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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
Repeated dose toxicity: oral
Administrative data
- 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: see 'Remark'
- Remarks:
- Acceptable, well-documented study which meets basic scientific principles. In this robust study summary results of male animals are reported. In the same study 13 females per each of the dosage groups were treated also. The results of the female animals are reported under IUCLID-Section 7.8.1 (toxicity to reproduction) and 7.8.2 (Developmental toxicity).
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
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)
- 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 for 42 days.
13 animals per each sex and dose were treated (whereas OECD 422 recommends that each group is started with at least 10 animals of each sex) - GLP compliance:
- not specified
- Remarks:
- but well documented study
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:
- Sprague-Dawley
- Details on species / strain selection:
- Sprague-Dawley Crj:CD, SPF
- Sex:
- male/female
- 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
- 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
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 1
- Humidity (%): 50-65
- Air changes (per hr): 15 times
- Photoperiod (hrs dark / hrs light): 12/12
- food and drinking water: ad libitum
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on oral 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
- Duration of treatment / exposure:
- males: 42 administrations, (2 weeks before mating, 2 weeks during mating and 2 weeks after mating period)
dissection ca. 24 hours after the last administration
females: In the same study 13 females per each of the dosage groups were treated also all in all between 38 to 52 days depending on the mating period. The results of the female animals are reported under IUCLID-Section 7.8.1 (toxicity to reproduction) and 7.8.2 (Developmental toxicity). - Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 40, 200, 1000 mg/kg body weight (mg/kg bw)
Basis:
other: Doses are based on the weekly measured body weights
- No. of animals per sex per dose:
- 13 males
In the same study 13 females per each of the dosage groups were treated also all in all between 38 to 52 days depending on the mating period. The results of the female animals are reported under IUCLID-Section 7.8.1 (toxicity to reproduction) and 7.8.2 (Developmental toxicity). - 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: randomly grouped
- Section schedule rationale: all animals were sacrificed - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- 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
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to autopsy
- Anaesthetic used for blood collection: Yes - pentobarbital anethesia
- Animals fasted: Yes , for ca. 24 hours
- How many animals: 13 per dose
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: following blood collection for hematology
- Animals fasted: Yes , for ca. 24 hours
- How many animals: 13 per dose
URINALYSIS: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes :The weights of liver, kidneys, lungs, thymus, testes, epididymis
HISTOPATHOLOGY: Yes: high dose and control animals: liver, heart, thymus, kidney, urinary bladder, lung, spleen, testis and epididymis, altered organs from all other animals (none found) - 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%.
Results and discussion
Results of examinations
- 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
- 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
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
- Details on results:
- CLINICAL SIGNS:
- 40 mg/kg bw/day:
no differences to the control animals observable
- 200 mg/kg bw:
salivation: 1 animal once,
abnormal respiratory sounds: 2 animals 1-2 times
- 1000 mg/kg bw:
salivation: 13 animals 3-34 times,
rhinorhea: 2 animals 1-2 times,
abnormal respiratory sounds: 5 animals 1 time,
MORTALITY: no
BODY WEIGHT GAIN: 1000 mg/kg bw: reduced
FOOD CONSUMPTION: no statistical differences
FOOD EFFICIENCY: not calculated
WATER CONSUMPTION: not examined
OPHTHALMOSCOPIC EXAMINATION: not examined
HAEMATOLOGY/ CLINICAL CHEMISTRY:
40 mg/kg bw:
reduced: white blood cell count, glucose (small difference)
increased: ratio of eosinophils
200 mg/kg bw:
reduced: lymphocyte ratio, platelet count, glucose
increased: inorganic phosphorus, calcium
1000 mg/kg bw:
reduced: white blood cell count, lymphocyte ratio, platelet count, total
serum protein, glucose
increased: A/G, GPT, GOT, inorganic phosphorus
Degree of variation in platelet count and acidophil ratio was within the
range of physiological variations.
Inorganic phosphorus and calcium varied within the range of
physiological variation.
URINALYSIS: not examined
NEUROBEHAVIOUR: not examined
ORGAN WEIGHTS: no statistical differences
GROSS PATHOLOGY: no dosage related effects
HISTOPATHOLOGY: NON-NEOPLASTIC: no statistical differences
HISTOPATHOLOGY: NEOPLASTIC: no statistical differences
HISTORICAL CONTROL DATA: not given
OTHER FINDINGS
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 40 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical biochemistry
- clinical signs
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: clinical signs; haematology
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effects on body weight change and food consumption, no histological and morphological changes, no adverse effects on hematological and blood chemical findings
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/kg bw/day (nominal)
- System:
- respiratory system: upper respiratory tract
- Organ:
- nasal cavity
- pharynx
- salivary glands
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- presumably yes
Applicant's summary and conclusion
- Conclusions:
- NOEL: 40 mg/kg bw.;
200 mg/kg bw: Clinical signs: salivation, abnormal respiratory sounds, Hematology/Clinical chemistry: reduced: lymphocyte count, platelet count;
1000 mg/kg bw: Clinical signs: salivation, rhinorhea, abnormal respiratory sounds, reduced: body weight gain, Hematology/Clinical Chemistry: reduced: white blood cell count, platelet count, total serum protein, increased: segmented neutrophil ratio, GPT, GOT, inorganic phosphorus.
The following significant differences were seen as merely statistical effects caused by the biological variation and not based on a test item related biological effect:
40 mg/kg bw.: reduced: glucose and white blood cell count, increased: ratio of eosinophil ,
200 mg/kg bw.: reduced: glucose, increased: blood calcium,
1000 mg/kg bw.: reduced: white blood cell count and glucose, increased A/G
Overall conclusion:
up to 1000 mg/kg bw.: no adverse effects on body weight change and food consumption, no histological and morphological changes, no adverse effects on hematological and blood chemical findings (As summarised in the OECD SIDS (1999)). - Executive summary:
Daily dosages of 0, 40, 200, and 1000 mg/kg bw. were administered by stomach tube to groups of 13 male rats for 42 days. In the same study 13 females per each of the dosage groups were treated also all in all between 38 to 52 days depending on the mating period. The results of the female animals are reported under IUCLID-Section 7.8.1 (toxicity to reproduction) and 7.8.2 (Developmental toxicity). The test-article was formulated in 0.5%CMC and administered in 5 ml/kg bw..
At a dosis of 40 mg/kg bw. the animals showed no differences to the control animals (NOEL).
200 mg/kg bw. lead to salivation and abnormal respiratory sounds. The lymphocyte ratio and the platelet count were reduced.
1000 mg/kg bw. caused salivation, rhinorhea, abnormal respiratory sounds, reduced body weight gain, white blood cell count, platelet count and total serum protein as well as increased segmented neutrophil ratio and increased activity of GPT, GOT and anorganic phosphorus in the serum, females: lung: inflamatory foci.
As summarised in the OECD SIDS (1999) a NOAEL of 1000 mg/kg bw./day was established: “4-Hydroxybenzoic acid induced rale and temporary salivation (sometimes accompanied by rhinorrhea) at 1,000 mg/kg and slightly at 200 mg/kg. These changes were suggesting the irritation of this chemical to respiratory tract. There were no adverse effects on body weight change and food consumption. At necropsy, no histological and morphological changes were observed. In hematological and blood chemical findings of males, decrease in the percentage of lymphocytes and the blood glucose at 200 mg/kg or more groups and decrease in total protein and increase in A/G ratio, GPT and GOT at 1,000 mg/kg were observed. These changes were significant, but not considered adverse effects. Therefore, NOAEL for systemic toxicity was considered to be 1,000 mg/kg/day.”
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