Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 224-069-3 | CAS number: 4191-73-5
- 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
Key value for chemical safety assessment
Effects on fertility
Description of key information
NOAEL was considered to be 62.5 mg/kg bw for when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
Link to relevant study records
- Endpoint:
- fertility, other
- Remarks:
- Estrogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Data is from peer-reviewed journal
- Qualifier:
- according to guideline
- Guideline:
- other: uterotrophic bioassay
- Principles of method if other than guideline:
- To study Estrogenic effect of isopropyl 4-hydroxybenzoate in female rats
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Isopropylparaben (isopropyl 4-hydroxybenzoate)
- Molecular formula (if other than submission substance): C10H12O3
- Molecular weight (if other than submission substance): 180.202 g/mole
- Substance type: Organic
- Physical state: Solid - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dea Han Biolink Co., Ltd. (Eumsung, Chungbuk, Korea).
- Age at study initiation: 21 days
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed in polycarbonate cages
- Diet (e.g. ad libitum): soy-free pellet food
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark
IN-LIFE DATES: From: To: No data available - Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: isopropylparaben was administrated in Corn oil
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle:0, 62.5, 250 and1000 mg/kg BW/day
- Amount of vehicle (if gavage): 5 ml/kg BW/day
- Lot/batch no. (if required): No data available
- Purity: No data available - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Vaginal plugs and/or sperm presence in the vaginal smear was taken as gestation day 0 (GD 0). - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 20 days
- Frequency of treatment:
- Daily
- Details on study schedule:
- No data available
- Remarks:
- 0, 62.5, 250 and1000 mg/kg BW/day
- No. of animals per sex per dose:
- Total: 50
0 mg/kg BW/day: 10 Female
62.5 mg/kg BW/day: 10 Female
250 mg/kg BW/day: 10 Female
1000 mg/kg BW/day: 10 Female
EE (mg/kg BW/day) (Positive control) : 10 Female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: No data available
- Rationale for animal assignment (if not random): prepubertal female rats were selected.
- Other:doses were adjusted daily for weight changes. - Positive control:
- Ethinylestradiol (EE) (1 mg/kg BW/day) were used as positive control.
- Parental animals: Observations and examinations:
- No data available
- Oestrous cyclicity (parental animals):
- proestrous, estrous, metestrous, and diestrous, were determined
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- No data available
- Postmortem examinations (parental animals):
- Changes in body weight, clinical signs and/or abnormal behavior, Clinical chemistry, organ weight and Histopathology were examined.
- Postmortem examinations (offspring):
- No data available
- Statistics:
- Data for the vaginal opening (VO) day, bodyweight, and organ weight of the rats were statistically evaluated by one-way ANOVA. Significant differences between treatment groups and the respective controls were tested using Tukey’s multiple regression test at p < 0.05. The variable category of the incidence data in the ovarian changes was used as the outcome. The occurrence of differences in histopathological changes, i.e., decrease of corpora lutea, increase in the number of cystic follicles or decrease of corpora lutea, increase in the number of cystic follicles, was verified using Fisher’s exact probability test between VE and EE, or paraben groups. The rejection value for the null hypothesis was p≤0.05.
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- 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:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
- Dose descriptor:
- other: not specified
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: not specified
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- 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:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
- Dose descriptor:
- other: not specified
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: not specified
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- effects observed, non-treatment-related
- 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:
- not specified
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Sexual maturation:
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- not specified
- Histopathological findings:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 62.5 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- sexual maturation
- body weight and weight gain
- clinical biochemistry
- organ weights and organ / body weight ratios
- histopathology: non-neoplastic
- other: No effect
- Remarks on result:
- other: non toxic
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- 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:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- other: not specified
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: not specified
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Relation to other toxic effects:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Conclusions:
- NOAEL was considered to be 62.5 mg/kg bw when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
- Executive summary:
In a reproductive estrogenicity study, Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate in the concentration of 0, 62.5, 250 and 1000 mg/kg bw from postnatal day 21–40 orally by gavage in corn oil and Ethinylestradiol (1 mg/kg BW/day) was used as a positive control. No significant change in body weight was observed in treated rat as compared to control. Significant decrease in tetra-iodothyronine (T4) level at 250 mg/kg bw and significant decrease in Estradiol level at 1000 mg/kg bw, were observed as compared to control. Similarly, significant delay in Vaginal opening (VO) day were observed at 250 and 1000 mg/kg bw as compared to control. Significant decrease in n the number of 4-day estrous cycles were observed at 1000 mg/kg bw as compared to control. In addition, significant decrease in ovary and Kidney weight were observed at 1000 mg/kg bw as compared to control. Decrease of corpora lutea and increase number of cystic follicles, myometrial hypertrophy of uterus, were observed at 1000 mg/kg bw as compared to control. 50% inhibition of ligand binding (IC50) was observed in treated female rats. Therefore, NOAEL was considered to be 62.5 mg/kg bw when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
Reference
Clinical chemistry:
When treated with 250 mg/kg bw, significant decrease in tetra-iodothyronine (T4) level were observed as compared to control.
When treated with 1000 mg/kg bw, significant decrease in Estradiol level were observed as compared to control.
Sexual maturation:
Vaginal opening (VO) day: When treated with 250 and 1000 mg/kg bw, significant delay in Vaginal opening (VO) day were observed as compared to control.
Estrous cycles: When treated with 1000 mg/kg bw, significant decrease in n the number of 4-day estrous cycles were observed as compared to control.
Organ weight:
When treated with 1000 mg/kg bw, significant decrease in ovary and Kidney weight were observed as compared to control.
Histopathology:
When treated with 1000 mg/kg bw, decrease of corpora lutea and increase number of cystic follicles, myometrial hypertrophy of uterus, were observed as compared to control.
Other effect:
Estrogen receptor competitive binding assay: 50% inhibition of ligand binding (IC50) was observed in treated female rats.
Measurement of vaginal opening (VO) day.
Chemical |
Dose (mg/kg BW/day) |
||
|
62.5 |
250 |
1000 |
VE |
|
33.6 ± 3.23 |
|
Isopropylparaben |
35.2 ± 3.26 |
36.2 ± 1.03a |
36.7 ± 0.71a |
a p < 0.05 compared with VE.
Effects of parabens on body weight and organ weight (uterine, pituitary, ovary, adrenal gland, thyroid gland, kidney, liver) in peripubertal female rats.
Groups |
Body weight (g) |
Uterus weight (mg/g BW) |
Pituitary weight (mg/g BW) |
Ovary weight (mg/g BW) |
Thyroid weight (mg/g BW) |
Kidney weight (mg/g BW) |
Adrenal weight (mg/g BW) |
Liver weight (mg/g BW) |
VE |
118.69 ± 6.4 |
1.29 ± 0.11 |
0.043 ± 0.008 |
0.51 ± 0.06 |
0.86 ± 0.07 |
8.31 ± 0.57 |
0.27 ± 0.01 |
42.90 ± 2.17 |
EE (mg/kg BW/day) |
61.56 ± 4.85b |
3.40 ± 0.30b |
0.077 ± 0.012b |
0.45 ± 0.05 |
1.23 ± 0.1b |
9.94 ± 0.63b |
0.38 ± 0.03b |
52.38 ± 2.77b |
Isopropylparaben (mg/kg BW/day) |
|
|
|
|
|
|
|
|
62.5 |
110.67 ± 7.85 |
1.19 ± 0.30 |
0.045 ± 0.005 |
0.41 ± 0.06 |
0.85 ± 0.07 |
8.04 ± 0.44 |
0.29 ± 0.03 |
41.22 ± 3.00 |
250 |
113.85 ± 5.87 |
1.15 ± 0.44 |
0.047 ± 0.009 |
0.04 ± 0.07 |
0.82 ± 0.06 |
7.66 ± 0.47 |
0.27 ± 0.02 |
40.58 ± 3.19 |
1000 |
102.45 ± 4.38 |
0.87 ± 0.22 |
0.044 ± 0.003 |
0.32 ± 0.05a |
0.88 ± 0.08 |
7.25 ± 0.35a |
0.3 ± 0.02 |
41.75 ± 2.04 |
Mean±SD; n = 10 prepubertal female rats/group.
ap < 0.05 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
bp < 0.01 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
Histopathological effects of parabens on the ovaries and uteri of peripubertal female rats.
Groups |
Ovary |
Uterus |
||
|
Decrease of corpora lutea, increase in the number of cystic follicles (n = 10), n (%) |
Not decrease of corpora lutea, increase in the number of cystic follicles (n = 10), n (%) |
P-value* |
Thickness of morphometric measurement (m) |
VE |
0 (0%) |
10 (100%) |
|
125.64 ± 4.44 |
EE (mg/kg BW/day) |
7 (70%) |
3 (30%) |
0.0015 |
253.85 ± 27.74b |
Isopropylparaben (mg/kg BW/day) |
|
|
|
|
62.5 |
2 (20%) |
8 (80%) |
0.2368 |
141.03 ± 8.88 |
250 |
3 (30%) |
7 (70%) |
0.1052 |
189.74 ± 32.03 |
1000 |
5 (50%) |
5 (50%) |
0.0162 |
212.82 ± 4.44a |
Mean±SD; 10 rats were examined for each dose.
* Fisher’s exact probability test for category variables (categorized histopathological changes: decrease of corpora lutea, increase in the number of cystic follicles or not decrease of corpora lutea, increase in the number of cystic follicles on the vehicle (VE) and EE or paraben exposure groups) respectively. There rejection value for the null hypothesis was p≤0.05.
ap < 0.05 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
bp < 0.01 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
Effects of parabens on circulating estradiol, prolactin, and T4 levels in peripubertal female rats.
Groups |
Estradiol (pg/ml) |
Prolactin (ng/ml) |
T4 (ng/ml) |
VE |
47.07 ± 14.72 |
9.81 ± 3.12 |
3.00 ± 0.32 |
EE (mg/kg BW/day) |
55.37 ± 14.77 |
238.93 ± 35.00b |
2.73 ± 0.50 |
Isopropylparaben (mg/kg BW/day) |
|
|
|
62.5 |
30.53 ± 15.91 |
45.10 ± 13.12 |
2.70 ± 0.39 |
250 |
25.20 ± 6.05 |
49.76 ± 58.31 |
1.73 ± 0.34b |
1000 |
16.23 ± 6.86a |
24.12 ± 6.46 |
3.06 ± 0.19 |
Mean±SD; n = 10 prepubertal female rats/group.
ap < 0.05 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
bp < 0.01 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
Relative binding affinities of various parabens to ERαand ERβ.
Compound |
ERα |
ERβ |
||
|
IC50a |
RBAb |
IC50a |
RBAb |
17βEstradiol |
2.99×10−9M
|
100
|
3.03×10−9M
|
100 |
Isopropylparaben |
1.52×10−5M
|
0.019
|
1.69×10−5M |
0.017 |
Each value was the mean of triplicate determinations in more than four experiments.
aIC50 is the concentration of the paraben compound that inhibits binding of Fluormone ES2 to ER by 50%.
bRBA was calculated by the equation: (IC50 of 17-estradiol/IC50 of parabens)×100.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 62.5 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Data is Klimisch 2 and from peer-reviewed journal
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Reproductive toxicity: Oral
In a study, isopropyl 4-hydroxybenzoate has been investigated for reproductive toxicity to a greater or lesser extent. The study based on in vivo experiments data in rodents, i.e. most commonly in rats for isopropyl 4-hydroxybenzoate.
In a experimental study conducted by Thuyet al(Reproductive Toxicology 29 (2010) 306–316), Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate in the concentration of 0, 62.5, 250 and 1000 mg/kg bw from postnatal day 21–40 orally by gavage in corn oil and Ethinylestradiol (1 mg/kg BW/day) was used as a positive control. No significant change in body weight was observed in treated rat as compared to control. Significant decrease in tetra-iodothyronine (T4) level at 250 mg/kg bw and significant decrease in Estradiol level at 1000 mg/kg bw, were observed as compared to control. Similarly, reproductive effects such as significant delay in Vaginal opening (VO) day were observed at 250 and 1000 mg/kg bw as compared to control. Significant decrease in n the number of 4-day estrous cycles were observed at 1000 mg/kg bw as compared to control. In addition, significant decrease in ovary and Kidney weight were observed at 1000 mg/kg bw as compared to control. Decrease of corpora lutea and increase number of cystic follicles, myometrial hypertrophy of uterus, were observed at 1000 mg/kg bw as compared to control. 50% inhibition of ligand binding (IC50) was observed in treated female rats. Therefore, NOAEL was considered to be 62.5 mg/kg bw for when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
Thus, based on the above studies and predictions on isopropyl 4-hydroxybenzoate, it can be concluded that NOAEL was 62.5 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, isopropyl 4-hydroxybenzoate can be “Not classified” as reproductive toxicity.
Effects on developmental toxicity
Description of key information
NOAEL was considered to be 62.5 mg/kg bw for F1 generation when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Data is from peer-reviewed journal
- Qualifier:
- according to guideline
- Guideline:
- other: uterotrophic bioassay
- Principles of method if other than guideline:
- To study Estrogenic effect of isopropyl 4-hydroxybenzoate in postnatal female rats
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Isopropylparaben (isopropyl 4-hydroxybenzoate)
- Molecular formula (if other than submission substance): C10H12O3
- Molecular weight (if other than submission substance): 180.202 g/mole
- Substance type: Organic
- Physical state: Solid - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dea Han Biolink Co., Ltd. (Eumsung, Chungbuk, Korea).
- Age at study initiation: 21 days
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed in polycarbonate cages
- Diet (e.g. ad libitum): soy-free pellet food
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark
IN-LIFE DATES: From: To: No data available - Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: isopropylparaben was administrated in Corn oil
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle:0, 62.5, 250 and1000 mg/kg BW/day
- Amount of vehicle (if gavage): 5 ml/kg BW/day
- Lot/batch no. (if required): No data available
- Purity: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Vaginal plugs and/or sperm presence in the vaginal smear was taken as gestation day 0 (GD 0). - Duration of treatment / exposure:
- 20 days
- Frequency of treatment:
- Daily
- Duration of test:
- 21 days (From post natal 21 days to 41 days)
- Remarks:
- 62.5, 250 and 1000 mg/kg bw/day
- No. of animals per sex per dose:
- Total: 50
0 mg/kg BW/day: 10 Female
62.5 mg/kg BW/day: 10 Female
250 mg/kg BW/day: 10 Female
1000 mg/kg BW/day: 10 Female
EE (mg/kg BW/day) (Positive control) : 10 Female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: No data available
- Rationale for animal assignment (if not random): prepubertal female rats were selected.
- Other:doses were adjusted daily for weight changes. - Maternal examinations:
- not specified
- Ovaries and uterine content:
- vaginal opening (VO) day and corpora lutea were examined.
- Fetal examinations:
- Changes in body weight, clinical signs and/or abnormal behavior, Clinical chemistry, organ weight and Histopathology were examined.
- Statistics:
- Data for the vaginal opening (VO) day, bodyweight, and organ weight of the rats were statistically evaluated by one-way ANOVA. Significant differences between treatment groups and the respective controls were tested using Tukey’s multiple regression test at p < 0.05. The variable category of the incidence data in the ovarian changes was used as the outcome. The occurrence of differences in histopathological changes, i.e., decrease of corpora lutea, increase in the number of cystic follicles or decrease of corpora lutea, increase in the number of cystic follicles, was verified using Fisher’s exact probability test between VE and EE, or paraben groups. The rejection value for the null hypothesis was p≤0.05.
- Indices:
- not specified
- Historical control data:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- 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:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- other: not specified
- Based on:
- not specified
- Basis for effect level:
- other: not specified
- Remarks on result:
- other: not specified
- Abnormalities:
- not specified
- Localisation:
- not specified
- Description (incidence and severity):
- not specified
- Fetal body weight changes:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- effects observed, treatment-related
- Details on embryotoxic / teratogenic effects:
- Body weight: No significant change in body weight was observed in treated rat as compared to control.
Clinical chemistry:
When treated with 250 mg/kg bw, significant decrease in tetra-iodothyronine (T4) level were observed as compared to control.
When treated with 1000 mg/kg bw, significant decrease in Estradiol level were observed as compared to control.
Sexual maturation:
Vaginal opening (VO) day: When treated with 250 and 1000 mg/kg bw, significant delay in Vaginal opening (VO) day were observed as compared to control.
Estrous cycles: When treated with 1000 mg/kg bw, significant decrease in n the number of 4-day estrous cycles were observed as compared to control.
Organ weight:
When treated with 1000 mg/kg bw, significant decrease in ovary and Kidney weight were observed as compared to control.
Histopathology:
When treated with 1000 mg/kg bw, decrease of corpora lutea and increase number of cystic follicles, myometrial hypertrophy of uterus, were observed as compared to control.
Other effect:
Estrogen receptor competitive binding assay: 50% inhibition of ligand binding (IC50) was observed in treated female rats. - Dose descriptor:
- NOAEL
- Effect level:
- 62.5 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- fetal/pup body weight changes
- visceral malformations
- other: No effect on chlinical chemistry,
- Abnormalities:
- not specified
- Localisation:
- other: not specified
- Description (incidence and severity):
- not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Conclusions:
- NOAEL was considered to be 62.5 mg/kg bw for F1 generation when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
- Executive summary:
In a developmental toxicity study, Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate in the concentration of 0, 62.5, 250 and 1000 mg/kg bw from postnatal day 21–40 orally by gavage in corn oil and Ethinylestradiol (1 mg/kg BW/day) was used as a positive control. No significant change in body weight was observed in treated rat as compared to control. Significant decrease in tetra-iodothyronine (T4) level at 250 mg/kg bw and significant decrease in Estradiol level at 1000 mg/kg bw, were observed as compared to control. Similarly, developmental effects such as significant delay in Vaginal opening (VO) day were observed at 250 and 1000 mg/kg bw as compared to control. Significant decrease in n the number of 4-day estrous cycles were observed at 1000 mg/kg bw as compared to control. In addition, significant decrease in ovary and Kidney weight were observed at 1000 mg/kg bw as compared to control. Decrease of corpora lutea and increase number of cystic follicles, myometrial hypertrophy of uterus, were observed at 1000 mg/kg bw as compared to control. 50% inhibition of ligand binding (IC50) was observed in treated female rats. Therefore, NOAEL was considered to be 62.5 mg/kg bw for F1 generation when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
Reference
Measurement of vaginal opening (VO) day.
Chemical |
Dose (mg/kg BW/day) |
||
|
62.5 |
250 |
1000 |
VE |
|
33.6 ± 3.23 |
|
Isopropylparaben |
35.2 ± 3.26 |
36.2 ± 1.03a |
36.7 ± 0.71a |
a p < 0.05 compared with VE.
Effects of parabens on body weight and organ weight (uterine, pituitary, ovary, adrenal gland, thyroid gland, kidney, liver) in peripubertal female rats.
Groups |
Body weight (g) |
Uterus weight (mg/g BW) |
Pituitary weight (mg/g BW) |
Ovary weight (mg/g BW) |
Thyroid weight (mg/g BW) |
Kidney weight (mg/g BW) |
Adrenal weight (mg/g BW) |
Liver weight (mg/g BW) |
VE |
118.69 ± 6.4 |
1.29 ± 0.11 |
0.043 ± 0.008 |
0.51 ± 0.06 |
0.86 ± 0.07 |
8.31 ± 0.57 |
0.27 ± 0.01 |
42.90 ± 2.17 |
EE (mg/kg BW/day) |
61.56 ± 4.85b |
3.40 ± 0.30b |
0.077 ± 0.012b |
0.45 ± 0.05 |
1.23 ± 0.1b |
9.94 ± 0.63b |
0.38 ± 0.03b |
52.38 ± 2.77b |
Isopropylparaben (mg/kg BW/day) |
|
|
|
|
|
|
|
|
62.5 |
110.67 ± 7.85 |
1.19 ± 0.30 |
0.045 ± 0.005 |
0.41 ± 0.06 |
0.85 ± 0.07 |
8.04 ± 0.44 |
0.29 ± 0.03 |
41.22 ± 3.00 |
250 |
113.85 ± 5.87 |
1.15 ± 0.44 |
0.047 ± 0.009 |
0.04 ± 0.07 |
0.82 ± 0.06 |
7.66 ± 0.47 |
0.27 ± 0.02 |
40.58 ± 3.19 |
1000 |
102.45 ± 4.38 |
0.87 ± 0.22 |
0.044 ± 0.003 |
0.32 ± 0.05a |
0.88 ± 0.08 |
7.25 ± 0.35a |
0.3 ± 0.02 |
41.75 ± 2.04 |
Mean±SD; n = 10 prepubertal female rats/group.
ap < 0.05 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
bp < 0.01 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
Histopathological effects of parabens on the ovaries and uteri of peripubertal female rats.
Groups |
Ovary |
Uterus |
||
|
Decrease of corpora lutea, increase in the number of cystic follicles (n = 10), n (%) |
Not decrease of corpora lutea, increase in the number of cystic follicles (n = 10), n (%) |
P-value* |
Thickness of morphometric measurement (m) |
VE |
0 (0%) |
10 (100%) |
|
125.64 ± 4.44 |
EE (mg/kg BW/day) |
7 (70%) |
3 (30%) |
0.0015 |
253.85 ± 27.74b |
Isopropylparaben (mg/kg BW/day) |
|
|
|
|
62.5 |
2 (20%) |
8 (80%) |
0.2368 |
141.03 ± 8.88 |
250 |
3 (30%) |
7 (70%) |
0.1052 |
189.74 ± 32.03 |
1000 |
5 (50%) |
5 (50%) |
0.0162 |
212.82 ± 4.44a |
Mean±SD; 10 rats were examined for each dose.
* Fisher’s exact probability test for category variables (categorized histopathological changes: decrease of corpora lutea, increase in the number of cystic follicles or not decrease of corpora lutea, increase in the number of cystic follicles on the vehicle (VE) and EE or paraben exposure groups) respectively. There rejection value for the null hypothesis was p≤0.05.
ap < 0.05 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
bp < 0.01 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
Effects of parabens on circulating estradiol, prolactin, and T4 levels in peripubertal female rats.
Groups |
Estradiol (pg/ml) |
Prolactin (ng/ml) |
T4 (ng/ml) |
VE |
47.07 ± 14.72 |
9.81 ± 3.12 |
3.00 ± 0.32 |
EE (mg/kg BW/day) |
55.37 ± 14.77 |
238.93 ± 35.00b |
2.73 ± 0.50 |
Isopropylparaben (mg/kg BW/day) |
|
|
|
62.5 |
30.53 ± 15.91 |
45.10 ± 13.12 |
2.70 ± 0.39 |
250 |
25.20 ± 6.05 |
49.76 ± 58.31 |
1.73 ± 0.34b |
1000 |
16.23 ± 6.86a |
24.12 ± 6.46 |
3.06 ± 0.19 |
Mean±SD; n = 10 prepubertal female rats/group.
ap < 0.05 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
bp < 0.01 vs. vehicle (VE) (Tukey’s multiple regression test at p < 0.05).
Relative binding affinities of various parabens to ERαand ERβ.
Compound |
ERα |
ERβ |
||
|
IC50a |
RBAb |
IC50a |
RBAb |
17βEstradiol |
2.99×10−9M
|
100
|
3.03×10−9M
|
100 |
Isopropylparaben |
1.52×10−5M
|
0.019
|
1.69×10−5M |
0.017 |
Each value was the mean of triplicate determinations in more than four experiments.
aIC50 is the concentration of the paraben compound that inhibits binding of Fluormone ES2 to ER by 50%.
bRBA was calculated by the equation: (IC50 of 17-estradiol/IC50 of parabens)×100.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 62.5 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Data is Klimisch 2 and from peer-reviewed journal
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Developmental toxicity:
In a study, isopropyl 4-hydroxybenzoate has been investigated for developmental toxicity to a greater or lesser extent. The study based on in vivo experiments data in rodents, i.e. most commonly in rats for isopropyl 4-hydroxybenzoate.
In a experimental study conducted by Thuyet al(Reproductive Toxicology 29 (2010) 306–316), Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate in the concentration of 0, 62.5, 250 and 1000 mg/kg bw from postnatal day 21–40 orally by gavage in corn oil and Ethinylestradiol (1 mg/kg BW/day) was used as a positive control. No significant change in body weight was observed in treated rat as compared to control. Significant decrease in tetra-iodothyronine (T4) level at 250 mg/kg bw and significant decrease in Estradiol level at 1000 mg/kg bw, were observed as compared to control. Similarly, developmental effects such as significant delay in Vaginal opening (VO) day were observed at 250 and 1000 mg/kg bw as compared to control. Significant decrease in n the number of 4-day estrous cycles were observed at 1000 mg/kg bw as compared to control. In addition, significant decrease in ovary and Kidney weight were observed at 1000 mg/kg bw as compared to control. Decrease of corpora lutea and increase number of cystic follicles, myometrial hypertrophy of uterus, were observed at 1000 mg/kg bw as compared to control. 50% inhibition of ligand binding (IC50) was observed in treated female rats. Therefore, NOAEL was considered to be 62.5 mg/kg bw for F1 generation when Sprague-Dawley female rats were treated with isopropyl 4-hydroxybenzoate orally by gavage for 20 days.
Thus, based on the above studies and predictions on isopropyl 4-hydroxybenzoate, it can be concluded that NOAEL was 62.5 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, isopropyl 4-hydroxybenzoate can be “Not classified” as developmental toxicity.
Justification for classification or non-classification
Based on the above studies and predictions on isopropyl 4-hydroxybenzoate, it can be concluded that NOAEL was 62.5 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, isopropyl 4-hydroxybenzoate can be “Not classified” as reproductive and developmental toxicity.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.