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EC number: 213-497-6 | CAS number: 959-26-2
- 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
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
Based on a conservative read-across from terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1), there was no evidence of reproductive toxicity following exposure to BHET (959-26-2; 213-497-6).
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Type of 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:
- accepted calculation method
- Justification for type of information:
- The basis for this read-across approach is that the target substance is expected to undergo transformation into terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1). The toxicity of the metabolites will accurately predict the toxicity of the bis(2-hydroxyethyl)terephthalate (BHET; 959-26-2; 213-497-6). Refer to the JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION in Section 13 of this dossier for further details.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Specific details on test material used for the study:
- Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data.
- Species:
- rat
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Absence of significant findings at the highest concentration assessed for the transformation products
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Absence of significant findings at the highest concentration assessed for the transformation products
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Absence of significant findings at the highest concentration assessed for the transformation products
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Absence of significant findings at the highest concentration assessed for the transformation products
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Executive summary:
A two-generation reproduction study was conducted with rats fed 1,000, 5,000, or 20,000 ppm terephthalic acid (Ball, et al., 2012). The delay in vaginal opening and reduced anogenital distance at the high dose in F1 female offspring, and the delay in preputial separation at the mid and high doses in F1 male offspring were attributed to reduced body weight. There is no evidence of terephthalic acid reproductive toxicity. No reproductive or dominant lethal effects were associated with the inclusion of as much as 1.0 g/kg bw/day of ethane-1,2-diol in the diet of Fischer 344 rats (DePass, et al., 1986). Ethane-1,2-diol administered continuously in drinking water at 0.25, 0 .5, and 1% dose levels had no effect on fertility in CD-1 mice (Lamb, et al., 1985). Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET is not reproductively toxic. BHET is predicted to have a NOAEL greater than 1,000 mg/kg bw/day.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- chronic
- Experimental exposure time per week (hours/week):
- 24
- Species:
- rat
Effects on developmental toxicity
Description of key information
Based on a conservative read-across from terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1), there was no evidence of developmental toxicity following exposure to BHET (959-26-2; 213-497-6).
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of 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:
- accepted calculation method
- Justification for type of information:
- The basis for this read-across approach is that the target substance is expected to undergo transformation into terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1). The toxicity of the metabolites will accurately predict the toxicity of the bis(2-hydroxyethyl)terephthalate (BHET; 959-26-2; 213-497-6). Refer to the JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION in Section 13 of this dossier for further details.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Specific details on test material used for the study:
- Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data.
- Details on test animals or test system and environmental conditions:
- Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data.
Rabbit selected for the read-across as most sensitive species - Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Abnormalities:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects observed
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- Ethane-1,2-diol (203-473-3; 107-21-1) is not a developmental toxicant in the rabbit, no classification is warranted.
No evidence of maternal or developmental toxicity was seen in an inhalation study with rats exposed to terephthalic acid (202-830-0; 100-21-0).
Based on the transformation products, BHET (959-26-2; 213-497-6) is not a developmental toxicant - Executive summary:
There was no evidence of terephthalic acid maternal or developmental toxicity in an OECD 414 GLP-compliant aerosol inhalation study with rats (OECD SIDS, 2001). The rats were dosed at levels up to 10.4 mg/m3. Administration of ethane-1,2-diol (203-473-3; 107-21-1) to New Zealand White rabbits (0, 100, 500, 1000, or 2000 mg/kg bw/day; p.o.) caused mortality in 42% of the does as a result of renal failure. In the offspring, no effects upon survival, foetal weight, or the incidences of external, visceral, or skeletal malformations or variations were observed at any dose level, including the progeny of surviving does treated with 2000 mg/kg/day ethane-1,2-diol. Ethane-1,2-diol resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology (Tyl, et al., 1993) yet no developmental effects were noted in the progeny. Given that glycolic acid disposition between the maternal blood and the embryo is driven by the polarity of MCT1 and MCT4 isoforms in the placenta, that glycolic acid is sequestered in the rat and not the rabbit, and that the rabbit and human placenta show similar polarity to each other and opposite to that of the rodent (Moore, et al., 2016; Settle et al., 2004), it is proposed that the rabbit is the most appropriate species for the basis of classification. As such, and since ethylene glycol is not a developmental toxicant in the rabbit, no classification is warranted. Information on the source substances was considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET as not developmentally toxic. BHET is predicted to have a NOAEL greater than 1000 mg/kg bw/day.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- chronic
- Experimental exposure time per week (hours/week):
- 24
- Species:
- rabbit
- Quality of whole database:
- Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data.
Rabbit selected for the read-across as most sensitive species
Toxicity to reproduction: other studies
Additional information
A two-generation reproduction study was conducted with rats fed 1 000, 5 000, or 20 000 ppm terephthalic acid (Ball, et al., 2012). The delay in vaginal opening and reduced anogenital distance at the high dose in F1 female offspring, and the delay in preputial separation at the mid and high doses in F1 male offspring were attributed to reduced body weight. There is no evidence of terephthalic acid reproductive toxicity. Also, there was no evidence of maternal or developmental toxicity in an OECD 414 GLP-compliant aerosol inhalation study with rats (OECD SIDS, 2001). The rats were dosed at levels up to 10.4 mg/m3.
The reproductive effects of ethylene glycol have been investigated in several mammalian species with rodent models identifying a development effect (Tyl et al., 1995a and 1995b, Lamb et al., 1985) and non-rodents not exhibiting the effect (Tyl et al., 1993). Therefore, further research into the species-specific aetiology of ethylene glycol-induced developmental toxicity were investigated. The work of Carney et al. (1999) demonstrated that the developmental anomalies reported in rats are attributable to the formation and accumulation of glycolic acid in the maternal blood, though acidosis may exacerbate the induced lesions.
The monocarboxylate transporter (MCT) protein family is believed to mediate the transfer of lactic acid and pyruvic acid between maternal and embryo-foetal compartments, although there are species differences in the characteristics of transplacental transfer. Nagai et al. (2010) examined the expression and subcellular localization of MCT isoforms in the ddY mouse placenta during gestation. Although six isoforms were initially studied, only two of these, MCT1 and MCT4, are known to be involved in the transport of monocarboxylates. Immunohistochemical staining for the two protein isoforms showed that MCT1, which is a high-affinity transporter, is localized in the apical membrane of the syncytiotrophoblast facing the maternal blood; MCT4, which is a low-affinity transporter, is localized in the basal plasma membrane close to the embryo-foetal blood. A similar partitioning of MCT1 and MCT4 has been recently identified in the CD rat placenta (Moore et al., 2016).
In contrast to the polarity of MCT1 and MCT4 in the rodent placenta, these isoforms show the opposite polarity in placenta from non-rodent species. Settle et al. (2004) described the localization of MCT1 and MCT4 in term human placenta. MCT1 was localized predominantly to the basal membrane (embryo-foetal side of the syncytiotrophoblast) while MCT4 was apparent on both plasma membranes with more intense staining on the microvillous membrane (maternal side). Moore et al. (2016) have evaluated the localization of these two isoforms in the New Zealand White rabbit placenta. Again, MCT1 was localized on the side apposed to the embryo-foetal circulation while MCT4 was localized to the side of the maternal blood.
From these physiological differences, a model for glycolic acid disposition in rodents and non-rodents is proposed. In this model, glycolic acid is sequestered from the maternal blood and transported across the syncytiotrophoblast to the embryonic blood. In the rodent, the high affinity MCT1 apposed to the maternal blood effectively transports glycolic acid to the embryo, while MCT4 does not sequester glycolic acid from the embryonic blood as effectively. In the non-rodent, the opposite is the case. It is proposed that this qualitative difference in MCT polarity underlies the quantitative differences in maternal-embryonal disposition and response to glycolic acid. Since the polarity of the MCT in the rabbit placenta is the same as that in human, the rabbit is a more appropriate model for evaluating the intrinsic hazard relevant to humans.
Administration of ethylene glycol to New Zealand White rabbits (0, 100, 500, 1 000, or 2 000 mg/kg bw/day; p.o.) caused mortality in 42% of the does as a result of renal failure. In the offspring, no effects upon survival, foetal weight, or the incidences of external, visceral, or skeletal malformations or variations were observed at any dose level, including the progeny of surviving female rabbits treated with 2 000 mg/kg/day ethylene glycol. Ethylene glycol resulted in profound maternal toxicity at 2 000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology [18] yet no developmental effects were noted in the progeny.
No reproductive or dominant lethal effects were associated with the inclusion of as much as 1.0 g/kg bw/day of ethylene glycol in the diet of Fischer 344 rats (DePass et al., 1986). Ethylene glycol administered continuously in drinking water at 0.25, 0 .5, and 1% dose levels had no effect on fertility in CD-1 mice (Lamb et al., 1985). Therefore, based on the work of DePass et al. (1986), Lamb et al. (1985), and Tyl et al. (1993), ethylene glycol does not adversely affect reproduction or development.
Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET is neither developmentally nor reproductively toxic. The target was predicted to have a NOAEL greater than 1 000 mg/kg bw/day.
Justification for classification or non-classification
Based on a conservative read-across from terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1), there is no evidence of reproductive or developmental toxicity following exposure to BHET (959-26-2; 213-497-6). Therefore, BHET does not meet the criteria for classification according to the European CLP (EC 1272/2008 as amended).
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.
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