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EC number: 701-402-5 | 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 observed "no-adverse-effect-level" of DMPPA_701-402-5 is 1000 mg/kg bw/day for males and females.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1992
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- Identification: DMPPA_701-402-5 (FAT 80001/I)
Description: White solid
Batch number: EN 746916/1991
Stability of test article: Expiry date: September 1996
Stability of test article dilution: Stable for atleast 48 h in water
Instructions for test article storage: At room temperature in the dark.
Vehicle: Bi-distilled water. - Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wölferstrasse 4 CH-4414 Fuellinsdorf
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 weeks
- Housing: Individually in Makrolon type-3 cages (size: 22 x 37.5 x 15 cm) with autoclaved standard softwood bedding ('Lignocel', Schill AG, CH-4132 Muttenz).
- Diet (e.g. ad libitum): Pelleted standard K U b a no. 343, Batches 87/91 and 79/92 rat maintenance diet ('Kliba', Klingentalmuehle AG, CH-4303 Kaiseraugst) ad libitum.
- Water (e.g. ad libitum): Community tap-water from Füllinsdorf was available ad libitum.
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 42 - 67
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h - Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- First, stock solutions of the test article in bidistilled water with concentrations of 1.12 mg/ml and 1.01 mg/ml were prepared as follows: 112 mg and 101 mg of the test article was each weighed into a 100 mL volumetric flask; then, about 70 mL of bidistilled water was added and these mixtures were treated in an ultrasonic bath for dissolution. Next, the volumetric flasks were filled to volume with bidistilled water. Finally, standard solutions were prepared by respective dilution of these stock solutions with bidistilled water to yield concentrations in the range from 10.1 µg/ml to 112.0 µg/ml. These standard solutions were used to calibrate the HPLC.
Analysis of Samples: About 2 g of each test article/vehicle mixture was precisely weighed (to the third decimal place) into a 100 mL volumetric flask. These mixtures were dissolved with about 70 mL of bidistilled water by treatment in an ultrasonic bath. Subsequently, the volumetric flasks were filled to volume with bidistilled water. These sample solutions were further diluted with bidistilled water to yield a concentration within the calibration range. Finally, an aliquot (10 µL) was quantified by HPLC.
HPLC-Determination: (Operating Conditions)
Apparatus:Merck L-6200 pump, Merck L-4000 photometer, Merck D-2500 integrator, Merck AS-2000 sampling unit.
Column: Nucleosil C-18 AB; 5 µm; 125 • 4.0 mm.
Eluent: Methanol: 30mL, Bi-distilled water 970 mL.
Flow rate: 0.5 ml/min.
Temperature: Room temperature
Injection volume: 10 µL
Detection: UV 200 nm - Duration of treatment / exposure:
- 28 d
- Frequency of treatment:
- daily, 7d/week
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Group 1: Control
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Group 2: Test group
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Remarks:
- Group 3: Test group
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4: Test group
- No. of animals per sex per dose:
- 10 males, 10 females (group 1 and 4)
5 males, 5 females (group 2 and 3) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:The dose levels were selected based on a previous non-GLP dose range finding toxicity study in Wistar rats.
- Rationale for animal assignment (if not random): Randomly allocated to groups by body weight. - Positive control:
- none
- Observations and examinations performed and frequency:
- FOOD CONSUMPTION: The food consumption was recorded once during the acclimatization period and weekly thereafter using an on-line electronic recording system consisting of a Mettler PM 4800 balance connected to the RCC computer.
BODY WEIGHTS: The body weight of each animal was recorded on the same days as the food consumption using the same recording system. Additionally, terminal body weights were recorded at necropsy.
VIABILITY / MORTALITY: Observations for viability and mortality were recorded once daily.
CLINICAL SIGNS: Signs of toxicity were assessed once dally. Descriptions of all abnormalities were recorded and the subsequent progress was monitored.
OPHTHALMOSCOPIC EXAMINATIONS
Dates:
at 4 weeks: March 27, 1992 (on all surviving animals)
at 6 weeks: April 10, 1992 (on all surviving animals of groups 1 and 4)
Ophthalmoscopic examinations were performed on all animals. A description of any abnormality was recorded. Examinations were performed at termination of treatment
and a second time on the recovery individuals of groups 1 and 4 at termination of the recovery period. 10 - 90 minutes after the application of a mydriatic solution (Dispersa AG, CH-8442 Hettlingen) the cornea, lens, anterior chamber, vitreous body and ocular fundus of both eyes were examined under dimmed light using a Heine BETA 200 Ophthalmoscope (Eisenhut Vet. AG, CH-4123 Allschwil).
CLINICAL INVESTIGATIONS: GENERAL
Blood samples for hematology and clinical biochemistry were collected from all animals under light ether anesthesia. The animals were fasted for approximately 18 hours before blood sampling but allowed access to water ad libitum. Blood samples were collected between 07.05 and 08.30 to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube. Urine was collected during the 18-hours fasting period into a specimen vial, using a metabolism cage.
Blood and urine sampling: The assays of blood and urine parameters were performed under internal laboratory quality control conditions to assure reliable test results.
ABSOLUTE AND RELATIVE ORGAN WEIGHTS
The following organ weights were taken from all animals necropsied at termination of treatment or recovery: Adrenals; Brain; Heart; Kidneys; Liver; Ovaries; Pituitary gland; Spleen; Testes; Thyroid, Parathyroid gland. - Sacrifice and pathology:
- NECROPSY:
All animals were weighed and necropsied and descriptions of all macroscopic abnormalities were recorded. Prior to necropsy, the animals were fasted for approximately 20 to 25 hours, but water was provided. Necropsies were performed by experienced prosectors. All animals surviving to the end of the observation period were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.
Samples of the following tissues and organs were collected from all animals at necropsy and fixed in phosphate buffered neutral 4 % formaldehyde solution: Adrenals; Aorta; Bone (sternum, femur); Bone marrow (sternum, femur); Brain; Cecum; Colon; Ouodenum; Epididymides; Esophagus; Eyes with optic nerve and Harderian gland; Mammary gland area; Femur including joint; Heart; Ileum; Jejunum; Kidneys; Larynx; Lacrimal gland, exorbital; Liver; Lung Infused with formalin; Lymph nodes, mandibular, mesenteric; Nasal cavity; Ovaries; Pancreas; Pituitary gland; Prostate gland; Rectum; Salivary gland, (mandibular, sublingual); Seminal vesicles; Sciatic nerve; Skeletal muscle; Skin; Spinal cord, (cervical, midthoradc, lumbar); Spleen; Stomach; Testes; Thymus; Thyroid incl. Parathyroid gland; Tongue; Trachea; Urinary bladder infused with formalin; Uterus; Vagina; Gross lesions.
HISTOPATHOLOGY
Slides of Adrenals, Heart, Kidneys, Liver, Spleen and Stomach collected at terminal sacrifice from the animals of the control and high-dose groups were examined by a pathologist. The same applied to all Gross lesions. All abnormalities were described and reported. - Other examinations:
- FOOD CONSUMPTION: The food consumption is calculated per rat individual and per food consumption interval. It expresses the average food consumed per animal and per day over the food consumption interval.
- Statistics:
- The following statistical methods were used to analyze the body weights, food consumption, organ weights, all ratios and clinical laboratory data:
- Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnetttest (many to one t-test) based on a pooled variance estimate was applied for the comparison between the treated groups and the control groups for each sex.
- The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The Fisher's exact test for 2x2 tables was applied to the overall spontaneous mortality data and for the overall ophthalmoscopy data.
- Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
- Individual values, means, standard deviations and statistics were round-off before printing. For example, test statistics were calculated on the basis of exact values for means and pooled variances and then rounded-off to two decimal places. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs of toxicity were observed in any animal throughout the entire study period.
- Mortality:
- no mortality observed
- Description (incidence):
- No death occurred throughout the entire study period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weight gain of male rats at 1000 mg/kg was slightly, but statistically significantly higher from treatment day 1 to 8, when compared with the corresponding controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption of male rats at 1000 mg/kg was slightly, but statistically significantly higher from treatment day 22 to 28, when compared with the corresponding controls.
- Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food consumption of male rats at 1000 mg/kg was slightly, but statistically significant higher from treatment day 22 to 28, when compared with the values of the corresponding controls.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities were detected on ophthalmoscopic examination in any animal.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- The assessment of hematological data included no changes of toxicological significance at termination of the treatment nor at the end of the treatment-free recovery period.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- The assessment of clinical bio data indicated no changes of toxicological significance at termination of the treatment nor at the end of the treatment-free recovery period. All differences in the results of the clinical laboratory data were considered to be incidental and of normal biological variation for rats of this strain and age.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- The assessment of urinalysis data indicated no changes of toxicological significance at termination of the treatment nor at the end of the treatment-free recovery period.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In female rats of group 2 (50 mg/kg) the heart weights as well as heart to body weight ratio were slightly, but statistically significantly higher when compared to the corresponding controls. In female rats of group 3 (200 mg/kg) a slightly, but significantly increased pituitary weight and pituitary to body weight ratio were noted. After termination of the recovery period a significantly higher spleen to brain weight ratio and a lower thyroid to body weight ratio were recorded in male rats of the high dose group (1000 mg/kg). No corresponding findings were observed in the females of the same group.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No treatment-related findings were detected during the necropsy.
The following findings are regarded as common:
kidneys: pelvic dilation, gravel in pelvis, cys
stomach/intestine: discolorations or red foci of the mucosa
thymus: discolorations and reddish or red foci
lymph nodes: discolorations and red foci
seminal vesicles: discoloration.
ovaries: discoloration.
uterus: discoloration.
exorbital lacrimal gland: red foci
The following findings are regarded as uncommon:
body cavities: black and firm nodule of the pancreatic tissue (animal no. 3, group 1)
testes: reduced in size, d=13x8 mm (animal no. 23, group 4)
Liver: diaphragmatic hernia and grey white foci (animal no. 52, group 4 ) . - Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The following, common microscopic findings correspond to some but not to all detected gross lesions:
foci/discolorations: congestion
pelvic dilation of kidneys: pelvic dilation
dilation of uterus: horn dilation (proestrus).
The nodule of the pancreatic adipose tissue of animal no. 3 was found to be an hemal lymph node. The testes of male no. 23 were hypoplastic with Sertoli's cells lining the tubules.
Corresponding to the diaphragmatic hernia of the liver of animal no. 52 was an hepatodiaphragmatic nodule which showed a slight, focal cholangiofibrosis and linear nuclear chromatin pattern. These nodules are a not uncommon spontaneous abnormality in rats.
All findings recorded are within the normal range of background alterations commonly observed in rats of this strain and at these ages. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- gross pathology
- mortality
- Critical effects observed:
- not specified
- Conclusions:
- The no-observed-adverse-effect-level (NOAEL) was set at 1000 mg/kg bw/day, the highest dose level tested.
- Executive summary:
The test article DMPPA_701-402-5 was administered orally by gavage, once daily at doses of 50, 200, and 1000 mg/kg/day for 28 consecutive days to rats of both sexes. This test was conducted in accordance with OECD TG 407 and EEC Directive 84/449 B.7 in a GLP compliant laboratory. The control animals received the vehicle (double-distilled water) only. After termination of the treatment period five rats per sex of the vehicle control group and at 1000 mg/kg/day were observed for a further 15-day treatment-free period. No death occurred throughout the entire study period and no clinical signs of toxicity were noted. The slightly, but statistically significantly higher food consumption during week 4 of treatment and body weight gain during week 1 in male rats at 1000 mg/kg are considered to be of coincidental origin. The assessment of hematological, clinical biochemical and urinalysis data indicated no changes of toxicological significance. No abnormalities were detected on ophthalmoscopic examination. The determination of organ weights and calculation of organ to body and organ to brain weight ratios revealed minor, but statistically significant deviations from the corresponding controls. Since no correlation with results of clinical laboratory investigations and pathological examinations could be established these deviations are considered to be of coincidental origin without any toxicological significance. There were no treatment-related macroscopic alterations detected at necropsy. The microscopic examination revealed no morphological evidence of toxicity produced by the treatment with DMPPA_701-402-5. Based on the results obtained in this study, the "no-adverse-effect-level" of DMPPA_701-402-5 is 1000 mg/kg body weight for male and female rats when administered orally by gavage for a period of 28 days.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- GLP guideline study
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
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
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
- Repeated dose toxicity, oral:
One fully reliable study is available (Brunke, 2010, Repeated dose toxicity: oral) conducted according to OECD 407 and GLP (28 d, oral gavage, doses: 50, 200 and 1000 mg/kg/ d, Wistar rats). No death occurred throughout the entire study period and no clinical signs of toxicity were noted. The slightly, but statistically significantly higher food consumption during week 4 of treatment and body weight gain during week 1 in male rats at 1000 mg/kg are considered to be of coincidental origin. The assessment of haematological, clinical biochemical and urinalysis data indicated no changes of toxicological significance. No abnormalities were detected on ophthalmoscopic examination. The determination of organ weights and calculation of organ to body and organ to brain weight ratios revealed minor, but statistically significant deviations from the corresponding controls. Since no correlation with results of clinical laboratory investigations and pathological examinations could be established these deviations are considered to be of coincidental origin without any toxicological significance. There were no treatment-related macroscopic alterations detected at necropsy. The microscopic examination revealed no morphological evidence of toxicity produced by the treatment with
DMPPA_701-402-5 . Based on the results obtained in this study, the "no-adverse-effect-level" of DMPPA_701-402-5 is 1000 mg/kg body weight for males and females.
- Repeated dose toxicity, inhalation:
Currently no study to assess the repeated dose inhalation toxicity potential of DMPPA_701-402-5 is available. However, the vapour pressure for the substance was found to be low (extrapolated <3 x 10E-02 Pa at 25 °C). Hence the substance is considered to have low volatility. Synthesis and formulation of this chemical is performed in a closed process; the final product consists of clear-viscous liquid with a low vapour pressure. All related products are not foreseen for spray application. Hence, the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur. Further, the chemical is found to have high water solubility of 8000 g/L, hence in the case of mists or vapours are inhaled and entering the respiratory tract, it will be trapped in the mucus and cleared, thereby further limiting the absorption. No systemic toxicity was observed when DMPPA_701-402-5 was administered up to 1000 mg/kg bw/day via gavage in a 28-day repeated dose toxicity study. Taking above arguments into consideration, low toxicity potential is expected on repeated exposure of DMPPA_701-402-5
via inhalation route and safety for human health can be estimated using the principles of route to route extrapolation. Hence, the conduct of repeated dose toxicity study via inhalation route for DMPPA_701-402-5 is considered to be scientifically not necessary.
- Repeated dose toxicity, dermal:
Currently no study to assess the repeated dose dermal toxicity of DMPPA_701-402-5 is available. It has water solubility of 8000 g/L and n-octanol/water partition coefficient (log P) of -1.86, indicating it being too hydrophilic to cross the lipid rich environment of the stratum corneum. Hence, the dermal uptake for the substance will be low. No systemic toxicity was observed when DMMPA_701-402-5 was administered upto 1000 mg/kg bw/day via gavage in a 28-day repeated dose toxicity study. Similarly, absence of systemic toxicity in skin irritation as well as sensitization studies, further supports the conclusion that low toxicity is expected for the chemical via the dermal route. Further experience with similar chemical substances has demonstrated that it is very unlikely that toxicity related to the intrinsic properties of the chemical only show up upon dermal exposure and not after systemic application. Taking into consideration the above arguments, low toxicity potential is expected on repeated exposure of DMPPA_701-402-5
via dermal route and safety for human health can be estimated using the principles of route to route extrapolation. Hence, the conduct of repeated dose toxicity study via dermal route for DMPPA_701-402-5 is considered to be scientifically not necessary.
Justification for classification or non-classification
Based on the available data, DMPPA_701-402-5 is not hazardous when exposed repeatedly via oral route. Therefore, no classification according to Regulation (EC) No. 1272/2008 is deemed to be required.
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