle:
- unchanged (no vehicle)
- Details on dermal exposure:
- PREPARATION OF TEST ITEM:
The test item contains 10.95% water. For the purposes of the study the test item concentration was corrected for this. The test item was weighed out according to each animal's individual bodyweight and moistened with distilled water prior to application.
The absorption of the test item was not determined.
TEST SITE
On the day before treatment the back and flanks of each animal were clipped free of hair.
Using available information on the toxicity of the test item, a group of five male and five female rats was treated with the test item at a dose level of 2246 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight).
The appropriate amount of test item, moistened with distilled water, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24-Hour exposure period. Shortly after dosing the dressings were examined to ensure that they were
securely in place.
REMOVAL OF TEST SUBSTANCE:
After the 24-Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item. The animals were returned to group housing for the remainder of the study period. - Duration of exposure:
- 24 hours
- Doses:
- 2246 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight).
- No. of animals per sex per dose:
- 5 male and 5 female at 2246 mg/kg (2000 mg ai/kg bodyweight).
- Control animals:
- not required
- 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 ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the Draize scale (see evaluation of skin reactions).
Any other skin reactions, if present were also recorded.
Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained. - Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- >= 2 000 mg/kg bw
- Based on:
- act. ingr.
- Remarks on result:
- other: Equivalent to >1580 mg/kg bw active acid
- Mortality:
- Individual mortality data are given in Table 1 (see attached background material).
There were no deaths. - Clinical signs:
- other: Individual clinical observations are given in Table 1 (see attached background material). There were no signs of systemic toxicity.
- Gross pathology:
- Individual necropsy findings are given in Table 5 (see attached background material).
No abnormalities were noted at necropsy. - Other findings:
- Dermal Reactions:
Individual dermal reactions are given in Table 2 and Table 3 (see attached background material).
There were no signs of dermal irritation. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2246 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight, equivalent to to 1580 mg/kg bw active acid).
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 1 580 mg/kg bw
Additional information
The key acute oral toxicity study, conducted according to OECD Test Guideline 423 and in compliance with GLP, identified an LD50 of 500-1000 mg/kg (equivalent to 250-500 mg/kg active acid substance, as the test material was a 50% aqueous solution) (SafePharm 2003a). In the study, a group of three fasted female rats was treated with the test item at a dose level of 2000 mg/kg bodyweight. This was followed by a second group of three fasted females treated at dose level of 300 mg/kg bw. The test item was administered orally by gavage. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. Two animals treated at a dose level of 2000 mg/kg bw were found dead or killed in extremis two hours or one day after dosing. There were no deaths at a dose level of 300 mg/kg bw. Signs of toxicity noted at a dose level of 2000 mg/kg bw were hunched posture, ataxia, decreased respiratory rate, gasping, laboured and noisy respiration, loss of righting reflex, piloerection, ptosis, pallor of the extremities and red/brown staining around the eyes. One animal treated at a dose level of 2000 mg/kg bw was comatose one hour after dosing. There were no signs of toxicity at a dose level of 300 mg/kg bw. The surviving animals showed expected gains in bodyweight over the study period. Abnormalities noted at necropsy of the animal that was found dead two hours after dosing were haemorrhagic lungs, dark liver, dark kidneys, haemorrhage of the non-glandular region of the stomach and severe haemorrhage of the gastric mucosa and small and large intestines. Abnormalities noted at necropsy of the animal that was killed in extremis one day after dosing were haemorrhage of the gastric mucosa and gaseous stomach and small and large intestines. The effects noted during the study and at necropsy were considered to be secondary to local effects of the substance based on the known pH (<2). No abnormalities were noted at necropsy of animals that were killed at the end of the study.
In a supporting acute oral toxicity study for HEBMP-xNa, conducted according to OECD Test Guideline 423 and in compliance with GLP, the LD50 value was concluded to be greater than 2246 mg/kg body weight (equivalent to 2000 mg active salt/kg body weight, equivalent to 1580 mg/kg body weight active acid) (Harlan Laboratories, 2012a). In the study, a group of three fasted females was treated with the test item at a dose level of 2246 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight). This was followed by a further group of three fasted females at the same dose level. The test item was administered orally as a solution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths during the 14-day study period. There were no signs of systemic toxicity. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy.
In the acute dermal toxicity study for HEBMP-xNa, conducted according to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was concluded to be greater than 2246 mg/kg bodyweight (equivalent to 2000 mg active salt/kg bodyweight, equivalent to 1580 mg/kg bw active acid, see Note 1 above) (Harlan Laboratories, 2012b). A group of ten animals (five males and five females) was given a single, 24-hour, semi‑occluded dermal application of the test item to intact skin at a dose level of 2246 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight). Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths. There were no signs of systemic toxicity. There were no signs of dermal irritation. Animals showed expected gains in bodyweight, except for one female which showed no gain in bodyweight during the first week but expected gain in bodyweight during the second week. No abnormalities were noted at necropsy.
Justification for classification or non-classification
Discussion of classification conclusion
The classification decision is based on data for the substance itself HEBMP-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, phosphoric acid, phosphonic acid and hydrogen chloride, are present at concentrations above 1 % in the registered substance and have classifications listed in Annex VI of Regulation (EC) No 1272/2008.
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 237-066-7) is present at the concentration range of 0-≤5 % w/w in the registered substance HEBMP-H (equivalent to 0-2.5% of a 50% aqueous solution; no solids products are on the market). It is classified for acute oral toxicity Cat 4 according to Annex VI of CLP Regulation (EC) No 1272/2008. The impurity does not contribute to the acute toxicity of the substance and does not affect the classification conclusion for HEBMP-H based on the additivity approach.
Hydrogen chloride (CAS 7647-01-0, EC 231-595-7) is present at the concentration range of 0-≤10 % w/w (equivalent to 0-5% 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) Cat 3, H355 "May cause respiratory irritation" according to Annex VI of CLP Regulation (EC) No 1272/2008. Since, the STOT SE classification is Cat 3, hydrogen chloride does not affect the classification conclusion for HEBMP-H.
The LD50 of 500-1000 mg/kg bw derived in the acute oral toxicity study with HEBMP-H indicates that the 50% aqueous solution of the substance as tested (if sold) should be classified as acutely toxic by the oral route, Category 4, H302: “Harmful if swallowed”. This is equivalent to an LD50 of 250-500 mg/kg bw for the active acid (the substance registered), therefore the active acid should be classified as acutely toxic by the oral route, Category 3, H301: “Toxic if swallowed”.
No classification is required for acute dermal or inhalation toxicity according to Regulation (EC) No 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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