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EC number: 202-804-9 | CAS number: 99-96-7
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented study which meets basic scientific principles
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
- Deviations:
- yes
- Remarks:
- : duration, number of animals, dosages, administration volume, hematology, clinical chemistry, organ weights, histopathologic examination, neurobehaviour
- Principles of method if other than guideline:
- daily administration by stomach tube : males for 42 days, females for 38 -52 days
13 animals per each sex and dose group were treated (whereas OECD 422 recommends that each group is started with at least 10 animals of each sex) - GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- 4-hydroxybenzoic acid
- EC Number:
- 202-804-9
- EC Name:
- 4-hydroxybenzoic acid
- Cas Number:
- 99-96-7
- Molecular formula:
- C7H6O3
- IUPAC Name:
- 4-hydroxybenzoic acid
- Details on test material:
- - Name of test material: 4-hydroxybenzoic acid
- Physical state: solid, white crystalline powder
- Analytical purity: 99.7%
- Impurities (identity and concentrations): 0.02 (w/w)% salicylic acid, 0.03 (w/w)% 4-hydroxyisophthalic acid
- Lot/batch No.: GI0681
- supplier: Ueno Seikyku Co., LTD.
- Storage condition of test material: room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Sprague-Dawley, Crj:CD, SPF
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Nippon Charles River Co., Ltd., Hino Rearing Center
- Age at purchase: 7 weeks
- weight rage at time of grouping: males 305.3 - 348.0 g, females 206.6 - 233.9 g
- Fasting period before study: no
- Housing: individually in metal cages with mesh floor (22 x 27 x 19 cm³) in a rearing room
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: one week
- Sex: male, female
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 1
- Humidity (%): 50-65
- Air changes (per hr): 15 times
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE: suspension in water
- Concentration in vehicle: 0.5% Carboxymethyl Cellulose Sodium (CMC), Maruishi Seiyaku Co. Ltd., Production No. 1527),
Japan Pharmacopeia injection-quality water, Hikari Seiyaku Co. Ltd., Production No. 9510AH
- Amount of vehicle: 5 ml/kg - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1 (Probably) (male animals: see Repeated dose Toxicity)
- Length of cohabitation: until copulation/ up to 14 days
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- males: 42 administrations, (2 weeks before mating, 2 weeks during mating and 2 weeks after mating period)
females: in total up to 52 days: 14 days pre-mating period and up to 14 days mating period (until copulation), through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period) - Frequency of treatment:
- daily by stomach tube
- Duration of test:
- up to 52 days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw./day
Basis:
actual ingested
Doses are based on the weekly measured body weights/body weights at the beginning of the pregnancy.
- No. of animals per sex per dose:
- 13
- Control animals:
- yes
- Details on study design:
- - Control groups: aqueous solution of 0.5% CMC Na
- Dose selection rationale:
Results of a pilot study with 14-days repeated oral administration to male and female rats:
250 mg/kg bw : salivation, abnormal respiratory sounds, rhinorrhea
females: reduced body weight gain
1000 mg/kg bw: salivation, abnormal respiratory sounds, rhinorrhea, reduced body weight gain,
females: reduced: food consumption
- Rationale for animal assignment: ramdomly grouped
- Section schedule rationale: all animals werde sacrificed
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: on administration days 1, 8, 15, 22, 29, 36, 42 and on day of autopsy
FOOD CONSUMPTION : on administration days 1, 8, 29, 36, 42
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
WATER CONSUMPTION): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on lactation day 4 (starting with day 0)
- Organs examined: liver, kidneys, lung, thymus, heart, urinary bladder, spleen
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Statistics:
- Mean graded data for histopathological findings were tested for significant differences between the control and various dosage groups using Mann-Whitney's U-test, and positive grade totals using Fisher's direct probability one-tailed test. For all other data, which values obtained for individuals the uniformity of distribution of the various groups was first tested by Bartlett's method. When this resulted in a uniform distribution, a one-dimensional distribution analysis was performed, and when intergroup significance was observed, the differences in the mean values between the control and various dosage groups were tested using Dunnett's method if the number of animals per group was the same, or Scheffé's method when it was not. When the distribution was not uniform or when there were groups for which the distribution was 0, the Kruskal-Wallis rank sum test was performed. When intergroup significance was observed, Dunnett's or Scheffé's method tests the differences between the control and various dosage groups were performed. The level of significance was 5% or 1%.
- Indices:
- implantation/fertility index, delivery index, live birth index, neonatal survival rate, copulation index, pairing days until copulation, lactation status, gestation period
- Historical control data:
- no
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- With doses 200 mg/kg bw. and above abnormal respiratory sounds or transient post-administration salivation
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- suppressed weight gain in males with doses of 1000 mg/kg bw./day
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- With doses 200 mg/kg bw. and above reduced lymophocyte ratio was abserved
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males with doses of 200 mg/kg bw and above reduced glucose was observed.
With dose of 1000 mg/kg bw. reduced total protein and elevated GPT, GOT and increased A/G ratio was observed. - Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- not examined
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects: yes.
Details on maternal toxic effects:
NOEL: 40 mg/kg bw
-200 mg/kg bw: abnormal respiratory sounds: 3 animals 1-2 times
-1000 mg/kg bw: salivation: 13 animals 2-23 times, rhinorhea: 1 animal 1time, abnormal respiratory sounds: 9 animals 1-10 times, lungs: inflamatory foci (1 in the control group, 4 cases in the dosage group)
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 40 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- 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
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- not examined
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects: no effects
Effect levels (fetuses)
- 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:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- external malformations
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- NOEL: 40 mg/kg bw.
200 mg/kg bw: clinical signs: abnormal respiratory sounds: 3 animals 1-2 times
1000 mg/kg bw: salivation: 13 animals 2-23 times, rhinorhea: 1 animal 1time, abnormal respiratory sounds: 9 animals 1-10 times,
histopathology: lung: inflammatory foci (1 in the control group, 4 cases in the dosage group)
No differences: food consumption, body weight, histopathology, organ weights, copulation index, number of pregnant animals, number of pregnant animals with pups alive, fertility index, pairing days until copulation, frequeny of vaginal estrus, delivery status, lactation status, birth rate, gestation index, birth index, live birth index, gestation period, number of corpora lutea, number of implantation sites, implantation index, pup weight, pup weight gain, sex ratio, viability index - Executive summary:
Daily dosages of 0, 40, 200, and 1000 mg/kg bw. were administered by stomach tube to groups of 13 male and female rats for a 14 days pre-mating period, for a mating period up to 14 days. Whereas OECD 422 recommends that each group is started with at least 10 animals of each sex. The administration to the males was continued for 2 further weeks, totally 42 days. The administration to the females was continued for the pregnancy period of 20 days and for a lactation period of 4 days. All in all between 38 to 52 days (depending on the mating period).
The test-article was formulated in 0.5%CMC , the administration volume was 5 ml/kg bw.
NOEL: 40 mg/kg bw..
200 mg/kg bw.: abnormal respiratory sounds: 3 animals 1-2 times,
1000 mg/kg bw: salivation: 13 animals 2-23 times, rhinorhea: 1 animal 1time, abnormal respiratory sounds: 9 animals 1-10 times, histopathology: lung inflammatori foci.
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