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EC number: 251-908-0 | CAS number: 34274-28-7
- 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
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Endpoint summary
Administrative data
Description of key information
There are no repeated dose toxicity data for ATMP-xNH4, therefore data were read-across from ATMP-H.
In a well-conducted key chronic toxicity/carcinogenicity study, ATMP-H (powder, 100% active acid) was administered via the diet to Long-Evans rats at dose levels of 50, 150 or 500 mg active acid/kg bw/day for 24 months. The NOAEL for carcinogenicity and general toxicity was at least 500 mg active acid/kg bw/day (BioDynamics Inc., 1979c).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 04.12.1975 to 03.12.1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Version / remarks:
- Test conducted prior to adoption of OECD test guideline.
- Deviations:
- yes
- Remarks:
- No satellite group, and reduced haematology, clinical chemistry and urinalysis parameters examined.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Long-Evans
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York.
- Age at study initiation: 6-7 weeks
- Weight at study initiation: mean 212.6g (males) and 149.0g (females)
- Fasting period before study:
- Housing: Individually in elevated stainless steel cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 18 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Monitored but no data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 17.11.1976 To: 30.11.1978 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Standard laboratory diet.
- Storage temperature of food: No data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- 50 g samples of the control feed and each dietary level were taken weekly and shipped to the sponsor. No further details.
- Duration of treatment / exposure:
- 24 months
- Frequency of treatment:
- continuous
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Remarks:
- active acid
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Remarks:
- active acid
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Remarks:
- active acid
- No. of animals per sex per dose:
- 70
- Control animals:
- yes, plain diet
- Details on study design:
- Post-exposure period: None
Satellite group: None - Positive control:
- None
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily for the first two months and then twice daily until termination.
- Cage side observations: mortality, gross signs of toxicology or pharmacologic effects.
Interim necropsies were performed on 10/sex/group after 6 and 12 months, then on all surviving animals after 24 months. Animals that died spontaneously or were killed in a moribund condition were also examined.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly, for signs of local or systemic toxicity, pharmacologic effects and palpation for tissue masses.
BODY WEIGHT: Yes
- Time schedule for examinations: Twice pre-test, weekly through to week 13 of treatment, every two weeks for weeks 14 to 26, then monthly, and finally at termination.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): pretest, weekly up to week 13, every other week for weeks 14 to 26 and then monthly.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest, then 3, 6, 12, 18 and 24 months.
- Dose groups that were examined: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 3, 6, 12, 18 and 24 months.
- Anaesthetic used for blood collection: Yes, ether.
- Animals fasted: Yes, overnight.
- How many animals: 6/sex from control and high dose groups.
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 3, 6, 12, 18 and 24 months.
- Animals fasted: Yes, overnight
- How many animals: 6/sex from control and high dose groups.
- Parameters checked in table [No.1] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: 6, 12 and 24 months all groups 6/sex; 3 months: 6/group (males) and 6/control and high dose groups (females); 18 months: 6/sex for control and high dose groups.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.1] were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2) - Other examinations:
- None
- Statistics:
- Body weight, food consumption, haematology and clinical chemistry parameters, organ weights, organ/body weight ratios and organ/brain weight ratios were analysed. Mean values of all dose groups were compared to control at each time interval. Haematology and clinical chemistry: intergroup comparison v control by F-test and Student's t-test (using t-test modification if variances differed). Body weight, food consumption, organ weights and ratios by Dunnett's t-test.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related clinical signs of toxicity.
- Mortality:
- no mortality observed
- Description (incidence):
- No treatment effects. Males (per 70) 18 (controls), 22 (low), 21 (medium) and 18 (high) died. Females (per 70), 23 (controls), 24 (low), 19 (medium) and 19 (high) died during study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- High dose males slightly reduced (5-10%) from week 16-87, resulting in slight reduction in terminal body weight (controls - 522.2+/-61.3; low dose - 520.5+/-72.5; medium dose - 508.2 +/-75.6 and high - 510.1 +/-52.2 g) which was not statistically significant. Other groups comparable to controls.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Mean food consumption for high dose males was greater than control group by 3-17%. Other groups comparable to controls.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences in any of the parameters measured for any group.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences for any of the parameters measured at any time point for any group.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes were observed in the highest dose group only. No other groups were affected at any sample time. Males: 15% reduction in absolute spleen weight at 24 months; 14% reduction in absolute and relative liver weight at 24 months; 23% increase in relative testes weight at 12 months, 14% increase in relative kidney weight at 12 months, 14% decrease in absolute liver weight at 6 months. Females: 13% decrease in absolute kidney weight at 12 months; 8% decrease in relative liver weight at 6 months. These changes were no considered adverse.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings. The following were found equally in control and treated groups: cortical vacuolation and hematocysts in adrenal glands, pituitary tumours, pulmonary lesions (varying degrees of severity of chronic murine pneumonia complex, lymphoid proliferations, abscesses and pneumonitis), chronic pleuritis, often with adhesions to the heart, varying degrees of chronic nephritis commonly observed, hepatic lesions in many; also bile duct hyperplasia, testicular atrophy, mammary galactocele in both sexes, possibly related to prolactin secreting pituitary tumours
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings (see Section 7.7).
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Remarks:
- active acid
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed.
- Critical effects observed:
- no
- Conclusions:
- In a well-conducted key chronic toxicity/carcinogenicity study, conducted in a similar manner to OECD Test Guideline 453 but pre-GLP, ATMP-H (powder, 100% active acid) was administered via the diet to Long-Evans rats at dose levels of 50, 150 or 500 mg active acid/kg bw/day for 24 months. The NOAEL for carcinogenicity and general toxicity was greater than 500 mg active acid/kg bw/day.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Key data for repeated-dose toxicity of ATMP-xNH4 are read-across from the category member, ATMP-H. See attachment to IUCLID Section 13 for justification of read-across.
In the key chronic toxicity and carcinogenicity study, conducted in a similar manner to OECD Test Guideline 453 but pre-GLP, ATMP-H (powder, 100% active acid) was administered via the diet to LongEvans rats (70/sex/dose) at dose levels of 50, 150 or 500 mg/kg bw/day (groups II to IV) for 24 months. Control animals received untreated diet (Group I). Animals were regularly observed for clinical signs of toxicity and body weights and food consumption were measured. Interim necropsies were performed at 6 and 12 months (10/sex/dose). Ophthalmoscopic examination, haematology, clinical chemistry and urinalysis were performed at months 3, 6, 12, 18 and 24. Histopathological examinations were conducted on all animals that died or had to be killed in extremis. In addition, histopathological examinations were conducted for 10 animals/sex for groups I and IV at 6 months and for all survivors in Groups I and IV at 24 months. The mean body weight values for the high dose males were slightly reduced (5-10%) from week 16 to 87. Mean food consumption values for the high dose males were generally comparable to or greater than those of the control group (3-17%) during most weeks. In the high dose group, statistically significant changes to organ weights occurred (adrenal glands, spleen, liver, pituitary). No treatment-related gross lesions or histopathological findings occurred in any of the groups. The NOAEL for carcinogenicity and general toxicity was concluded to be at least 500 mg active acid/kg bw/day (BioDynamics Inc., 1979c).
In a supporting 28-day repeated dose toxicity study not conducted according to an OECD Test Guideline or in compliance with GLP, 2000 mg/kg bw/day ATMP-xNa (an aqueous solution containing 30% w/ w active acid neutralized to pH 7 with NaOH) were administered to Birmingham Wistar rats by oral gavage for 28 days. Single animals were killed on Days 7, 14, 21 and 28, and the remaining surviving animals were observed for a further treatment-free days. The health and clinical condition of the treated animals showed no significant difference from the controls. There were some dosing problems towards the end of the study, these were thought to be due to possible unpalatability of the test material. There was approximately a 13% reduction in body weights at the study termination. There were also minor elevations in urea (32% at Day 21, 3% at Day 28) and creatinine (16% at Day 21), which reversed after two weeks recovery. No statistics were performed. Vacuoles in kidney tubules were noted in control animals on Day 28 and treated animals after 14 days. Duodenal damage was observed at test animals necropsies on days 14, 21 and 28, which was attributable to local irritation and considered by the study authors to be due to the test substance's high osmolality. Based on the limited information given in the study, there were overall no adverse systemic effects and the systemic NOAEL was concluded to be at least 2000 mg/kg bw/day (presumed equivalent to 600 mg active acid/kg bw/day if the dose was not corrected for purity) (Manley, 1981).
In another supporting 90-day feeding study, not conducted according to OECD Test Guidelines but claiming to have been conducted in compliance with GLP, ATMP-xNa (an aqueous solution containing 32% active acid) was administered at 6000 ppm (calculated to be equivalent to 161 and 175 mg active acid/kg bw/day, in males and females, respectively) continuously in diet, to five male and five female Sprague-Dawley rats for 90 days. There were no test material-related adverse effects in any of the test animals, including mortality, clinical effects, effects on food consumption or body weight changes, or effects on haematology and clinical chemistry parameters. No urinalysis was conducted. One control male died on day 23, for which gaseous distension of the gastrointestinal tract was observed at necropsy and considered to be the cause of death for this animal. At the end of the exposure period the surviving animals were killed and a gross macroscopic examination was performed. No abnormal findings were observed in any of the test animals. No histopathological examination was conducted. The systemic NOAEL was concluded to be at least ≥6000 ppm (equivalent to 161 and 175 mg active acid/kg bw/day, in males and females, respectively) (SafePharm Laboratories Ltd. 1982).
In a supporting dose range finder for a carcinogenicity study, conducted prior to OECD Test Guidelines and GLP, a NOAEL was concluded to be ≥1000 mg/kg bw/day. This was based on no observed statistically significant findings in mortality, body weight, food consumption, necropsy or clinical signs (BioDynamics Inc., 1976).
In another supporting repeated dose toxicity study, conducted prior to the adoption of OECD Test Guideline and pre-GLP, ATMP-H was administered to groups of albino rats (15/sex/dose) at dietary levels of 600, 2000 or 6000 ppm (equivalent to 48, 162 and 486 mg/kg bw/day in male rats and 54, 182 and 546 mg/kg bw/day in female rats) for 90 days. Control animals received untreated diet. Five deaths occurred during the study, one of which was a result of respiratory infection, and the others resulted from trauma incurred during collection of blood samples. There were no effects on the body weights, food consumption, haematology parameters, clinical chemistry, urinalysis parameters, macroscopic findings and no treatment-related histopathological findings. There was a statistically significant decrease in the liver weights for males and females of the high and mid dose group. The difference was less than 20% in the high dose males, 10% in the high dose females and less than 10% in the mid dose females. In the absence of histopathological findings, it was concluded that these findings were of questionable significance. Therefore, the NOAEL was concluded to be ≥ 6000 ppm (equivalent to 486 and 546 mg/ kg bw/day in male and female rats, respectively) (Industrial Biotest Laboratories Inc., 1973).
In a supporting pre-GLP, repeated dose toxicity study ATMP-H was administered to albino rats (5/sex/ dose) for 14 days at dietary levels of 100, 300, 1000, 3000, 10000, and 30000 ppm (equivalent to 12, 35, 118, 354, 1180 and 3540 mg/kg bw/day in males and 12, 35, 117, 351, 1170 and 3510 mg/kg bw/ day in females). All rats fed 30000 ppm had significantly reduced body weight gains compared with the controls. This reduced weight gain coincided with significantly reduced food consumption. One male from the 100 ppm group died early in the treatment period, but the death was not attributed to treatment. One male from the 30000 ppm dietary level died during the investigation, and three males from this dose level showed general body redness, especially in the areas of the ears and scrotum, where swelling also occurred. Five animals were sacrificed one male and female control, one male and female from the 30000 ppm group, and one male from the 10000 ppm group. All tissues and organs from each animal were normal, except for an enlarged spleen in the 30000 ppm male. The NOAEL was concluded to be 10000 ppm (equivalent to 1180 and 1170 mg/kg bw/day in males and females, respectively) (Industrial Biotest Laboratories Inc., 1972).
Justification for classification or non-classification
Based on the available data, no classification is required for target organ toxicity following repeated exposure for ATMP-xNH4 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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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