Registration Dossier

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
Reference
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:
11 day inhalation toxicity study
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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:
mortality observed, treatment-related
Description (incidence):
for effects see below
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
Dose descriptor:
NOEL
Effect level:
60 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; hematology; clinical chemistry; gross pathology; histopathology
Critical effects observed:
not specified

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

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, 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 liver
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, 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.

Endpoint conclusion
Dose descriptor:
NOAEC
60 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
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:
11 day inhalation toxicity study
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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:
mortality observed, treatment-related
Description (incidence):
for effects see below
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
Dose descriptor:
NOEL
Effect level:
60 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; hematology; clinical chemistry; gross pathology; histopathology
Critical effects observed:
not specified

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

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, 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 liver
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, 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.

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.