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EC number: 948-071-5 | 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 February 2017 to 02 November 2017
- 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 guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of C12-14 tert-alkylamines and dimethyl hydrogen phosphate and methyl dihydrogen phosphate
- EC Number:
- 948-071-5
- IUPAC Name:
- Reaction mass of C12-14 tert-alkylamines and dimethyl hydrogen phosphate and methyl dihydrogen phosphate
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- -Purity: > 98%
-Physical description: Yellow semi-solid
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Details on test animals or test system and environmental conditions:
- Following receipt and until pairing, all F0 animals were housed 2–3 rats/cage by sex in clean, solid-bottom cages with bedding material (Bed-O'Cobs®; The Andersons, Cob Products Division, Maumee, OH).
The basal diet used in this study, PMI Nutrition International, LLC Certified Rodent LabDiet® 5002, was a certified feed with appropriate analyses performed by the manufacturer and provided to Charles River.
Actual mean daily temperature ranged from 72.5°F to 73.0°F (22.5°C to 22.8°C) and mean daily relative humidity ranged from 38.4% to 56.7% during the study. Fluorescent lighting provided illumination for a 12-hour light (0600 hours to 1800 hours)/12-hour dark photoperiod.
Air handling units were set to provide a minimum of 10 fresh air changes per hour.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples for concentration analysis were collected from the middle stratum of first, middle, and last dosing formulations (including the vehicle control group) prepared that included all dose groups. One set of samples from each collection was analyzed using a validated high performance liquid chromatography method with charged aerosol detection. The retention time of the test substance was approximately 1.5 to 2.1 minutes.
- Details on mating procedure:
- The animals were paired on a 1:1 basis within each treatment group following 14 days of treatment for the males and females.Positive evidence
of mating was confirmed by the presence of a vaginal copulatory plug or the presence of sperm following a vaginal lavage and verified by a second biologist. Each mating pair was examined daily. The day when evidence of mating was identified was termed Gestation Day 0 and the
animals were separated. If evidence of copulation was not detected after 14 days of pairing, the animals were separated without further opportunity for mating. - Duration of treatment / exposure:
- Males and females were approximately 10 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through Lactation Day 13 for a total of 49–54 doses; females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (Postcohabitation Day 25 or Postmating Day 25, respectively) for a total of 40–52 doses.
- Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- The dose selection was based upon a range-finding study (please see RSS section 7.5.1 Supporting study, Charles river, 2017).
Examinations
- Maternal examinations:
- All rats were observed twice daily, once in the morning and once in the afternoon, for moribundity and mortality.
Clinical observations, body weights, and food consumption recorded at appropriate intervals.
Motor activity was assessed for 5 animals/sex/group during the last week of dose administration (Study Day 25, males) or on Lactation Day 13 (females).
Blood samples for clinical pathology evaluations (hematology, coagulation, and serum chemistry) were collected from 5 animals/sex/group at the scheduled necropsies (Study Day 28 for males and Lactation Day 14 for females).
A complete necropsy was conducted on all F0 parental animals found dead or at the scheduled termination.
All F0 adults were euthanized by carbon dioxide inhalation. - Ovaries and uterine content:
- Vaginal lavages were performed daily and the slides were evaluated microscopically to determine the stage of the estrous cycle of each female for 14 days prior to randomization and continuing until evidence of copulation was observed or until termination of the mating period for females with no evidence of mating.
- Fetal examinations:
- Each litter was examined daily for survival, and all deaths were recorded. Each pup received a clinical examination on PND 1, 4, 7, 10, and 13. Pups were individually weighed on PND 1, 4, 7, 10, and 13. Pups were individually sexed on PND 0, 4, and 13. On PND 13, all F1 male offspring were evaluated for the presence of thoracic nipples/areolae.
On PND 13, surviving F1 rats were euthanized via an intraperitoneal injection of sodium pentobarbital. Blood samples were collected for thyroid hormone analysis immediately prior to euthanasia. - Statistics:
- Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals (N) used to calculate the mean. Statistical analyses were not conducted if the number of animals was 2 or less.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Females in the 250 mg/kg/day group had clinical observations of tremors, clonic convulsions, rales, and/or dilated pupils noted primarily at approximately 1.5 hours following dose administration; the observations of tremors, clonic convulsions, and dilated pupils were noted generally 1–4 days prior to the day of death while rales was observed throughout.
Other remarkable clinical observations noted occasionally throughout the dosing period for females that were found dead at 250 mg/kg/day included yellow material on various body surfaces (hindlimbs, urogenital area, anogenital area, and/or ventral trunk) noted at the detailed physical and/or daily examinations, and salivation, clear and/or red material around the mouth and/or nose, and clear nasal discharge noted at approximately 1.5 hours following dose administration. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 5 females were found dead at 250 mg/kg/day. Histologic findings indicate acute inflammation in the non-glandular stomach.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related, significantly (p < 0.05 or p < 0.01) lower mean body weight gains were noted in the 250 mg/kg/day group F0 males during Study Days 0–7 and 13–21 compared to the vehicle control group; mean body weight gains in this group were similar to the vehicle control group during Study Days 7–13 and 21–27.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related lower mean food consumption was noted in the 250 mg/kg/day group F0 males during Study Days 0–7 and 7–13 compared to the vehicle control group; the difference was significant (p < 0.05) during Study Days 0–7.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A significantly (p < 0.05) lower activated partial thromboplastin time (APTT) value was noted in the 250 mg/kg/day group F0 males compared to the vehicle control group; this difference was of minimal magnitude and was considered to be the result of normal biological variation and not test substance-related.
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- A significantly (p < 0.05) higher mean adrenal gland weight relative to final body weight was noted in the 250 mg/kg/day group F0 males. There were no histologic correlates and the mean remained within the historical control reference range. Thus, this finding was considered to be due to biologic variation and not test substance-related.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related raised and eroded areas in the stomach were noted in the 250 mg/kg/day group F0 females. These observations correlated with acute inflammation in the non-glandular stomach.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related microscopic findings were noted in the kidneys and stomach (glandular and non-glandular), these alterations were not considered adverse.
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- All 5 F0 females that were found dead at 250 mg/kg/day had 1–2 early and/or late resorptions in utero.
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- All 5 F0 females that were found dead at 250 mg/kg/day had 9–13 dead fetuses, but with no apparent malformations.
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 75 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- mortality
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Male and female F1 pup body weights at 250 mg/kg/day were lower (up to 38.2% and 40.7%, respectively) than the vehicle control group from PND 1 to 13.
- 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
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related effects on thyroid hormone values in the F1 males and females at any dosage level on PND 13. Differences from the vehicle control group were considered to be the result of normal biological variation and were not considered to be of toxicological significance.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 75 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for neonatal toxicity was 75 mg/kg/day based on the lower live litter size, lower postnatal survival, and lower pup body weights and body weight gains in the 250 mg/kg/day group.
- Executive summary:
The objectives of the study were to evaluate the potential toxic effects of the test material when administered to rats for at least 28 days and to evaluate the potential of the test substance to affect male and female reproductive performance such as gonadal function, mating behavior, and conception through day 13 of postnatal life. The study was performed to the standardized guideline OECD 422, under GLP conditions.
Under the conditions of this screening study, no test substance-related effects were observed on reproductive performance at any dosage level. Therefore, a dosage level of 250 mg/kg/day, the highest dosage level evaluated, was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of the test material when administered orally by gavage to Crl:CD(SD) rats.
Adverse lower mean body weights, body weight gains, and food consumption were noted for F0 males throughout the study and for F0 females at the beginning of the premating period and during gestation in the 250 mg/kg/day group.
Macroscopic findings consisted of raised and eroded areas in the stomach noted in the 250 mg/kg/day group females and histologic findings consisted of inflammation in the glandular and non-glandular stomach noted in the 250 mg/kg/day group males and females.
Based on these results, the NOAEL for parental systemic toxicity was considered to be 75 mg/kg/day.
The NOAEL for neonatal toxicity was 75 mg/kg/day based on the lower live litter size, lower postnatal survival, and lower pup body weights and body weight gains in the 250 mg/kg/day group.
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