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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
Endpoint summary
Administrative data
Description of key information
oral (42 d male rats):
- NOEL=40 mg/kg bw/day LOEL =200 mg/kg bw/day (Basis for effect: clinical signs, haematology, clinical chemistry)
- NOAEL= 1000 mg/kg bw/day (highest dose)
dermal: no study available with repeated dermal application. Oral administration is the relevant way for testing the toxicity of 4-HBA. It is assumed that toxicity after oral administration is representative for the toxicity after dermal administration. However, a study on dermal resorption (Hughes, 1997) with radiolabelled compound showed that only 4% of the applied dosage were resorbed into the body.
inhalative (11 d, rats, males and females): NOEC=60 mg/m3
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- days of exposure: Feb 15 - Feb 26 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: acceptable, well-documented study which meets basic scientific principles
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- 12 day inhalation toxicity study
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Sprague-Dawley derived CD
- Source: Charles River Breeding Laboratories, Kingston, New York
- Age at study initiation: males: 41 days; females: 57 days
- Weight at study initiation: males: (mean: 198) 192-210 g; females: (mean: 183) 173-197 gram
- Fasting period before study: no
- Housing:Individual in hung stainless steel, wire mesh-bottom cages
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow (5001) ad libitum
- Water (e.g. ad libitum):Citx-tap water (Elizabethtown Water Co.) ad libitum
- Acclimation period: 12 days - Route of administration:
- inhalation: dust
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:glas chamber
- Method of holding animals in test chamber: individual stainless steeel, wire mesh cages
- Air: dry air at a pressure of 5 psi
- System of generating particulates/aerosols: Wright Dust Feed Mechanism
- Air flow rate: 155-245 liters per minute
- Air change rate: every 6.5 - 4.1 minutes
TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric sampling, particle size distribution: Batelle cascade impactor
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- gravimetric control of the total airborne concentration
- Duration of treatment / exposure:
- exposure of 6 hours per day on 5 consecutive days, 2 days interruption and another 5 days exposure for 6 hours per day
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0, 20, 60, 200 mg/m³
Basis:
nominal conc. - No. of animals per sex per dose:
- 5 per sex and dose
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice weekly
BODY WEIGHT: Yes
- Time schedule for examinations: before and after exposures 1, 5 and 10.
HAEMATOLOGY: Yes
- Time schedule for collection of blood:before the last exposure period:
- Parameters checked: hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before and after exposures 1, 5 and 10.
- How many animals: control and high dose animals
- Parameters checked: blood urea nitrogen, serum glutamic pyruvic transaminase, glucose, total protein. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: kidneys, liver, lungs, nasal passages, trachea - Statistics:
- The animals were randomly distributed to the groups.
Body weights, organ weights, and organ/body weight ratios were statistically evaluated. Statistical evaluation of equality of means was made by the appropriate one way analysis of variance technique, followed by a multiple comparison procedure if needed.
hematology and clinical chemistry: To statistically determine if the two means were equal, first, test if the variances of the two groups could be considered as equal. If the variances were equal a standard, independent, two sample t-test was used to determine the equality of means. If the variances differed, Welch's t-test was used to determine equality of means. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- for effects see below
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
overall effects: increased instances of dried material around the facial area were detected in all exposure groups,
high dose only (200 mg/m³): ocular irritation (swollen eyelids, injection of conjunctival blood vessels),
hematology: males: elevated hematocrit, reduction in MCHC values, depressed clotting time
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver
BODY WEIGHT: no effect
HAEMATOLOGY: 200 mg/m³, males: elevated hematocrit, reduction in MCHC values
CLINICAL CHEMISTRY: 200 mg/m³, males: depressed clotting time
ORGAN WEIGHTS: no effect
GROSS PATHOLOGY: no test article related effects
HISTOPATHOLOGY: 200 mg/m³: 2 males, 1 female: increased mitotic activity of parenchymal liver
Particle size distribution:
- Aerodynamic mass median diameter (group II, III, IV) in µm/ % of Particles 10 µm or less in diameter: 4.74; 5.55; 6.26/ 73.51; 77.47; 70.39 - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 60 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical signs; hematology; clinical chemistry; histopathology
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/m³ air
- System:
- respiratory system: upper respiratory tract
- Organ:
- blood
- cornea
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- presumably yes
- Conclusions:
- An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.
Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.
20 mg/m³: no differences to the data of the control animals,
60 mg/m³: no differences to the data of the control animals,
200 mg/m³: The observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood. - Executive summary:
An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.
Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.
20 mg/m³: no differences to the data of the control animals,
60 mg/m³: no differences to the data of the control animals,
200 mg/m³: swollen eyelids (6 animals day 2), area around the eye swollen (1 animal day 9), injection of conjunctival blood vessels (5 animals on day 12)
clinical chemistry: males: elevated hematocrit, reduction in MCHC values;
hematology: males: depressed clotting time
histopathology: Lungs: chronic interstitial pneumonia, 2 males, 2 females; partial atelectasis: 2 females; perivascular edema/cellular infiltrate: 1 female; alveolar septa: polymorphonuclear infiltrate: 1 female; alveolar epithelium: desquamation: 1 female; alveolar haemorrhage: 1 male, 2 females; increased mitotic activity of parenchymal liver: 2 males, 2 females.Increased instances of dried material around the facial area were detected in all exposure groups,
high dose only: ocular irritation (swollen eyelids, injection of conjunctival blood vessels)
clinical chemistry: males: elevated hematocrit, reduction in MCHC values, depressed clotting time,
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liverThe observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood.
Reference
overall effects:
Increased instances of dried material around the facial area were detected in all exposure groups,
high dose only (200 mg/m³): ocular irritation (swollen eyelids, injection of conjunctival blood vessels)
clinical signs: males: elevated hematocrit, reduction in MCHC values, depressed clotting time,
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver
Endpoint conclusion
- Dose descriptor:
- NOAEC
- 60 mg/m³
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- days of exposure: Feb 15 - Feb 26 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: acceptable, well-documented study which meets basic scientific principles
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- 12 day inhalation toxicity study
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Sprague-Dawley derived CD
- Source: Charles River Breeding Laboratories, Kingston, New York
- Age at study initiation: males: 41 days; females: 57 days
- Weight at study initiation: males: (mean: 198) 192-210 g; females: (mean: 183) 173-197 gram
- Fasting period before study: no
- Housing:Individual in hung stainless steel, wire mesh-bottom cages
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow (5001) ad libitum
- Water (e.g. ad libitum):Citx-tap water (Elizabethtown Water Co.) ad libitum
- Acclimation period: 12 days - Route of administration:
- inhalation: dust
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:glas chamber
- Method of holding animals in test chamber: individual stainless steeel, wire mesh cages
- Air: dry air at a pressure of 5 psi
- System of generating particulates/aerosols: Wright Dust Feed Mechanism
- Air flow rate: 155-245 liters per minute
- Air change rate: every 6.5 - 4.1 minutes
TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric sampling, particle size distribution: Batelle cascade impactor
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- gravimetric control of the total airborne concentration
- Duration of treatment / exposure:
- exposure of 6 hours per day on 5 consecutive days, 2 days interruption and another 5 days exposure for 6 hours per day
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0, 20, 60, 200 mg/m³
Basis:
nominal conc. - No. of animals per sex per dose:
- 5 per sex and dose
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice weekly
BODY WEIGHT: Yes
- Time schedule for examinations: before and after exposures 1, 5 and 10.
HAEMATOLOGY: Yes
- Time schedule for collection of blood:before the last exposure period:
- Parameters checked: hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before and after exposures 1, 5 and 10.
- How many animals: control and high dose animals
- Parameters checked: blood urea nitrogen, serum glutamic pyruvic transaminase, glucose, total protein. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: kidneys, liver, lungs, nasal passages, trachea - Statistics:
- The animals were randomly distributed to the groups.
Body weights, organ weights, and organ/body weight ratios were statistically evaluated. Statistical evaluation of equality of means was made by the appropriate one way analysis of variance technique, followed by a multiple comparison procedure if needed.
hematology and clinical chemistry: To statistically determine if the two means were equal, first, test if the variances of the two groups could be considered as equal. If the variances were equal a standard, independent, two sample t-test was used to determine the equality of means. If the variances differed, Welch's t-test was used to determine equality of means. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- for effects see below
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
overall effects: increased instances of dried material around the facial area were detected in all exposure groups,
high dose only (200 mg/m³): ocular irritation (swollen eyelids, injection of conjunctival blood vessels),
hematology: males: elevated hematocrit, reduction in MCHC values, depressed clotting time
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver
BODY WEIGHT: no effect
HAEMATOLOGY: 200 mg/m³, males: elevated hematocrit, reduction in MCHC values
CLINICAL CHEMISTRY: 200 mg/m³, males: depressed clotting time
ORGAN WEIGHTS: no effect
GROSS PATHOLOGY: no test article related effects
HISTOPATHOLOGY: 200 mg/m³: 2 males, 1 female: increased mitotic activity of parenchymal liver
Particle size distribution:
- Aerodynamic mass median diameter (group II, III, IV) in µm/ % of Particles 10 µm or less in diameter: 4.74; 5.55; 6.26/ 73.51; 77.47; 70.39 - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 60 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical signs; hematology; clinical chemistry; histopathology
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/m³ air
- System:
- respiratory system: upper respiratory tract
- Organ:
- blood
- cornea
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- presumably yes
- Conclusions:
- An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.
Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.
20 mg/m³: no differences to the data of the control animals,
60 mg/m³: no differences to the data of the control animals,
200 mg/m³: The observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood. - Executive summary:
An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.
Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.
20 mg/m³: no differences to the data of the control animals,
60 mg/m³: no differences to the data of the control animals,
200 mg/m³: swollen eyelids (6 animals day 2), area around the eye swollen (1 animal day 9), injection of conjunctival blood vessels (5 animals on day 12)
clinical chemistry: males: elevated hematocrit, reduction in MCHC values;
hematology: males: depressed clotting time
histopathology: Lungs: chronic interstitial pneumonia, 2 males, 2 females; partial atelectasis: 2 females; perivascular edema/cellular infiltrate: 1 female; alveolar septa: polymorphonuclear infiltrate: 1 female; alveolar epithelium: desquamation: 1 female; alveolar haemorrhage: 1 male, 2 females; increased mitotic activity of parenchymal liver: 2 males, 2 females.Increased instances of dried material around the facial area were detected in all exposure groups,
high dose only: ocular irritation (swollen eyelids, injection of conjunctival blood vessels)
clinical chemistry: males: elevated hematocrit, reduction in MCHC values, depressed clotting time,
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liverThe observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood.
Reference
overall effects:
Increased instances of dried material around the facial area were detected in all exposure groups,
high dose only (200 mg/m³): ocular irritation (swollen eyelids, injection of conjunctival blood vessels)
clinical signs: males: elevated hematocrit, reduction in MCHC values, depressed clotting time,
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 60 mg/m³
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
In Nagao et al. (1997): Daily dosages of 0, 40, 200, and 1000 mg/kg bw/day 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. 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.
The doses in this study were selected from the results of a preceding preliminary test with 14 -day repeated oral administration. With administration of 1000 mg/kg bw in male animals and 250 mg/kg bw or more in female animals, tendencies toward suppressed body weight gain were observed. Also, a slight reduction in food consumption was observed in female animals with doses of 1000 mg/kg bw. However, from the fact that no pronounced changes in food consumption, urinalysis, haematology tests, blood biochemistry tests, organ weight or autopsies were observed during administration, it was concluded that 1000 mg/kg bw was an amount less than the maximum tolerated dose and was set as the maximum dose for the combined test. Below this, with a common factor of 5, an intermediate dose of 200 mg/kg bw and a minimum dose of 40 mg/kg bw were established. This dose selection is in line with the general rules of toxicology: the lowest dose should be a no effect dose, the highest dose should show some toxicity without lethal effects during the study period. 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 haematological 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.”
NOEL = 40 mg/kg bw
200 mg/kg bw/day lead to abnormal respiratory sounds and additionally with the male animals to salivation and reduced lymphocyte ratio and platelet count.
1000 mg/kg bw/day: salivation, abnormal respiratory sound, rhinorrhoea, males: reduced body weight gain, white blood cell count, platelet count, total serum protein, increased: segmented neutrophil ratio, GPT, GOT, inorganic phosphorus, females: lung: inflammatory foci.
It is not clear whether this finding (mild and unspecific histopathologic changes-inflammatory foci in lung) is really a toxic action of 4 -HBA or only an accidental statistical deviation. Nevertheless it is clear that the changes are reversible as no histopathologic changes in the lung have been found in studies with longer duration (study with read across substance methylparaben, 96 weeks, oral, rat from Matthews at al., 1956). Findings of red spots in the lung during autopsy were not confirmed by histopathology.
NOAEL for systemic toxicity was considered to be 1,000 mg/kg/day because the above changes are not considered adverse effects, which complies with the evaluation of OECD SIDS(1999).
- NOAEL for Repeated dose toxicity: 1000 mg/kg bw/day
- NOEL for Reproductive toxicity: 1000 mg/kg bw/day
- NOEL for Developmental toxicity: 1000 mg/kg bw/day
Within the study, reproductive organs in male and female rats (testes, epididymis, ovaries and uterus) as well as functional aspects on fertility (spermatogenesis, copulation index, fertility index, estrus cycles), which are assumed to be possibly affected by estrogens, were investigated. With these parameters no significant differences between p-hydroxybenzoic acid treated animals and controls have been observed. Hence, results of the reliable in vivo repeated dose-toxicity study in rats did not give any hint on an estrogenic activity of p-hydroxybenzoic acid.
Further, data of methylparaben and ethylparaben can be taken for the evaluation of 4-HBA as there is a close structural similarity and the fact that 4-HBA is the main breakdown product of the precursor methylparaben and ethylparaben after oral administration.Justification for read-across: similar chemical structure (common functional group) and common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals (for justification see appendix with read-across rationale to the Chemical Safety Report in IUCLID section 13).
Repeated dose toxicity of methyl- and ethylparaben was evaluated in a number of species, covering not only 90-days, but longer intervals as well. Matthews et al. (1956) evaluated methylparaben and ethylparaben in a repeated dose study in rats, with dose levels of 2% and 8% in diet, with exposure for 96 weeks and 12 weeks (84 days), respectively. Based on dietary intake, the doses translated to 0.9 – 1.2 g/kg bw, and 5.5 – 5.9 g/kg bw, respectively. Sado (1973, cited in Liebert, 1984) describes an even longer duration study for ethylparaben, with exposure at 0.2, 1.0 and 2.0% (corresponding to approximately 120, 600 and 1200 mg/kg bw/d) for 25 weeks (175 days). Given the prediction of ~100% hydrolysis of both methylparaben (Jones, 1956; Aubert, 2009) and ethylparaben (Kiwada, 1980), and the fact that this hydrolysis results in equimolar production of 4-HBA, the corrected doses would be as presented in the following Table:
Table. 4-HBA equivalent doses from read-across substances
Study |
Benozic Acid Ester doses |
4-HBA equivalent doses |
Matthews, et al., 1956 |
0.9 – 1.2 g/kg bw/d methylparaben 5.5 – 5.9 g/kg bw/d methylparaben 0.9 – 1.2 g/kg bw/d ethylparaben 5.5 – 5.9 g/kg bw/d ethylparaben |
0.82 – 1.09 g/kg bw/d 4-HBA 4.99 – 5.35 g/kg bw/d 4-HBA 0.7 – 1.0 g/kg bw/d 4-HBA 4.6 – 4.9 g/kg bw/d 4-HBA |
Sado, 1973 |
120 mg/kg bw/d ethylparaben 600 mg/kg bw/d ethylparaben 1200 mg/kg bw/d ethylparaben |
99.6 mg/kg bw/d 4-HBA 498 mg/kg bw/d 4-HBA 996 mg/kg bw/d 4-HBA |
Between the studies, the exposure durations and dose levels covered in a guideline 90-day repeated dose toxicity study would be more than adequately covered.
The 90 day repeated dose toxicity study does not need to be conducted on 4-HBA because 2 reliable chronic toxicity studies with an oral administration of methylparaben to rats (96 weeks) and dogs (up to 422 days) and 2 reliable studies with oral administration of ethylparaben to rats (for 12 weeks and 25 weeks) are available (see also section Carcinogenicity). As demonstrated in the section toxicokinetics, metabolism and distribution (IUCLID section 7.1) methyl- and ethylparaben are totally metabolized to 4-HBA in the body. Thus, the studies with methyl- and ethylparaben can be used for the evaluation of the toxicity of 4-HBA also (please refer to the read across rationale as justification in the appendix to the Chemical Safety Report in IUCLID section 13). These studies are considered as reliable chronic toxicity studies with appropriate species and route of administration. The chronic toxicity of 4 -HBA can be evaluated from these studies.
No endocrine-mediated (see section 5.10.1.3. “Specific investigations: other studies” and section 5.10.3. “Summary and discussion of specific investigations”) and no neurotoxic effects were found in the available repeated dose toxicity studies.
In compliance with the specific rules for adaptation from standard information requirements of annex IX 8.6.2 (REACH) (reliable chronic toxicity studies (of Matthews, 1956 and of Sado (1973, cited in Liebert, 1984)) are available, with appropriate species and route of administration of 2 read across substances (methyl- and ethyl-paraben) and in compliance with the “weight of evidence” (Annex XI (1.2) REACH) and the “read across approach” (Annex XI (1.5), REACH) as outlined in this chemical safety report and the attached read across rationale no further studies are necessary.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study according to OECD guideline.
Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: blood coagulation; digestive: liver; respiratory: lung
Justification for classification or non-classification
According to the rules of regulation (EC) No. 1272/2008 4-HBA has to be classified with respect to the target organ toxicity as a category 3 substance (respiratory system). The inhalation toxicity study and the repeated oral dose study revealed effects on the respiratory tract especially the lung, and on the blood and liver. These effects were not severe and not considered adverse. The induced rale and temporary salivation (sometimes accompanied by rhinorrhoea) were suggesting the irritation of this chemical to the respiratory tract. However, there are no human data available.
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