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EC number: 416-900-5 | CAS number: 79723-02-7 TMAP
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- September 1993 - March 1993
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
- Report date:
- 1994
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Tetramethylammonium hydrogen phthalate
- EC Number:
- 416-900-5
- EC Name:
- Tetramethylammonium hydrogen phthalate
- Cas Number:
- 79723-02-7
- Molecular formula:
- C12H17NO4
- IUPAC Name:
- tetramethylazanium 2-carboxybenzoate
- Test material form:
- other: white solid
- Details on test material:
- - Name of test material (as cited in study report): TMAP, Tetramethylammonium hydrogen phthalate
- Physical state: white solid
- Storage condition of test material: room temperature over silica gel
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (U.K.) Limited, Hanston, Kent
- Age at study initiation: approximately five to six weeks old
- Weight at study initiation: males weighed 145g to 172g, females weighed 132g to 177g
- Fasting period before study: no
- Housing: in groups of five by sex in polypropylene gridfloor cages suspended over trays lined with absorbent paper
- Diet: free access to food, a pelleted diet (Rat and Mouse SQC Expanded Diet No. 1, Special Diets Services limited, Witham, Essex, U.K .)
- Water: free access to mains water
- Acclimation period: nine days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 42 - 81
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 3 September 1993 To: 1 October 1993
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared weekly and stored at 4°C in the dark. Treatment volume was 5 mL/kg bw. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken of each test material formulation, and concentrations were determined spectrophotometrically.
Homogeneity was determined by visual examination. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
5, 15, 75 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a range-finding study (rats, 3/sex/dose, were treated for 14 days to dose levels 0, 15, 40, 70, 100 mg/kg bw/day)
- Positive control:
- not required
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Immediately before dosing and one and five hours after dosing during the working week. Animals were observed immediately before dosing and one hour after dosing at weekends .
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: Individual bodyweights were recorded on Day 0 (the day before the start of treatment) and on Days 7, 14, 21 and 28.
FOOD CONSUMPTION: yes
- Food consumption was recorded for each cage group at weekly intervals throughout the study.
WATER CONSUMPTION: Yes
- Time schedule for examinations: Daily visual inspection of the water bottles during the first week of treatment revealed overt intergroup differences. Water intake was therefore measured and recorded for each cage group from Day 8 onwards.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all
- Parameters examined: Ht, Hb, RBC, WBC, differential leucocyte count, platelet count, MCH, MCV, MCHC, clotting time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study
- Animals fasted: No
- How many animals: all
- Parameters examined: blood urea, total protein, albumin, albumin/globulin ratio, sodium, potassium, chloride, calcium, inorganic phosphorus, creatinine, alkaline phosphatase (AP), alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), glucose, total bilirubin
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: selected organs from animals that were killed at the end of
the study, were weighed before fixation: adrenals, brain, gonads, heart, kidneys, liver, pituitary, spleen - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, according to guideline - Statistics:
- Data were processed to give group mean values and standard deviations where appropriate.
Absolute and relative organ weights, haematological and blood chemical data were analysed by one way analysis of variance incorporating 'F-max ' test for homogeneity of variance. Data showing heterogeneous variances were analysed using Kruskal Wallis non-parametric analysis of variance and Mann Whitney U-Test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY: No mortality observed. At the highest dose level clinical signs of toxicity, possibly associated with an adverse effect on the CNS, were seen on isolated occasions and included ptosis, lethargy and ataxia (shortlived and were no longer apparent by the following day). Increased salivation either before or immediately after dosing from Day 12 onwards. Associated findings of red/brown staining of the snout, red/brown staining around the mouth and fur wetting together with red/brown staining of the fur and red/brown staining around the ana-genital region. Abdominal distension was observed for two high dose males from Day 6 of treatment and for progressively more animals from Day 12 such that all high dose males had a distended abdomen throughout the second half of the treatment period. Several high dose animals of either sex occasionally appeared hunched during the second half of the treatment period or had red/brown staining around the eyes.
BODY WEIGHT AND WEIGHT GAIN: High dose males showed a lower bodyweight gain than controls over the treatment period, most notably during Week 1. High dose females also showed a lower bodyweight gain than controls during the first three weeks of treatment.
FOOD CONSUMPTION: The dietary intake of high dose males was lower than that of controls over the treatment period, particularly during Week 1 when food efficiency was also slightly reduced. High dose females showed a slightly lower dietary intake than controls during Week 1 only but food efficiency was unaffected by treatment in these animals.
WATER CONSUMPTION: Daily visual inspection of water bottles revealed overt intergroup differences during the first week of treatment and measurement of water consumption was therefore initiated on Day 8. A slight increase in water consumption was demonstrated for high dose animals of either sex in comparison with controls.
HAEMATOLOGY: High dose males showed a slight but statistically s ignificant increase in clotting time compared with controls; such findings are often associated with an adverse effect on the liver and, in this instance, a treatment related effect cannot be entirely ruled out.
Statistically significant reductions in haemoglobin concentration, haematocrit, platelet count, lymphocyte count and mean corpuscular haemoglobin concentration were confined to intermediate or low dose animals. These findings were not dose-related and were therefore considered not to be treatment-related.
CLINICAL CHEMISTRY: High dose animals showed statistically significant increase in plasma AP concentration and reduction in total plasma protein and albumin levels together with a rise in the albumin/globulin ratio. Statistically significant increases in ALAT and ASAT together with a reduction in plasma urea were confined to females (probably associated with the morphological hepatic changes detected histopathologically). High dose males showed a slight but statistically significant reduction in plasma sodium concentration whilst plasma calcium was slightly reduced in high dose females.
High dose animals of either sex showed a slight but statistically significant reduction in plasma creatinine concentration. None of the individual values were abnormally low and, in any case, a reduction in this parameter is unlikely to be associated with chemically-induced injury.
ORGAN WEIGHTS: High dose females showed a slight but statistically significant increase in relative liver weight compared with controls.
Statistically significant increases in female relative kidney weight and male relative testicular weight were detected at the high dose level. Most of the individual values were within the normally expected range for rats of the strain and age used in this study and, in the absence of any morphological renal or testicular changes, these findings were considered not to be toxicologically significant.
GROSS PATHOLOGY: All high dose males had a distended stomach at terminal kill. Multiple raised white foci were al so seen on the non-glandular gastric epithelium of one of these animals at necropsy.
HISTOPATHOLOGY: in high dose females hepatocyte basophilia and enlargement were observed in relation to treatment.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 15 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Oral administration of TMAP to rats for a period of twenty-eight consecutive days by gavage, resulted in toxicologically significant effects at 75 mg/kg/day (clinical signs related to CNS toxicity, decreased bw gain, lower food consumption, increased water consumption, increased clotting time (m), increased plasma AP, ALAT (f) and ASAT (f), reduced plasma protein and albumin, reduced plasma urea (f), distended stomach (m), increased liver weight (f), hepatocyte basophilia and enlargement (f)). Based on these observations, the NOAEL for repeated dose toxicity is set at 15 mg/kg bw/day.
- Executive summary:
TMAP was administered by gavage in a 28-day repeated dose toxicity study (OECD 407) with rats (10/dose) at dose levels of 0, 5, 15 and 75 mg/kg bw/day. Toxicologically significant effects were observed at 75 mg/kg bw/day and included clinical signs related to CNS toxicity, decreased bodyweight gain, lower food consumption, increased water consumption, increased clotting time (m), increased plasma AP, ALAT (f) and ASAT (f), reduced plasma protein and albumin, reduced plasma urea (f), distended stomach (m), increased liver weight (f), hepatocyte basophilia and enlargement (f). Based on these observations, the NOAEL for repeated dose toxicity is set at 15 mg/kg bw/day.
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