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EC number: 701-337-2 | 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 15 April 1996 - 9 January 1997
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study was conducted under GLP conditions and according to a guideline equivalent or similar to OECD guideline 416.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
- Reference Type:
- publication
- Title:
- Two-generation oral (diet) reproductive toxicity study of resorcinol bis-diphenylphosphate (Fyrolflex RDP) in rats
- Author:
- Henrich, R., Ryan, B.M., Selby, R., Garthwaite, S., Morrisey, R., Freudenthal, R.I.
- Year:
- 2 000
- Bibliographic source:
- International Journal of Toxicology, 19, 243-255
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3-[(diphenoxyphosphoryl)oxy]phenyl diphenyl phosphate
- EC Number:
- 701-337-2
- Cas Number:
- not available
- Molecular formula:
- C30H24O8P2
- IUPAC Name:
- 3-[(diphenoxyphosphoryl)oxy]phenyl diphenyl phosphate
- Details on test material:
- - Name of test material (as cited in study report): Fyrolflex RDP
- Physical state: Liquid
- Lot/batch No.: Confidential information
- Storage condition of test material: In original container at room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms (Germantown, NY)
- Age at study initiation: (P) 6 wks
- Weight at study initiation: (P) Males: 113-138 g; Females: 101-128 g
- Housing: Individually under standard conditions
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum, municipal tap water
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Batches of dosing formulation were prepared weekly by mixing amounts of Fyrolflex RDP appropriate to each dose level with powdered rodent chow.
DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Purina Certified Rodent Meal - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability and homogeneity under the conditions of this study was confirmed.
- Duration of treatment / exposure:
- (P) Males: 10 weeks prior to mating, during and up to 2-3 weeks of mating and until sacrifice
(P) Females: 10 weeks prior to mating, during and up to 2-3 weeks of mating, during gestation up to weaning of F1 (postnatal day 25) and until sacrifice
(F1) Males: 11 weeks starting at weaning, during and up to 2 weeks of mating and until sacrifice
(F1) Females: 10 weeks prior to mating, during and up to 2-3 weeks of mating, during gestation up to weaning of F1 (postnatal day 25) and until sacrifice
(F2) No treatment - Frequency of treatment:
- Continuous (in diet)
- Details on study schedule:
- - Selection of parents from F1 generation when pups were 25 days (weaning) of age.
- Age at mating of the mated animals in the study: 14 weeks
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 1000, 10000, 20000 mg/kg (ppm) food
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
0, 49, 520, 995 mg/kg bw/day
Basis:
analytical conc.
(P) males
- Remarks:
- Doses / Concentrations:
0, 59, 602, 1199 mg/kg bw/day
Basis:
analytical conc.
(P) females
- Remarks:
- Doses / Concentrations:
0, 55, 602, 1260 mg/kg bw/day
Basis:
analytical conc.
(F1) males
- Remarks:
- Doses / Concentrations:
0, 63, 683, 1411 mg/kg bw/day
Basis:
analytical conc.
(F1) females
- No. of animals per sex per dose:
- (P) 30 males and 30 females
(F1) 60 animals - Control animals:
- yes, plain diet
- Details on study design:
- No data
- Positive control:
- Not relevant
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations: morbidity and mortality, also parturition in dams during gestation
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly prior to mating, but not during mating. Thereafter, males weekly until sacrifice, females on day 0, 6, 12, 18 and 20 of gestation and on postnatal day 0, 4, 7, 14 and 21.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly prior to mating, but not during mating. After mating, male food consumption was measured weekly until sacrifice, female food consumption on day 0, 6, 12, 18 and 20 of gestation, on postnatal day 0, 4, 7, 14 and 21 and weekly thereafter. - Oestrous cyclicity (parental animals):
- Daily vaginal smears were collected for the (P) and (F1) females for three weeks prior to mating to ensure and evaluate cyclicity. In addition, vaginal smears were collected and evaluated from these rats for two to three days prior to, and on the day of necropsy to determine the stage of the estrus cycle at termination
- Sperm parameters (parental animals):
- Parameters examined in P and F1 male parental generations: testis weight, epididymis weight, sperm count in epididymides, sperm motility, sperm morphology
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- Maximum of 4 pups/sex/litter; excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals between end of mating and weaning of pups
- Maternal animals: All surviving animals after weaning of pups
GROSS NECROPSY
- Gross necropsy included examination of the external surface and pleural, peritoneal and cranial activities
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared and examined for gross lesions:
Vagina, uterus, ovaries with oviducts, cervix, stomach, pituitary, testes, epididymides, prostate, brain, liver, kidneys, adrenals, spleen, thymus, seminal vesicles.
Tissues below were also weighed:
Uterus, ovaries with oviducts, testes, epididymides, prostate, brain, liver, kidneys, adrenals, spleen, thymus, seminal vesicles.
Tissues below were also processed for histopathology:
Vagina, uterus, ovaries with oviducts, cervix, testes, epididymides, prostate, seminal vesicles. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 25 days and 21 days of age, respectively.
- These animals were not subjected to postmortem examinations
GROSS NECROPSY
- Gross necropsy of F1 included examination of the external surface and pleural, peritoneal and cranial activities. F2 generation rats were euthanized and discarded without necropsy.
HISTOPATHOLOGY / ORGAN WEIGTHS
The F1 tissues indicated below were prepared weighed and examined for gross lesions, the tissues with an asterisk (*) were also processed for histopathology.
Vagina (*)
Uterus (*)
Ovaries with oviducts (*)
Cervix (*)
Stomach
Pituitary
Testes (*)
Epididymides (*)
Prostate (*)
Brain
Liver - Statistics:
- ANOVA, followed by Dunnett's test were appropriate for body weights, body weight gains, food consumption and organ weight data.
Comparison of litter parameters was complicated by the fact that pup weight is dependent upon, among other factors, litter size. Litter size was accounted for by least squares comparisons for covariance. - Reproductive indices:
- Not relevant
- Offspring viability indices:
- Not relevant
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- 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)
One animal died without clinical signs that were considered treatment related
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Male food consumption and absolute body weight were significantly decreased during first week of test substance administration in high dose males. Only on postnatal day 21 food consumption was significantly decreased in females of the mid and high dose groups. These effects were most likely associated with flavor aversion to the test substance in the food and in dams also with concomitant decreased food consumption by the weanlings.
ORGAN WEIGHTS (PARENTAL ANIMALS)
Significant increases observed in liver weight in male and female rats in a dose-related fashion, but these were attributed to metabolic adapation after histopathology. Increased adrenal weight was presumed to be related to stress associated with the initital flavor aversion and the resulting food avoidance in the mid and high dose groups.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 995 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: No treatment related effects
- Dose descriptor:
- NOAEL
- Effect level:
- 1 199 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: No treatment related effects
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
F1: Two animals died without clinical signs that were considered treatment related
BODY WEIGHT AND FOOD CONSUMPTION (OFFSPRING)
F1: Decreased body weight observed on postnatal day 7 and 14 until weaning, but this was considered related to the taste aversion phenomenon (decreased food consumption). Mean body weights decreased (significant for mid and high dose group) during 11-week pre-mating period, induced by decreased food consumption in the first 2 weeks.
F2: Decrease in body weight observed up on to postnatal day 21, which was considered to be related to litter size
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 260 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: No treatment related effects
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 411 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: No treatment related effects
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
RESULTS OF TEST | DOSING GROUPS | |||
Control (plain diet) | Low (1000 ppm) | Medium (10000 ppm) | High (20000 ppm) | |
ANALYSES | ||||
Actual concentration in diet | Within 3% of target levels | |||
Stability | Confirmed | |||
Homogeneity | Confirmed | |||
Test substance intake | 0 mg/kg bw/day | (P) M/F: 49 and 59 mg/kg bw/day | (P) M/F: 520 and 602 mg/kg bw/day | (P) M/F: 995 and 1199 mg/kg bw/day |
0 mg/kg bw/day | (F1) M/F: 55 and 63 mg/kg bw/day | (F1) M/F: 602 and 683 mg/kg bw/day | (F1) M/F: 1260 and 1411 mg/kg bw/day | |
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL | ||||
PARENTAL DATA (P) | ||||
Number of animals (M/F) | 30/30 | 30/30 | 30/30 | 30/30 |
Mortality (numbers) | x | x | x | 1 female: dead during lactation |
Body weight | x | x | x | Males: absolute weight significantly decreased in first week of treatment |
Food consumption | x | x | Females: significantly decreased on postnatal day 21 | Males: significantly decreased in first week of treatment, Females: significantly decreased on postnatal day 21 |
Clinical signs | x | x | x | x |
Organ weights | x | M/F: Significant increase in absolute and relative liver weight | M/F: Significant increase in absolute and relative liver weight | M/F: Significant increase in absolute and relative liver weight |
Macroscopy | x | x | x | x |
Microscopy | Hepatic periportal hypertrophy (adaptive) | Not done | Not done | Hepatic periportal hypertrophy (adaptive) |
Sperm count | x | x | x | x |
Sperm motility | x | x | x | x |
Sperm morphology | x | x | x | x |
Length of oestrus cycle | x | x | x | x |
Ovarian primordial follicle counts | 82.4 +/- 33.8 | Not done | Not done | 73.0 +/- 29.8 |
Number of females successful mated | 29 | 27 | 28 | 29 |
Mating index (%) | 97 | 90 | 93 | 97 |
Number selected for littering | 27 | 25 | 28 | 29 |
No. of litters | 23 | 25 | 28 | 26 |
Gestation index (%) | 85 | 100 | 100 | 90 |
Litter size per dam (mean +/- SD) | 12.3 +/- 1.80 | 11.7 +/- 2.72 | 11.7 +/- 2.51 | 11.0 +/- 2.6 |
PARENTAL DATA (F1) | ||||
Number of animals (M/F) | 25/25 | 25/25 | 28/28 | 26/26 |
Mortality (numbers) | ||||
Body weight | x | M/F: Sporadic but significant differences | M/F: Significant decrease throughout study. M: mean body weight gain significantly decreased | M/F: Significant decrease throughout study. M: mean body weight gain significantly decreased |
Food consumption | M/F: Sporadic but significant differences | x | x | |
Clinical signs | x | x | x | x |
Organ weights | M/F: Significant increase in absolute and relative liver weight | M/F: Significant increase in absolute and relative liver weight | M/F: Significant increase in absolute and relative liver weight | |
Macroscopy | x | x | x | x |
Microscopy | Hepatic periportal hypertrophy (adaptive) | Not done | Not done | Hepatic periportal hypertrophy (adaptive) |
Sperm count | x | x | x | x |
Sperm motility | x | x | x | x |
Sperm morphology | x | x | x | x |
Length of oestrus cycle | x | x | x | x |
Ovarian primordial follicle counts | 73.4 +/- 18.9 | Not done | Not done | 82.1 +/- 24.8 |
Number of females successful mated | 25 | 25 | 26 | 26 |
Mating index (%) | 100 | 100 | 93 | 100 |
No. of litters | 23 | 25 | 22 | 24 |
Gestation index (%) | 92 | 100 | 85 | 92 |
Litter size per dam (mean +/- SD) | 12.1 +/- 3.45 | 12.9 +/- 3.02 | 12.7 +/- 1.73 | 11.6 +/- 2.67 |
OFFSPRING TOXICITY (F1) | ||||
Litter size (mean +/- SD) | 12.3 +/- 1.80 | 11.7 +/- 2.72 | 11.7 +/- 2.51 | 11.0 +/- 2.6 |
Foetal weight (mean +/- SD) | 6.78 +/- 0.327 | 6.84 +/- 0.428 | 6.89 +/- 0.528 | 7.05 +/- 0.466 |
Viability index (%) | 97 | 99 | 94 | 96 |
Post natal survival until weaning (%, based on mean litter survival) | 64 | 68 | 66 | 69 |
Visible abnormalities | x | x | x | x |
Postnatal growth, growth rate (body weight gain) | x | x | M/F: significant decrease PD14-21 | F: significant decrease PD7-21, M: significant decrease PD14-21 |
Vaginal opening (F) or preputial separation (M) | x | x | Delayed development (related to body weight) | Delayed development (related to body weight) |
OFFSPRING TOXICITY (F2) | ||||
Litter size (mean +/- SD) | 12.1 +/- 3.45 | 12.9 +/- 3.02 | 12.7 +/- 1.73 | 11.6 +/- 2.67 |
Foetal weight (mean +/- SD) | 6.84 +/- 0.501 | 6.69 +/- 0.448 | 6.73 +/- 0.410 | 6.87 +/- 0.385 |
Viability index (%) | 98 | 98 | 96 | 97 |
Post natal survival until weaning (%, based on mean litter survival) | 64 | 60 | 61 | 65 |
Postnatal growth, growth rate (body weight gain) | x | M/F: significantly decreased on PD4-21 | M/F: significantly decreased on PD4-21 | M/F: significantly decreased on PD4-21 |
x = no effects (as compared to control group) |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this two-generation reprotoxicity study, Fyrolflex RDP induced no adverse effects in doses up to 20,000 ppm in parental, F1 and F2 animals. Therefore, a NOAEL of 20,000 ppm was established - representing measured concentrations of 995, 1199, 1260 and 1411 mg/kg bw/day for P: males, P: females, F1: males, F1: females, respectively. The substance does not need to be classified as toxic to reproduction based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.
- Executive summary:
In this two-generation reproduction toxicity study, male and female rats (P and F1) were exposed to 0, 1000, 10000 or 20000 ppm Fyrolflex RDP in diet for approximately 11 weeks prior to mating, during and up to 2 -3 weeks of mating and until sacrifice (males) or during gestation up to the weaning of the pups (females). Mortality, clinical signs, body weights, food consumption and organ weights were recorded, reproductive function was assessed and gross necropsy and histopathology were performed.
The administered concentrations were analytically determined to be 0, 49, 520 and 995 mg/kg bw/day for males and 0, 59, 602 and 1199 mg/kg bw/day for females (P). For F1, this was 0, 55, 602 and 1260 mg/kg bw/day for males and 0, 63, 683 and 1411 mg/kg bw/day for females.
No treatment related adverse effects were observed in P, F1 or F2 (no necropsy performed). Effects that were seen were related to flavor aversion to the test substance in food, resulting in a decrease in food consumption and alterations in body and organ weights. Liver effects could be attributed to a metabolic adaptation to the test substance.
Under the conditions of this two-generation reprotoxicity study, Fyrolflex RDP induced no adverse effects in doses up to 20,000 ppm in parental, F1 and F2 animals. Therefore, a NOAEL of 20,000 ppm was established - representing measured concentrations of 995, 1199, 1260 and 1411 mg/kg bw/day for P: males, P: females, F1: males, F1: females, respectively. The substance does not need to be classified as toxic to reproduction based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.
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