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EC number: 908-996-7 | 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:
- 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- dimethoxyphosphinic acid; methoxyphosphonic acid; phosphoric acid
- EC Number:
- 908-996-7
- IUPAC Name:
- dimethoxyphosphinic acid; methoxyphosphonic acid; phosphoric acid
- Test material form:
- other: liquid
- Details on test material:
- Reaction mass of methyl dihydrogen phosphate and orthophosphoric acid and dimethyl hydrogen phosphate
EC No.: 908-996-7
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- Test Animals
Source - Vivo Bio Tech Ltd, Sy # 349/A, Pregnapur-502311, Gajwel Mandal, Medak District, Telangana, India
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulation analysis was carried out from samples prior to the initiation of treatment and before the termination.
The prepared formulations was sampled in duplicate sets wherein one set was used for analysis and another was kept as back up set which was stored at room temperature in the experimental room. For each set, composite samples were drawn in three triplicates for each dose formulation. In case of control, duplicate composite samples were drawn. Dose formulations were sent for formulation analysis to determine the concentration of the test item using a validated analytical method (Study No.: G16490).
Formulations were considered acceptable if the overall mean result (calculated using all the 3 replicate values) is within ± 15.0 % of the claimed concentration and the relative standard deviation (% RSD, calculated using all the 3 replicate values) is equal to or less than 10.0 %.
The back up samples were either used for reanalysis when the results of first set of analysis were outside the acceptable limits or discarded if the results of first set of analysis were within the acceptable limits
- Details on mating procedure:
- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 12 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0] of pregnancy - Duration of treatment / exposure:
- 15 days
- Frequency of treatment:
- Gestation day 5 to Gestation day 19
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day
- Remarks:
- Group 2 (Low dose)
- Dose / conc.:
- 120 mg/kg bw/day
- Remarks:
- Group 3 (Mid dose)
- Dose / conc.:
- 300 mg/kg bw/day
- Remarks:
- Group 3 (High dose)
- No. of animals per sex per dose:
- Day '0" Pregnant rats : 24
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose Selection rationale
Based on the dose range finding study carried out by the sponsor at the doses of 100, 300 and 1000 mg/kg/day, the dose levels of 50 (G2), 120 (G3) and 300 (G4) mg/kg/day have been selected for this study in consultation with the Sponsor.
Vehicle control - 0 mg/kg/day
Low dose - 50 mg/kg/day
Mid dose - 120 mg/kg/day
High dose - 300 mg/kg/day
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day (pre dose and post dose)
- Cage side observations checked in table [No.2] were included
- At necropsy Thyroid gland was collected and weighed and subjected to histopathology
- Thyroid harmone analysis [T3, T4, TSH] - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Gross evaluation of placenta: Yes - Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
- Ano-genital distance: Yes: [all per litter]
- Fetus sex (external determination based on anogenital distance and internal sex based on gonadal examination) - Statistics:
- The data on maternal body weight, body weight change in interval, gravid uterine weight, body weight change corrected to gravid uterine weight, maternal food consumption, hormone analyses (T4, T3, TSH), weight of thyroid gland were analyzed using Analysis of Variance (ANOVA) after testing for homogeneity for intra group variance using Levene’s test. Where intra group variances are heterogeneous, ANOVA was performed after suitable transformation of data. Dunnett’s pairwise comparison of the treated group means with the control group mean was performed, when the group differences are found significant.
Fetal weight for male and female was analyzed using Analysis of Covariance (ANCOVA) taking litter size as covariate for group. Anogenital distance for male and female were analyzed using Analysis of Covariance (ANCOVA) taking weight as covariate for group.
Number of corpora lutea, number of implantations, early and late resorptions, pre-implantation and post-implantation loss, external, visceral and skeletal observations for variations were analyzed using Kruskal Wallis test for group comparison. Wilcoxon (Mann-Whitney) pairwise comparison of the treated groups with the control group was performed, when the group differences were significant.
The incidence of dams with and without resorptions was tested using Cochran Armitage trend test followed by Fisher’s exact test for group association.
Statistically significant differences (p<0.05) were designated as * throughout the report - Historical control data:
- Refer: Annexure 7 iin the Report
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs findings at any of the doses tested.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no mortalities at any of the doses tested
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean body weights and gains were comparable across the tested doses.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption were comparable across the tested doses.
- Clinical biochemistry findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Thyroid gland weights were unaffected by treatment.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross necropsy findings at any of the doses tested
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Histopathology of thyroid gland were unaffected by treatment.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Thyroid hormone profile (T3, T4 and TSH) were unaffected by treatment.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- Mean values of maternal parameters comprising uterine weight and number of corpora lutea, implantations, early deaths, late deaths,
pre-implantation loss and post implantation loss were statistically comparable to the vehicle control group up to the highest dose of
300 mg/kg/day - Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Pre-implantation loss and post implantation loss were statistically comparable to the vehicle control group up to the highest dose of
300 mg/kg/day - Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Early deaths and late deaths were statistically comparable to the vehicle control group up to the highest dose of
300 mg/kg/day
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- maternal abnormalities
- other: Teratogeneicity
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Male and female fetal weights were statistically comparable to vehicle control group up to the highest tested dose of 300 mg/kg/day
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- Fetal external examination revealed no signs of teratogenicity up to the highest tested dose of 300 mg/kg/day
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Fetal skeletal examination revealed no signs of teratogenicity up to the highest tested dose of 300 mg/kg/day
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Fetall visceral examination revealed no signs of teratogenicity up to the highest tested dose of 300 mg/kg/day
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: ne effects observed up to the highest dose tested
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Based on the findings of the OECD 414 study, the No Observed Adverse Effect Level (NOAEL) for maternal toxicity and fetal developmental toxicity is 300 mg/kg/day (highest dose tested).
- Executive summary:
An OECD 414 study was performed with the test substance. Ninety six presumed pregnant Wistar rats were assigned to four groups bybody weight stratification (Group 1 to Group 4) and each group (G1: control, G2: low dose, G3: mid dose and G4: high dose) consisted of 24 presumed pregnant rats (gestation day 0). Day `0' of gestation for each individual female rat in the study was considered as the day on which vaginal smear was found positive for sperm.
The test substance in vehicle (Milli-Q water) was administered at 0, 50, 120 and 300 mg/kg/day. The control group received the vehicle only. A constant dose volume of 10 mL/kg body weight was administered to all groups.
All rats were observed for clinical signs, morbidity and mortality, body weight changes and food consumption. Prior to caesarean section, blood was collected for Thyroid hormone analysis. At caesarean section on GD 20, dams were examined for gross pathological changes and thyroid gland was collected, weighed and subjected to histopathological examination. The uterus was removed by laparotomy, weighed and the contents were examined for number of implantation sites, early and late resorptions and number of fetuses. The number of corpora lutea in ovaries was counted. All the fetuses were sexed, weighed and examined for external malformations. Approximately half the number of fetuses from each dam was examined for visceral malformations and the remaining half was evaluated for skeletal malformations.
The main findings of the study are presented below:
- There were no mortalities, clinical signs or gross necropsy findings at any of the doses tested.
- Mean body weights and gains, food consumption were comparable across the tested doses.
- Mean values of maternal parameters comprising uterine weight and number of corpora lutea, implantations, early deaths, late deaths, pre-implantation loss and post implantation loss were statistically comparable to the vehicle control group up to the highest dose of 300 mg/kg/day.
- The litter parameters comprising total number of fetuses, number of live fetuses, male and female fetal weights, anogenital distance in male and female fetuses were statistically comparable to vehicle control group up to the highest tested dose of 300 mg/kg/day.
- Fetal external, visceral and skeletal examination revealed no signs of teratogenicity up to the highest tested dose of 300 mg/kg/day.
- Thyroid hormone profile (T3, T4 and TSH), thyroid gland weights and histopathology of thyroid gland were unaffected by treatment with the test item up to the highest dose of 300 mg/kg/day.
In conclusion, based on the above findings, the No Observed Adverse Effect Level (NOAEL) for maternal toxicity and fetal developmental toxicity is 300 mg/kg/day.
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