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EC number: 941-634-6 | CAS number: 1228284-78-3
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Remarks:
- The developmental toxicity study was conducted solely to comply with non-EU national registration requirement, and has been provided here in accordance with REACH, Article 22(1)e.
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26 January 2016 to 30 May 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: JMAFF, 12 - NohSan 8147
- Version / remarks:
- 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- methoxy[1-(2,4,6-trichlorophenyl)propan-2-yl]amine
- EC Number:
- 941-634-6
- Cas Number:
- 1228284-78-3
- Molecular formula:
- C10H12Cl3NO
- IUPAC Name:
- methoxy[1-(2,4,6-trichlorophenyl)propan-2-yl]amine
- Test material form:
- other: liquid
- Details on test material:
- - Physical state: Brown liquid
- Expiration date of the lot/batch: Recertification date end May 2017
- Storage condition of test material: Room temperature (<30°C), protected from light and humidity
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, CT9 4LT, England
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 182 to 244 g
- Housing: individually in grid-floor cages over paper lined trays
- Diet and Water (e.g. ad libitum): A pelleted rodent diet, VRF1 (manufactured by SDS) supplied by Charles River (UK) Limited, Margate, Kent, CT9 4LT, England, and mains tap water (in bottles) were freely available
- Acclimation period: At least two days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 °C to 23 °C
- Humidity (%): 40 % to 70 %
- Air changes (per hr): not specified (air-conditioned)
- Photoperiod (hrs dark / hrs light): illuminated by fluorescent light set to give a cycle of 12 hours light and 12 hours dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: as a suspension in 1 % (w/v) carboxymethylcellulose with 1 % (v/v) Tween 80
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
A weighed quantity of test item was added to the final preparation container and approximately 90 % of the final weight of vehicle was added gradually, whilst stirring. The formulation was then stirred and heated to a maximum of 50 °C until a homogeneous mixture was formed. The formulation was allowed to cool before adding vehicle up to the final weight and stirring until mixed. All formulations prepared for Group 4 (formulation concentrations of 12 mg/mL) were homogenised, with the exception of that given on Day 1. The formulation was then divided between amber glass bottles for dosing and stored refrigerated.
Formulations were removed from refrigerated storage and stirred for at least 15 minutes before the start of dosing and until completion of dosing. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples taken from each test item formulation prepared for the first day of dosing were analysed for the test substance using a validated method (BFI030LC (4)) to confirm homogeneity and also achieved concentrations. Having confirmed homogeneity for the first day of dosing for Groups 2 and 3, samples were taken from all test item formulations prepared for use towards the last day of dosing and analysed to confirm concentration only. For Group 4 only, formulations prepared on each occasion were assessed for homogeneity and achieved concentrations. For formulations prepared for Control animals, samples were taken from formulations prepared for the first day of dosing and towards the end of the dosing period and were analysed to confirm absence of test item.
All remaining samples were retained and discarded once the final formulation analysis results were accepted. - Details on mating procedure:
- For mating, each female was paired with a male of the same strain. The day on which mating was detected was designated Day 0 of gestation.
- Duration of treatment / exposure:
- From Day 6 to Day 19 of gestation, inclusive,
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day
- Dose / conc.:
- 25 mg/kg bw/day
- Dose / conc.:
- 60 mg/kg bw/day
- No. of animals per sex per dose:
- 22 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were selected on the basis of results from a previous study performed at Sequani (28 Day Oral gavage Stuy Sequani Study Numbers: BFI0239 (1) and Reproduction/Developmental Toxicity Screening Study BFI0319 (2)).
- Species selection rationale: The Han Wistar derived rat is commonly used in reproduction studies because of the good fertility and fecundity of the strain. Background data on the rate of spontaneous malformations have been accumulated by Sequani.
The route of administration was oral (gavage) in accordance with OECD Test Guideline 414, as the oral route is considered a possible route of human exposure.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were examined twice daily for mortality and morbidity and were given a detailed clinical examination daily.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on Day 0 of gestation by the supplier. At Sequani, body weights were recorded daily from Day 5 to 20 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
The amount of food consumed by each animal was recorded over Days 6 to 9, 9 to 12, 12 to 15, 15 to 18, and 18 to 20 of gestation.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The major organs were examined. Gravid uterus and placenta weights were recorded and organs or tissues showing any macroscopic abnormalities were removed and retained in fixative.
The uterus of any apparently non-pregnant female was stained with ammonium sulphide to confirm pregnancy status. The uterus was then retained in 70 % IDA (industrial denatured alcohol) for approximately seven days and then transferred and retained in neutral buffered formaldehyde.
OTHER: - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes /
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- On Day 20 of gestation, live foetuses were killed by rapid cooling, weighed, sexed and examined for external abnormalities.
Approximately 50 % of the live foetuses were allocated to the fixed head examination. All foetuses were briefly placed in 70 % alcohol and subjected to micro-dissection, where the viscera were examined and the foetuses eviscerated. The foetuses allocated to the fixed head examination were decapitated and the heads were fixed in Bouin's fluid for serial sectioning. A coronal section was made through the head of the intact foetuses along the frontal parietal suture and the brain examined. All carcasses were then cleared in potassium hydroxide, stained with Alizarin red S and Alcian blue to visualise the ossified skeleton and cartilage and examined.
Structural congenital abnormalities that impair, or potentially impair, the survival or constitution of the foetus were classified as major abnormalities. Other defects were classified as minor abnormalities or variants.
Foetuses with major external or visceral abnormalities were photographed.
For archiving, all foetal heads fixed in Bouin's fluid were stored in neutral buffered formaldehyde and all skeletal specimens were stored in aqueous glycerol with thymol crystals (to prevent fungal growth). - Statistics:
- For Quantitative Data: Body weight, cumulative body weight gain from the start of dosing, food intake, terminal body weight, numbers of corpora lutea, implants, live foetuses, dead foetuses, early deaths, late deaths, gravid uterus weight, total litter weight, placental weight and mean foetal weight (sexes separately and combined) were analysed using a parametric ANOVA.
For Percentages: Pre-implantation loss, post-implantation loss, sex ratios and litter based mean percentages were analysed using a parametric ANOVA, following a double arcsine transformation.
Maternal Performance: (e.g. the proportion of females with live foetuses at termination, abortions, total resorptions) were analysed by a two-tailed Fisher’s Exact Text, comparing each treated group to the control group.
Foetal Morphology Data: The incidence of foetal malformations and developmental variations (external, visceral and skeletal) were summarised as the proportion of foetuses affected, the proportion of litters affected and the proportion of foetuses affected within each litter. The proportions of litters affected were analysed by the exact version of the CochranArmitage Test. The percentages of foetuses affected within each litter will be analysed by the exact version of the Jonckheere Trend Test. In both cases the tests will be performed in a step-wise manner, where, when a test is significant at the 5% level, the test is repeated after removing the then top dose, until only the control group is left. Tests will be one-sided looking for increase in treated groups versus the control group.
Dunnett’s Test: Dunnett’s Test was used to compare the control and treated groups, based on the error mean square in the ANOVA or ANCOVA. The Dunnett’s Test was performed for all continuous data parameters, regardless of whether the initial ANOVA or ANCOVA was statistically significant, and statistical flags were presented in the tables of results in the final report.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no test item-related clinical observations during the study.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no deaths during the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 60 mg/kg/day, there was a group mean body weight loss from Day 6 to 8 of gestation, resulting in a statistically significantly lower (p<0.05) mean body weight on Day 9 of gestation (6 %) only. However, when adjusted for the weight of the gravid uterus, the mean body weight gain over the dosing period was 29 % lower than the Controls, which was statistically significant (p<0.01).
For animals given 25 mg/kg/day, mean body weight gain was initially lower than the Controls over Days 6 to 7 of gestation. However, from Day 7 of gestation mean body weight gain was similar to the Controls, with overall body weight gain and absolute body weight on Day 20 of gestation, when adjusted for the weight of the gravid uterus, also similar to that of the Control group. The slight effect on body weight gain only at the start of the dosing period is not considered adverse.
At 10 mg/kg/day, body weight and body weight gains were similar to the Controls - Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Food intake for animals given 60 mg/kg/day was statistically significantly lower than the Controls throughout most of the dosing period, resulting in 14 % lower overall mean food intake for this group.
For animals given 10 or 25 mg/kg/day, food intake was similar to Controls throughout the dosing period. - Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no maternal necropsy findings that were considered to be related to the substance.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- With the exception of one female given 25 mg/kg/day, all females were pregnant, resulting in 22, 22, 21 and 22 females with live foetuses in the groups given 0, 10, 25 and 60 mg/kg/day, respectively, on Day 20 of gestation.
For females given 10, 25 and 60 mg/kg/day, the mean number of implantations and the mean number of live foetuses were unaffected by the test item administration. - Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- For females given 10, 25 and 60 mg/kg/day, the incidences of pre- and post-implantation loss were unaffected by the test item administration.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- the mean number of live foetuses were unaffected by the test item administration.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 25 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There was no adverse effect of test item administration on mean foetal or placental weight, values were similar to the Control group.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- There was no effect of the substance on the incidence of major malformation.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no major foetal abnormalities noted in the Controls or the groups given 25 or 60 mg/kg/day. Major foetal abnormalities were noted in two foetuses from two litters in the group given 10 mg/kg/day. These were as follows:
10 mg/kg/day
Female 35 Foetus L7 One or more bifid sternebra
Female 42 Foetus R6 Absent hemicentrum from the thoracic vertebra Absent neural arch from the thoracic vertebra One or more ribs arising from the same neural arch
There was no effect of the test item on the incidence of minor foetal malformations and no adverse effect on the incidence of foetal variations. Although slight differences in foetal variations on the rate of cartilaginous and skeletal development were observed between the groups, achieving slight statistical differences on some occasions, all elements within the cartilage and/or skeleton were considered to be developing normally, following the expected chronological pattern for normal development. Consequently, the changes in incidence of the foetal variations recorded were considered to be transient and not to be indicative of abnormal cartilage or skeletal development. - Visceral malformations:
- no effects observed
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- skeletal malformations
Fetal abnormalities
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- skeletal: rib
- skeletal: vertebra
- Description (incidence and severity):
- Major foetal abnormalities were noted in two foetuses from two litters in the group given 10 mg/kg/day CA5204A. These were as follows:
10 mg/kg/day
Female 35 Foetus L7 One or more bifid sternebra
Female 42 Foetus R6 Absent hemicentrum from the thoracic vertebra
Absent neural arch from the thoracic vertebra
One or more ribs arising from the same neural arch
Overall developmental toxicity
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 25 mg/kg/day, while the NOAEL for embryo-foetal development was considered to be 60 mg/kg/day.
- Executive summary:
Four groups of 22 sexually mature timed-mated female Crl:WI(Han) rats were dosed, once daily by oral gavage, with the test item or vehicle, 1 % (w/v) carboxymethylcellulose with 1 % (v/v) Tween 80. Animals were given 0, 10, 25 or 60 mg/kg/day from Day 6 to Day 19 of gestation, inclusive.
Body weights, food intake and clinical observations were recorded. All animals were killed on Day 20 of gestation, a necropsy performed and the internal organs examined for gross abnormalities. The progress and outcome of pregnancy were assessed and maternal dead body weight, gravid uterus and placenta weights were recorded. The foetuses were removed from the uterus, weighed, sexed and examined for external, visceral and skeletal abnormalities.
There were no deaths and no test item-related clinical observations.
At 60 mg/kg/day, there was an initial loss in group mean body weight from the start of the dosing period which resulted in an overall body weight gain for the dosing period which was lower than the Controls. Despite an initial reduction in body weight gain after the start of dosing at 25 mg/kg/day, overall body weight gain in the groups given 10 or 25 mg/kg/day was similar to the Control group.
At 60 mg/kg/day, mean food intake was reduced throughout most of the dosing period, resulting in overall mean food intake being 14 % lower than Controls. Food intake at 10 or 25 mg/kg/day was similar to the Controls.
There were no test item-related maternal necropsy findings and there was no effect of CA5204A on uterine or implantation data. Mean foetal and placental weights and foetal sex ratio were unaffected by CA5204A.
On this basis the No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 25 mg/kg/day, while the NOAEL for embryo-foetal development was considered to be 60 mg/kg/day.
There was no adverse effect of CA5204A on the incidences of major, minor or variant foetal abnormalities.
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