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EC number: 432-770-2 | CAS number: 139189-30-3
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29 November 2011 - 11 January 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to current OECD guidelines in compliance with GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Reference substance name:
- -
- EC Number:
- 432-770-2
- EC Name:
- -
- Cas Number:
- 139189-30-3
- Molecular formula:
- C38 H40 O8 P2
- IUPAC Name:
- 3-{[bis(2,6-dimethylphenoxy)phosphoryl]oxy}phenyl bis(2,6-dimethylphenyl) phosphate
- Test material form:
- other: granular solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Wistar rat was selected due to experience with this strain of rat in reproduction toxicity studies and known fertility.Young adult rats, approximately 10 weeks old at starting and 12 weeks at mating. The age range within the study was kept to the minimum practicable.Rodents were group-housed as practical, up to 5 animals/ group/cage (paired or single-housed during the mating and gestation/delivery period, respectively). Group housing allows social interaction and the deep wood sawdust bedding allows digging and other normal rodent activities (i.e. nesting).
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on exposure:
- The dosing solutions were administered daily by oral gavage, using a tipped gavage needle attached to a syringe. A volume of 4 mL/kg bw was administered to all animals. The actual volume administered was calculated and adjusted based on each animal’s most recent body weight. The test item was administered daily by oral gavage on a 7 days/week basis. Control animals were treated concurrently with the vehicle only. Dosing of both sexes began after a minimum of five days acclimatisation (A) and 2 weeks before mating and continued up to and including the day before the necropsy. Mating began after the animals have attained full sexual maturity and continued in both sexes during the mating period.
- Details on mating procedure:
- Mating began 2 weeks after the initiation of treatment with one female and one male of the same dose group (1:1 mating) in a single cage. Females remained with the same male until copulation occurred, up to 4 days. A vaginal smear was prepared daily for each female during the mating period and stained with 1% aqueous methylene blue solution. The smears were examined with a light microscope, the presence of vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (Day 0 of pregnancy as defined by the relevant guidelines). Sperm positive females were caged individually. Mating pairs were clearly identified in the data, mating of siblings was avoided.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of test item formulations for concentration and homogeneity was performed in the Analytical Laboratory of CiToxLAB Hungary Ltd. Top, middle and bottom duplicate samples were taken from test item formulations on 3 occasions, during the first and last week and midway (29 November 2011, 21 December 2011 and 09 January 2012), one set to analyse, collected in replicates as practical, and one set as a back-up, which was not required for confirmatory analyses. Similarly, one sample was taken in duplicate from the Group 1 (control) solution for concentration measurements.
- Duration of treatment / exposure:
- 1/Control002/Low dose5012.53/Mid dose25062.54/High dose1000250
- Frequency of treatment:
- Females were dosed for 14 days pre-mating, for up to 4 days mating period, through gestation and up to and including the day before necropsy, 4 days post-partum dosing. The day of birth (viz. when parturition was complete) was defined as Day 0 post-partum. There was no female during the study that showed no-evidence of copulation (non-mated). Not-delivered female 2502 was sacrificed 26 days after the last day of mating, as practical. Female 4503 was found dead and underwent necropsy with macroscopic examination on Day 11, before the onset of mating.
- Details on study schedule:
- Details of schedule attached to technical dossier.The dosing solutions were administered daily by oral gavage, using a tipped gavage needle attached to a syringe. A volume of 4 mL/kg bw was administered to all animals. The actual volume administered was calculated and adjusted based on each animal’s most recent body weight. The test item was administered daily by oral gavage on a 7 days/week basis. Control animals were treated concurrently with the vehicle only. Dosing of both sexes began after a minimum of five days acclimatisation (A) and 2 weeks before mating and continued up to and including the day before the necropsy. Mating began after the animals have attained full sexual maturity and continued in both sexes during the mating period.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:50Basis:nominal conc.peanut oil
- Remarks:
- Doses / Concentrations:250Basis:nominal conc.peanut oil
- Remarks:
- Doses / Concentrations:1000Basis:nominal conc.peanut oil
- No. of animals per sex per dose:
- 48 male, 48 female rats and sufficient spare animals/sex, 12 male and 12 female rats/group, 4 groups, were assigned to the study
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- Females were allowed to litter and rear their offspring. Delivery process was carefully observed. All observations were recorded and the animals monitored for any evidence of abnormal deliveries. The duration of gestation was recorded and was calculated from Day 0 of pregnancy. Dams were observed to record whether they form a nest from the bedding material and cover their new-borns or not. The efficiency of suckling was observed by the presence of milk in the pups' stomach. All observations were recorded. Each litter was examined as soon as possible after delivery to establish the number and sex of pups, stillbirths, live births, runts (pups that are significantly smaller than normal pups) and the presence of gross abnormalities. Live pups were counted, sexed, weighed individually within 24 hours of parturition (on the first day after parturition was complete, i.e. Day 0 or 1 post-partum) and on Day 4 post partum with an accuracy of 0.01g.Observations are reported individually for each adult animal. In addition to the observations on parent animals, the offspring F1 generation was examined daily for the number of viable and dead pups or any clinical or behavioural abnormalities.
- Oestrous cyclicity (parental animals):
- A vaginal smear was prepared daily for each female during the mating period and stained with 1% aqueous methylene blue solution. The smears were examined with a light microscope, the presence of vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (Day 0 of pregnancy as defined by the relevant guidelines). Sperm positive females were caged individually. Mating pairs were clearly identified in the data, mating of siblings was avoided.
- Litter observations:
- All F1 offspring were terminated on Day 4 post-partum.
- Postmortem examinations (parental animals):
- Gross necropsy was performed on each animal irrespective of the date of death. Terminally (one day after the last treatment), animals were sacrificed under pentobarbital anaesthesia (details are presented in "Details of Other Materials") by exsanguination. After exsanguination the external appearance was examined, cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed macroscopically. Any abnormality was recorded with details of the location, colour, shape and size, as appropriate. Special attention was paid to the organs of the reproductive system. The number of implantation sites and of corpora lutea was recorded.At the time of termination, body weight and weight of the following organs of all parental animals were determined:- With a precision of 0.01 g: uterus (with and without cervix), vagina, testes, epididymides (total and cauda), prostate, seminal vesicles with coagulating glands, brain- With a precision of 0.001 g: ovaries, pituitary Paired organs were weighed individually; absolute organ weights were measured and are reported. Relative organ weights (to body and brain weight) were calculated and are reported. The weighed organs and all organs showing macroscopic lesions of all adult animals were preserved. The eyes with the optic nerve were retained in modified Davidson’s fixative. Testes and epididymides were preserved in Bouin’s solution, all other organs in 10% buffered formalin solution.
- Postmortem examinations (offspring):
- Pups euthanized at PND 4 were carefully examined at least externally for gross abnormalities. Detailed histological examination was performed on the selected list of retained organs in the control and high dose groups, found dead female 4503, and any macroscopic findings (abnormalities) observed. Special attention was paid to evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.The retained tissues and organs were embedded in paraffin wax, sections were cut at 4-6µ by microtome and transferred to slides. Tissue sections were stained with haematoxylin-eosin/phloxine and examined by light microscope. No additional examination was required, as no test item related findings were noted.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to adverse toxic effects at highest dose / concentration tested
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to adverse toxic effects at highest dose / concentration tested
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Summary of report
| Dose (mg/kg bw/day) | |||
Control | 50 | 250 | 1000 | |
Pairs started (N) | 12 | 12 | 12 | 11$ |
Surviving females showing evidence of copulation (N) | 12/12 | 12/12 | 12/12 | 11/11 |
Females achieving pregnancy (N) | 12/12 | 11/12 | 12/12 | 11/11 |
Conceiving days 1 - 5 (N) | 12 | 11 | 12 | 11 |
Pregnancy ≤ 21 days (N) | 1 | 4 | 4 | 2 |
Pregnancy = 22 days (N) | 11 | 7 | 8 | 9 |
Pregnancy ≥ 23 days (N) | 0 | 0 | 0 | 0 |
Dams with live young born (N) | 12 | 11 | 12 | 11 |
Dams with live young at PN4 (N) | 12 | 11 | 12 | 11 |
Corpora lutea/dam (mean) | 13.25 | 14.27 | 13.42 | 12.55 |
Implantations/dam (mean) | 13.00 | 14.00 | 12.92 | 12.27 |
Live pups/dam at birth (mean) | 12.75 | 13.73 | 12.83 | 11.91 |
Live pups/dam at day 4 (mean) | 12.67 | 13.64 | 12.67 | 11.73 |
Sex ratio at birth (mean) | 50.56 | 54.86 | 57.34 | 39.19 |
Sex ratio at PN4 (mean) | 50.82 | 54.51 | 56.83 | 39.70 |
Litter weight (g) at birth (mean) | 85.2 | 87.3 | 81.2 | 78.1 |
Litter weight (g) at day 4 (mean) | 132.2 | 140.6 | 128.7 | 124.3 |
Pup weight (g) at birth (litter mean) | 6.708 | 6.367 | 6.429 | 6.579 |
Pup weight (g) at day 4 (litter mean) | 10.493 | 10.364 | 10.325 | 10.728 |
STRUCTURALLY ABNORMAL PUPS | ||||
Dams with 0/Dams with live born | 12/12 | 11/11 | 12/12 | 11/11 |
Dams with 1 or ≥2 | 0 | 0 | 0 | 0 |
LOSS OF OFFSPRING | ||||
Pre-implantation (corpora lutea minus implantations) | ||||
Females with 0 | 10/12 | 8/12# | 9/12 | 9/11 |
Females with 1 | 1/12 | 3/12# | 2/12 | 1/11 |
Females with 2 | 1/12 | 0/12# | 0/12 | 1/11 |
Females with ≥3 | 0/12 | 1/12# | 1/12 | 0/11 |
Pre-natal/post-implantations (implantation's minus live births) (intrauterine) | ||||
Females with 0 | 9/12 | 8/11 | 11/12 | 9/11 |
Females with 1 | 3/12 | 3/11 | 1/12 | 1/11 |
Females with 2 | 0/12 | 0/11 | 0/12 | 0/11 |
Females with ≥3 | 0/12 | 0/11 | 0/12 | 1/11 |
Post-natal (live births minus alive at post-natal day 4) | ||||
Females with 0 | 11/12 | 10/11 | 11/12 | 10/11 |
Females with 1 | 1/12 | 1/11 | 0/12 | 0/11 |
Females with 2 | 0/12 | 0/11 | 1/12 | 1/11 |
Females with ≥3 | 0/12 | 0/11 | 0/12 | 0/11 |
Applicant's summary and conclusion
- Conclusions:
- The no observed effect level NOEL and no observed adverse effect level NOAEL of PX-200 for the parent P males and for the offspring F1 generation was considered to be equal to or greater than 1000 mg/kg bw/day.
- Executive summary:
The purpose of this study was to obtain initial information on the possible effects of the test item on reproduction and development by repeated oral gavage daily administration to Wistar rats at 50, 250 and 1000 mg/kg bw/day, 4 mL/kg in peanut oil, compared to control animals,treated with the vehicle only.As a screening test, it was intended to provide initial information on possible effects on male and female reproductive performance such as gonadal function, mating behaviour, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to Day 4 post-partum associated with administration of repeated doses. Twelve male andtwelvefemale Wistar rats/group were treated according to the followingExperimental Design:
Group no./ Designation
Dose Level
(mg/kg bw/day)
Concentration
(mg/mL)
Dose volume
(mL/kg)
Animal Numbers
Male
Female
1/Control
0
0
4
1001-1012
1501-1512
2/Low dose
50
12.5
2001-2012
2501-2512
3/Mid dose
250
62.5
3001-3012
3501-3512
4/High dose
1000
250
4001-4012
4501-4512
Dose formulation preparation was conducted for use within 1 day at room temperature or 5 days when stored refrigerated at 2-8°C, according to the stability assessment on CiToxLAB study code 10/235-316AN. Analysis of test item formulations for concentration and/or homogeneity was performed at CiToxLAB Hungary Ltd. Top, middle and bottom duplicate samples were taken from test item formulations during the first and last week and midway (29 November 2011, 21 December 2011 and 09 January 2012), and one sample was taken from the Group 1 (control) solution for concentration measurements.
No test item was identified in the control samples. The test item formulations appeared homogenous by visual inspection and had actual concentrations of 99-103% of the nominal concentrations. These results were considered within the acceptance criteria of 100±10% and suitable for the study purposes.
Adult animals were inspected for signs of morbidity and mortality twice daily. Clinical observations were performed once daily, with detailed examination performed weekly. Special attention was paid to evaluation of the mating, pregnancy, parturition and post-partum periods, and relevant parameters and/or indices were measured and/or calculated. Body weight and food consumption were measured at least weekly.
After delivery, all pups from each litter were counted, sex established, weighed on post-natal days PND 0 and 4, offspring evaluated for presence of stillbirths, live births, runts (pups that are significantly smaller than normal pups) or any gross abnormalities, then examined clinically at least daily.
Gross necropsy of the adult parental animals was conducted at the end of the treatment period and weights of standard list of organs were measured. Pups euthanized at PND 4 were carefully examined at least externally for gross abnormalities.
Detailed histological examination was performed on the selected list of retained organs in the control and high dose groups, found dead female 4503, and any macroscopic findings (abnormalities) observed. Special attention was paid to evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.
There were no test item-related clinical signs or unscheduled mortality recorded during the study.
One female was found dead on Day 11, before the onset of mating, due a dosing accident, unrelated to the test item. As of Day 8, prior to its death, clinical signs including red liquid from the nostrils and hunched back position were noted, followed by decreases in activity on Day 10, then death on Day 11. At necropsy, oesophagus perforation confirmed the dosing accident, associated with white, creamy material in the thoracic cavity, dark red discoloration noted in the lungs and thickened rough surface in the pericardium and pleura. The cause of death was not ascribed to a test item-related effect, but considered due to the moderate, mixed cellular inflammation in the pleura, pericardium and oesophagus caused by the perforation (misgavage) of the oesophagus.
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