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EC number: 257-182-1 | CAS number: 51410-72-1
- 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
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 15 June - 10 August 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: compliance to GLP and testing guideline, coherence between data, results and conclusions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (3-methacrylamidopropyl)trimethylammonium chloride
- EC Number:
- 257-182-1
- EC Name:
- (3-methacrylamidopropyl)trimethylammonium chloride
- Cas Number:
- 51410-72-1
- Molecular formula:
- C10 H21 N2 O. Cl
- IUPAC Name:
- trimethyl-[3-(2-methylprop-2-enoylamino)propyl]azanium chloride
- Test material form:
- other: liquid
- Details on test material:
- Identity : 3-Trimethylammonium propyl methacrylamide chloride (50% solution in water)
Alternative names : VISIOMER® MAPTAC; VISIOMER® MAPTAC 50% in water;
N-Trimethylammoniumpropylmethacrylamid-chlorid
CAS number : 51410-72-1
EINECS number : 257-182-1
Batch Number : 7201235T05
Date of expiry : 19 September 2012
Appearance : Undefined clear free-flowing yellow liquid
Storage conditions : Room temperature, protected from light
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- A total of 90 Sprague Dawley [Crl:CD(SD)BR] rats (45 males and 45 virgin females), 6 to 7 weeks old and weighing 176 to 200 g for males and 151 to 175 g for females, were ordered from Charles River Italia S.p.A., Calco (Lecco), Italy.
After arrival the weight range for each sex was determined (194-210 g for males and 168-196 g for females) and the animals were temporarily identified within the cage by means of a coloured mark on the tail. A health check was then performed by a veterinarian.
An acclimatisation period of approximately 3 weeks was allowed before the start of treatment, during which time the health status of the animals was assessed by thorough observations.
Animal room controls were set to maintain temperature and relative humidity at 22°C +/- 2°C and 55% +/- 15% respectively; actual conditions were monitored, recorded and the records retained. No relevant deviations from these ranges were recorded during the study. There were approximately 15 to 20 air changes per hour and the rooms were lit by artificial light for 12 hours each day.
In-life data from 15 June to 10 August 2012
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- The test item was administered orally by gavage at a dose volume of 10 mL/kg body weight. Control animals received the vehicle alone at the same dose volume.
The required amount of 3-Trimethylammonium propyl methacrylamide chloride (50% solution in water) was dissolved in the vehicle (purified water) at the concentrations of 10, 30 and 100 mg/mL. The formulations were prepared daily and the concentrations were calculated and expressed in terms of test item corrected for active ingredient purity (50 %).
Dose levels, selected in consultation with the Sponsor based on information from a previous non GLP Compliant study (RTC Study no.: 90940EXT), were 100, 300 and 1000 mg/kg/day. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Before treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable and that the stability of the formulation is satisfactory.
The stability was found to be 24 hours at room temperature in the concentration range of 10 to 100 mg/mL.
Samples of the formulations prepared on Weeks 1 and 6 (when all females were present) were also analysed to check the concentration. The overall results of the analyses were within the limits of acceptance stated in RTC SOPs for concentration of solutions (95-105%).
Chemical analysis was carried out by the Analytical Chemistry Department at RTC according to a validated method (RTC Study no. 90930) in the range from 1 to 200 mg/mL. The software used for this activity was the Empower® Pro build No. 2154. - Duration of treatment / exposure:
- Males
Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing and thereafter through the day before necropsy.
Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females
Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum or the day before sacrifice.
Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
During the gestation period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post coitum and on Day 1 post partum. Thereafter individual dose volumes remained constant. - Frequency of treatment:
- daily
- No. of animals per sex per dose:
- 10 per sex per dose
- Details on study design:
- The test item was administered orally, by gavage, to parental animals at 10 mL/kg body weight. The oral route was selected as it is a possible route of exposure of the test item in man.
The dosages, selected in consultation with the Sponsor, were 100, 300 and 1000 mg/kg/day.
Examinations
- Observations and examinations performed and frequency:
- Mortality
Throughout the study, all animals were checked in each working day early in the morning and in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
Clinical signs
Once before commencement of treatment (data not presented) and at least once daily during the study, each animal was observed and any clinical signs recorded.
Clinical observations (Functional Observation Battery Tests)
Once before commencement of treatment and at least once a week thereafter, each animal was given a detailed clinical examination. Each animal was removed from the home cage and observed in an open arena. The tests included observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern).
All observations were recorded for individual animals.
Grip strength and sensory reactivity to stimuli
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group for evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli) and for assessment of grip strength.
Motor activity assessment (MA)
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group and the motor activity was measured (for approximately 5 minutes) by an automated activity recording device.
Food consumption
The weight of food consumed by each cage of males and females was recorded weekly (whenever possible) during the pre-mating period starting from allocation. Individual food consumption for the females was measured on gestation Days 7, 14 and 20 starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum.
Body weight
Males were weighed weekly from allocation to termination. Males were weighed on the day of allocation to treatment groups, on the day of treatment commencement, weekly thereafter and at termination.
Females were weighed on the day of allocation to treatment groups, on the day of treatment commencement, weekly thereafter until pairing and on Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4 post partum.
Clinical pathology investigations
As a part of the sacrificial procedure, samples of blood were withdrawn under isofluorane anaesthesia from the abdominal vena cava from 5 males and 5 females (females with viable litters) randomly selected from each group, under condition of food deprivation.
The blood samples collected were divided into tubes as follows:
EDTA anticoagulant: for haematological investigations
Heparin anticoagulant: for biochemical tests
Citrate anticoagulant: for coagulation tests
The measurements performed on blood samples are listed below:
Haematology
Haematocrit
Haemoglobin
Red blood cell count
Reticulocyte count
Mean red blood cell volume
Mean corpuscular haemoglobin
Mean corpuscular haemoglobin concentration
White blood cell count
Differential leucocyte count - Neutrophils
- Lymphocytes
- Eosinophils
- Basophils
- Monocytes
- Large unstained cells
Platelets
Coagulation tests
Prothrombin time
Clinical chemistry
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Gamma-glutamyltransferase
Urea
Creatinine
Glucose
Triglycerides
Bile acids
Phosphorus
Total bilirubin
Total cholesterol
Total protein
Albumin
Globulin
A/G Ratio
Sodium
Potassium
Calcium
Chloride
Urinalysis (Only males)
At the same time interval of the clinical pathology investigations, individual overnight urine samples were also collected from the same animals under the same conditions. Before starting urine collection, water bottles were removed from each cage and each animal received approximately 10 mL/kg of drinking water by gavage, in order to obtain urine samples suitable for analysis.
The measurements performed on urine samples are listed below:
Appearance
Volume
Specific gravity
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
The sediment, obtained from centrifugation at approximately 3000 rpm for 10 minutes, was examined microscopically for:
Epithelial cells
Leucocytes
Erythrocytes
Crystals
Spermatozoa and precursors
Other abnormal components - Sacrifice and pathology:
- Parental animals were killed by exsanguination under isofluorane anaesthesia.
Parental males:
The males were killed after completion of mating period after 31 days of treatment.
Parental females:
The females with live pups were killed on Day 4 post partum.
The females which did not give birth 25 days after positive identification of mating were killed shortly after.
Necropsy
The clinical history of the males and females of the parental generation was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices).
Changes were noted, the requisite organs weighed and the required tissue samples preserved in fixative and processed for histopathological examination.
Females:
All females were examined also for the following:
a) number of visible implantation sites (pregnant animals);
b) number of corpora lutea (pregnant animals).
Uteri of females with no visible implantations were immersed in a 10-20% solution of ammonium sulphide to reveal evidence of implantation.
Organ weights
From all animals completing the scheduled test period, the organs were dissected free of fat and weighed.
The ratios of organ weight to body weight were calculated for each animal.
Tissues fixed and preserved
Samples of all the tissues were fixed and preserved in 10% neutral buffered formalin (except eyes, optic nerves and Harderian glands, testes and epididymides which were fixed in modified Davidson's fluid and preserved in 70% ethyl alcohol).
Histopathological examination
After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin.
In addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS). The morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed.
The examination was restricted as detailed below:
a) Tissues specified in Annex 1 of protocol, from 5 males and 5 females randomly selected (animals evaluated for clinical pathology) in the control and high dose group killed at term.
b) All abnormalities in all groups. - Statistics:
- Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the non-parametric version of the Williams test. The criterion for statistical significance was p<0.05.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study.
A total of 6 females were found not pregnant at necropsy and distributed in the groups as follows:
Two in the control group (animal nos. 90950011 and 90950015);
One in the low dose group (animal no. 90950029);
One in the mid-dose group (animal no. 90950045);
Two in the high dose group (animal nos . 90950061 and 90950073).
The number of females with live pups on Day 4 post partum was: 8 in each of the control and high dose groups, 9 in each of the low and mid-dose groups.
Clinical signs
No relevant signs were observed in males and females throughout the study.
NEUROBEHAVIOUR
Clinical observations (Functional Observation Battery Tests) and Neurotoxicity assessment (removal of animals from the home cage and open arena)
Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test item.
Motor activity and sensory reaction to stimuli
No relevant differences were noted in all parameters investigated between control and treated groups.
BODY WEIGHT AND WEIGHT GAIN
No differences of toxicological significance were seen. The reduction in body weight gain noted on Day 15 of the mating phase in high dose males was considered incidental.
FOOD CONSUMPTION
No intergroup differences were seen in food consumption.
HAEMATOLOGY
No changes of toxicological significance were recorded.
The difference of platelets between control and treated animals was due to the low value of one control animal (no. 90950020).
The statistically significant difference of mean corpuscular volume recorded between control and animals dosed with 100 mg/kg/day (6%) was considered unrelated to treatment.
No changes were recorded at the coagulation tests.
CLINICAL CHEMISTRY
Males dosed with 1000 mg/kg/day showed statistically significant increase of protein (9%), albumin (7%), phosphorus (12%), calcium (6%) and decrement of chloride (2%). Those receiving 300 mg/kg/day showed increase of phosphorus (13%) and decrease of glucose (27%).
Females dosed with 300 and/or 1000 mg/kg/day showed decreases of aspartate aminotransferase (up to 23%) and urea (22%).
The above changes were of low severity or not dose-related, therefore considered of no toxicological relevance.
Bile acids showed a 7-fold increment in males receiving 1000 mg/kg/day. However, since only 2 animals (nos. 90950072 and 90950076) showed high values and due to the lack of other relevant findings (e.g. liver markers), this alteration was considered of no toxicological significance.
URINALYSIS
No changes were recorded in urinalysis parameters.
ORGAN WEIGHTS
No differences in terminal body weight or organ weights were seen between the controls and treated animals of both sexes.
GROSS PATHOLOGY
No treatment-related changes were noted.
All observed changes had comparable incidence in the control and treated groups and/or are known to occur spontaneously in untreated Sprague Dawley rats of the same age, under our experimental conditions.
HISTOPATHOLOGY
No treatment-related changes were noted.
All observed changes had comparable incidence in the control and treated groups and/or are known to occur spontaneously in untreated Sprague Dawley rats of the same age, under our experimental conditions.
Spermatogenic cycle
Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.
A single control male (no. 90950012) showed severe bilateral tubular atrophy. Such lesion was considered an expression of spontaneous pathology.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- 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:
- On the basis of the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for general toxicity is determined to 1000 mg/kg/day for males and females.
- Executive summary:
Study design
The effects of3-Trimethylammonium propyl methacrylamide chloride (50% solution in water)after repeated dosing, as well as any affects and on reproductive function such as gonadal function, mating behaviour, conception, parturition and development of offspring up to Day 4post partumwere evaluated in rats.
The test item, dissolved inpurified water, was administered by oral gavage to 3 groups of 10 males and 10 females each as indicated below. A similar constituted control group (Group 1) received the vehicle alone during the treatment period.
Group
Number
Treatment
(mg/kg/day)
Level
Number of animals
1
2
3
4
0
100
300
1000
Control
Low
Medium
High
10 males + 10 females
10 males + 10 females
10 males + 10 females
10 males + 10 females
Males were treated for 31 days including 2 weeks prior to pairing and continuously thereafter, up to the day before necropsy.
Females were dosed throughout the study including 2 weeks before pairing, thereafter during pairing, gestation and lactation periods until Day 3post partum.
The following parameters were evaluated in parental animals: body weight, clinical signs(including neurotoxicity assessment, motor activity and sensory reaction to stimuli), food consumption, oestrous cycle, mating performance, clinical pathology investigations (haematology, clinical chemistry and urinalysis only males), litter data, macroscopic observations, organ weights and histopathological examination.
Mortality and fate of females
No mortality occurred in the study.
A total of 6 females were found not pregnant at necropsy: two in each of the control and high dose groups and one in each of the low dose and mid-dose groups.
The number of females with live pups on Day 4post partumwere: 8 in each of the control and in the high dose groups, 9 in each of the low and mid-dose groups.
Clinical signs and clinical observations (Functional ObservationBatteryTests)
Clinical signs and functional observation battery tests were unaffected by treatment.
Body weight and body weight gain
Body weight and body weight gain were unaffected by treatment.
Food consumption
No effects on food consumption were observed.
Motor activity and sensory reaction to stimuli
No relevant differences were noted in all parameters investigated between control and treated groups.
Haematology
No changes of toxicological significance were observed in haematological parameters and coagulation tests.
Clinical chemistry
No toxicological relevant changes were noted, even if an increased value of bile acids was observed only in single males treated at 1000 mg/kg/day.
Urinalysis
No changes were recorded.
Terminal body weight and organ weights
No differences in terminal body weight or organ weights were seen between the controls and treated animals of both sexes.
Macroscopic and microscopic observations
No treatment-related changes were noted at macroscopic and microscopic examinations.
Evaluation of the spermatogenic cycle did not show differences between the groups. Regular layering in the germinal epithelium was noted.
Conclusion
On the basis of the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for general toxicity is determined to 1000 mg/kg/day for males and females.
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