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EC number: 203-509-8 | CAS number: 107-66-4
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study (OECD combined repeat dose and reproductive/developmental toxicity screening test)
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Crj:CD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: males: 331-262 g; females: 192-215 g
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3
- Humidity (%): 55 +- 10 - Route of administration:
- oral: gavage
- Vehicle:
- other: sesame oil
- Duration of treatment / exposure:
- 44 days (male) and from 14 days before mating to day 3 of lactation (females)
- Frequency of treatment:
- once daily
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 male and 10 female animals per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- preliminary reproduction toxicity screening test performed as dose range finder with doses of 0, 50, 100, 200, 500, and 1000 mg/kg bw/day
sacrifice:
males on day 45
females on day 4 of lactation - Positive control:
- not adequate
- Observations and examinations performed and frequency:
- MORTALITY: Yes
CLINICAL SIGNS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations:
males: days 1, 8, 15, 22, 29, 36, and 43/44
females: days 1, 8, 15 (days of premating); days 0, 7, 14, 20 (days of pregnancy); days 0 and 4 (days of lactation)
HAEMATOLOGY: Yes
- How many animals: 10 males (high dose: 7 males)
- Parameters checked in table [No. 1 - see attachment] were examined.
CLINICAL CHEMISTRY: Yes
- How many animals: 10 males (high dose: 7 males)
- Parameters checked in table [No. 1 - see attachment] were examined.
PLASMA/SERUM HORMONES/LIPIDS: Yes
- How many animals: 10 males (high dose: 7 males)
- Parameters checked in table [No. 1 - see attachment] were examined. - Sacrifice and pathology:
- ORGAN WEIGHTS: Yes (table 2 - see attachment)
- males (10 animals): liver, kidneys, thymus, testes, epididymides (absolute and relative weight)
- females (5 to 10 animals): liver, kideys, thymus (absolute and relative weight)
HISTOPATHOLOGY: Yes (table 3 - see attachment)
- males (10 animals): lung, heart, liver, stomach, cecum, kidney, urinary bladder, adrenals, thymus, spleen data shown - Statistics:
- yes
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- red urine in 4 males at 100 mg/kg, 7 males at 300 mg/kg, and 5 male survivors at 1000 mg/kg bw
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 3 males and 2 females died in the 1000 mg/kg bw group.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain significantly decreased in males at 1000 mg/kg bw/day (about -14% at termination) - see figures 1 and 2 attached
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No effects on urinary, hematological and blood chemical findings in the males (females not given), see Table 1 attached.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No effects on urinary, hematological and blood chemical findings in the males (females not given), see Table 1 attached
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No effects on urinary findings in the males (females not given), see Table 1 attached.
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw - see Table 2 attached
- Gross pathological findings:
- not specified
- Description (incidence and severity):
- Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. - see Tables 3 and 4 attached
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- Transient red urine and a decrease in food consumption with >= 100 mg/kg bw (males). 3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL 30 mg/kg bw for both sexes. For reproductive effects see chapter 7.8 (Toxicity to reproduction).
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other:
- Remarks:
- Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw.
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 100 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- bladder
- Treatment related:
- yes
- Dose response relationship:
- yes
- Conclusions:
- The NOEL is considered to be 30 mg/kg bw for both sexes.
Transient red urine and a decrease in food consumption with >= 100 mg/kg bw (males). 3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL 30 mg/kg bw for both sexes. - Executive summary:
In an OECD combined repeated dose and reproductive/developmental toxicity screening test 10 male and 10 female rats per group were administered doses of 0, 30, 100, 300 or 1000 mg/kg bw of the test substance per gavage. Administration period for males were 44 days , and for females, from 14 days before mating to day 3 of lactation. Mortality, clinical signs, body weight, urinary, hematological and blood chemistry were examined and a histophatological examination conducted. Males were sacrificed on day 45. Females were sacrificed on day 4 of lactation.
3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL 30 mg/kg bw for both sexes.
Transient red urine and a decrease in food consumption with >= 100 mg/kg
bw (males). 3 males and 2 females died in the 1000 mg/kg bw group.
No effects on urinary, hematological and blood
chemical findings in the males (females not given).
Histopathology showed epithelial hyperplasia accompanied by
degeneration and ulceration of the urinary bladder mucosa in males and
females with >= 100 mg/kg bw. Epithelial hyperplasia
and hyperkeratosis of the forestomach (some with erosion and ulceration
in the gastric mucosa) were noted in both sexes >= 300 mg/kg
bw. Increase of absolute and relative liver weight and hepatocellular
swelling in females with 1000 mg/kg bw.
NOEL 30 mg/kg bw for both sexes. For reproductive effects see chapter
7.8 (Toxicity to reproduction).
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 995
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dibutyl hydrogen phosphate
- EC Number:
- 203-509-8
- EC Name:
- Dibutyl hydrogen phosphate
- Cas Number:
- 107-66-4
- Molecular formula:
- C8H19O4P
- IUPAC Name:
- dibutyl hydrogen phosphate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Crj:CD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: males: 331-262 g; females: 192-215 g
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3
- Humidity (%): 55 +- 10
preliminary reproduction toxicity screening test performed as dose range finder with doses of 0, 50, 100, 200, 500, and 1000 mg/kg bw/day
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: sesame oil
- Details on mating procedure:
- Male and female animals were exposed to the test substance 14 days before mating.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Exposure period: 44 days (male) and from 14 days before mating to day 3 of lactation (females).
- Frequency of treatment:
- once daily
- Details on study schedule:
- Males were sacrificed on day 45. Females were sacrificed on day 4 of lactation.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 male and 10 female animals per dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- MORTALITY: Yes
CLINICAL SIGNS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations:
males: days 1, 8, 15, 22, 29, 36, and 43/44
females: days 1, 8, 15 (days of premating); days 0, 7, 14, 20 (days of pregnancy); days 0 and 4 (days of lactation)
for further information see chapter 7.8.1 (reference to same study) - Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities - Postmortem examinations (parental animals):
- see IUCLID chapter 7.5.1
plus: histopathology of reproductive organs (e.g. ovary) - Postmortem examinations (offspring):
- external anomalies and visceral anomalies
- Reproductive indices:
- copulation index, fertility index, implantation index, gestation index, delivery index
- Offspring viability indices:
- live birth index, viability index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- red urine in 4 males at 100 mg/kg, 7 males at 300 mg/kg, and 5 male survivors at 1000 mg/kg bw
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 3 males and 2 females died in the 1000 mg/kg bw group.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain significantly decreased in males at 1000 mg/kg bw/day (about -14% at termination) - see figures 1 and 2 attached
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Decrease in food consumption at >= 100 mg/kg bw (males).
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No effects on urinary, hematological and blood chemical findings in the males (females not given).
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No effects on urinary, hematological and blood chemical findings in the males (females not given).
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females treated with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw - see Tables 3 and 4 attached
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 30 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fertility
- Remarks on result:
- other: The parental animals exhibited no significant effects on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index and gestation lengths.
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- the number of pups alive on day 4 of lactation was reduced in the 1000 mg/kg bw group compared to control (in male pups not significant; in female pups significant (p<0.05)) - see Table 6 attached
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- body weight on day 0 of male and female pups in 1000 mg/kg bw group lower than control (not significant) - see Table 6 attached
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- no treatment related external or visceral anomalies - see Table 7 attached
Effect levels (F1)
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- other: The number of live pups and the viability index on day 4 of lactation decreased with 1000 mg/kg.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 300 mg/kg bw/day
- Treatment related:
- yes
- Relation to other toxic effects:
- not specified
- Dose response relationship:
- yes
Any other information on results incl. tables
The parental animals exhibited no significant effects at dosages of 30, 100, 300, or 1000 mg/kg bw/day on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index, gestation lenght, absolute and relative weight of examined reproductive organs and histopathological findings.
Applicant's summary and conclusion
- Executive summary:
In an OECD combined repeat dose and reproductive/developmental toxicity screening test 10 male and 10 female rats per group were administered doses of 0, 30, 100, 300 or 1000 mg/kg bw of the test substance per gavage. Administration period for males were 44 days , and for females, from 14 days before mating to day 3 of lactation. Absolute and relative reproductive organ weight and reproductive parameters were determined.
Maternal toxicity became obvious as body weight gain decrease in males and mortality of 3 males and 2 females in the 1000 mg/kg bw groups. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL for maternal toxicity was thus determined with 30 mg/kg bw for both sexes.
The parental animals exhibited no significant effects at dosages of 30, 100, 300, or 1000 mg/kg bw/day on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index, gestation length, absolute and relative weight of examined reproductive organs and histopathological findings. The NOEL for reproductive toxicity is therefore 1000 mg/kg bw/day for both sexes.
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