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EC number: 606-441-0 | CAS number: 201305-16-0
- 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
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Data waiving – OECD 416: PFAE aromatic category
According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", “information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. In accordance with Section 1.2 of REACH Annex XI, there is sufficient weight of evidence from several independent sources of information leading to the conclusion that Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0) does not cause toxicity to reproduction and thus does not have to be classified, because based on an analogue approach.
- in vitro hydrolysis evaluated according to the method described in EFSA Note for Guidance for Food Contact Materials indicates rapid ester hydrolysis of the registered substance in digestive fluid resulting in the formation of 4-hydroxy benzoic acid (excreted via urine) and ultimately C18-C22 fatty acids which will then depending on the energy needs of the body undergo fatty acid ana- or catabolism, thus 4 hydroxy benzoic acid is the main metabolite that should be considered when addressing reproductive toxicity
- no effects on reproductive organs and no influence on sperm parameters and testosterone, LH/FSH blood levels when applied up to 1000 mg/kg bw/d to male rats was observed in a 56 day dietary study in Methylparaben (Oishi, 2004, as cited in Soni et al. 2005)
- no significant effect was seen in the uterotrophic assay with Methylparaben up to 800 mg/kg bw/d (Routledge,J. et al., 1998, as cited in Soni et al., 2005)).
- no influence on reproductive performance was noted in a female dog which had been mated towards the end of a non-rodent subchronic study where it was dosed with 500 mg/kg bw Methylparaben for more than 300 days. The animal delivered a litter of healthy pubs (Matthews et al., 1956)
- in developmental studies in rabbits, rats, hamsters and guinea pigs no maternal or developmental effect was seen with 4-hydroxy benzoic acid esters (FDRL, 1973, FDRL, 1972, as cited in Soni et al. 2005)
It can therefore be concluded with sufficient certainty that Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0) will not cause toxicity to reproduction and that testing is not scientifically necessary.
A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.
Short description of key information:
data waiving
Effects on developmental toxicity
Description of key information
Developmental toxicity study (similar to OECD 414), oral, rabbit: NOEL maternal: ≥300 mg/kg bw/day; NOEL developmental: ≥300 mg/kg bw/day; NOEL teratogenicity: ≥300 mg/kg bw/day,
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well documented study, conducted similar to guideline.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- (only 12 animals were tested in the high dose group and body weights were recorded every 6 days only)
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rabbit
- Strain:
- other: Dutch-belted
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: virgin, adult females
- Housing: individually in mesh bottom cages
- Diet: ad libitum
- Water: tap water, ad libitum
ENVIRONMENTAL CONDITIONS
Temperature and humidity controlled (not further specified) - Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: artificial insemination
On Day 0, each doe was given an injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. 3 hours later, each doe was inseminated artificially with 0.3 mL of diluted semen from a proven donor buck using approximately 20E+6 motile sperm. - Duration of treatment / exposure:
- Test item:
Day 6 through Day 18 of gestation
Positive control substance:
on Day 9 of gestation - Frequency of treatment:
- Test groups: daily
Positive control group: single gaveage - Duration of test:
- 29 days
- No. of animals per sex per dose:
- - Vehicle control: 14 inseminated animals (11 pregnant animals)
- Positive control: 17 inseminated animals (10 pregnant animals)
- Test item 3.0 mg/kg bw/d Methylparaben: 20 inseminated animals (9 pregnant animals)
- Test item 14.0 mg/kg bw/d Methylparaben: 20 inseminated animals (9 pregnant animals)
- Test item 65.0 mg/kg bw/d Methylparaben: 14 inseminated animals (10 pregnant animals)
- Test item 300.0 mg/kg bw/d Methylparaben: 12 inseminated animals (9 pregnant animals) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Positive control animals were treated with a single gavage of 6-Aminonicotinamide 2.5 mg/kg bw on test Day 9.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: on Days 0, 6, 12, 18 and 29 of gestation
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 29
- Organs examined: Caesarean section; the urogenital tract of each animal was examined in detail for normality. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of dead foetuses: Yes - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of the neonatal survival. - Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
- All pregnant animals (except of 1 female in the control group) survived until scheduled necropsy and no clinical signs were noted
- Body weights were not affected by treatment
- The relevant reproduction parameters (no. of Corpora lutea, implantation sites/dam, resorptions etc.) were not affected by treatment with the test item - Dose descriptor:
- NOEL
- Effect level:
- >= 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOEL
- Effect level:
- >= 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
- Sex ratio and fetal body weight were not affected by treatment
- No dose related skeletal findings or soft tissue abnormalities - Dose descriptor:
- NOEL
- Effect level:
- >= 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- The available information comprises an adequate, reliable (Klimisch score 2) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional groups, common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
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
Justification for grouping of substances and read-across
No data are available on the acute toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0). In order to fulfil the standard information requirements set out in Annex VIII in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.
In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).
Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the substances depicted in the table below are selected as source substances for assessment.
The read-across is based on the identified structural similarities and the likelihood of common breakdown products by biological processes (metabolism). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).
CAS |
201305-16-0 TARGET SUBSTANCE |
99-76-3 |
Chemical Name |
Benzoic acid, 4-hydroxy-, C18-22-alkyl esters |
Methyl 4-hydroxybenzoate |
MW |
390.60-446.71 g/mol |
152.15 g/mol |
Developmental Toxicity |
RA from CAS 99-76-3 |
Experimental result: Rabbit: |
Discussion
Developmental toxicity
No data are available on the developmental toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0), but there is one reliable study via the oral route from the structurally related substance Methyl 4-hydroxybenzoate (Methylparaben, CAS 99-76-3), which is used for read-across based on an analogue approach.
Oral
In a prenatal developmental toxicity study similar to OECD guideline 414, the effects of Methylparaben (CAS 99-76-3) on inseminated female Dutch-belted rabbits were investigated during Days 6 to 18 of gestation (FDRL, 1973). Groups of 12 to 20 female rabbits received the test substance via gavage at dose levels of 3, 14 and 65 and 300 mg/kg bw/day. A further group of 14 inseminated female rabbits served as vehicle controls. On Day 29 of gestation, does were sacrificed and maternal as well as foetal examinations were performed. All pregnant animals (except of 1 female in the control group) survived until scheduled necropsy and no clinical signs were noted. Body weights and the relevant reproduction parameters (no. of Corpora lutea, implantation sites/dam, resorptions etc.) were not affected by treatment with the test item. The sex ratio and foetal body weights were not affected by treatment and no dose related skeletal findings or soft tissue abnormalities were noted. Thus, there was no evidence at any dose level, that the test substance was teratogenic in rabbits.
Based on the results of the study, the NOEL for developmental toxicity in Dutch-belted rabbits was set at ≥ 300 mg/kg bw/ day. The NOAEL for maternal toxicity in Dutch-belted rabbits was set at ≥ 300 mg/kg bw/ day.
Conclusion on developmental toxicity
In conclusion, the available data on developmental toxicity of the structural analogue substance indicate that Benzoic acid, 4-hydroxy-, C18-22-alkyl esters will not induce developmental or teratogenic effects after repeated oral exposure.
Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue/surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).
Justification for classification or non-classification
Based on read-across from a structurally similar substance, the available data on developmental toxicity do not meet the classification criteria according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.
Data are lacking for toxicity to reproduction (fertility).
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.