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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
Description of key information
Oral NOAEL = 307 mg/kg bw/day
CLP Classification: STOT RE Category 2 (oral, kidney)
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- 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.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 307 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Dose descriptor:
- NOAEL
- Effect level:
- 2.4 other: mmol/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 614 mg/kg bw (total dose)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Information on the source substances terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) are considered to be directly applicable to an equivalent molar amount of the target substance. The most conservative chronic NOAEL value was 150 mg/kg bw/day for ethane-1,2-diol or 2.4 mmol/kg bw/day. Therefore the concentration for further safety assessment of the target substance will be 2.4 mmol/kg bw/day or 307 mg/kg bw/day.
The European CLP (EC 1272/2008 as amended) classification of ethane-1,2-diol was qualitatively determined to be STOT RE Category 2 (oral, kidney) as the effect concentrations in the available animal studies do not trigger CLP classification, yet kidney effects have been reported in humans following chronic exposure to ethane-1,2-diol. Following a precautionary approach, the target substance will similarly be classified as STOT RE Category 2 (oral, kidney). - Executive summary:
The primary adverse effect of lifetime (2-year) high doses of terephthalic acid to rats was almost completely restricted to the urinary tract. Terephthalic acid induced bladder stones were seen in the high dose (1 000 mg/kg bw/day) female group. Bladder calculi cannot occur unless the solubility of the stone components were exceeded. Based on urinary solubility of Ca-terephthalate, normal human urine would become saturated with Ca-terephthalate at a terephthalic acid concertation of approximately 8 to 16 mM. The concentration of terephthalic acid that would need to be absorbed to produce this effect in humans is approximately 2 400 mg/kg bw/day. The 2-year LOAEL for female rats due to bladder calculi formation was 1 000 mg/kg bw/day (6.0 mmol/kg bw/day).
The chronic toxicity of ethylene glycol was assessed in rats. Groups of Fischer 344 rats were fed diets yielding approximate dosages of 40, 200, or 1 000 mg/kg b/day of ethylene glycol for two years. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. The LOAEL of 1 000 mg/kg bw/day and the NOAEL of 200 mg/kg bw/day for repeated oral toxicity were reported. A one-year repeated oral dose study exposed Wistar Han rats to 40, 150, 300, or 400 mg/kg bw/day ethylene glycol in feed. The NOAEL in Wistar rats was determined to be 150 mg/kg bw/day, and the LOAEL was 300 mg/kg day/day for renal toxicity in the Wistar rats for 1 year of exposure in diet. All sub-chronic and chronic oral studies in rats appear to converge in a NOAEL around 150 mg/kg bw/day. The LOAEL and NOAEL values determined for ethylene glycol do not trigger the European CLP classification; however, due to the potential of oxalate nephrosis following oral exposure, ethylene glycol has been classified as Specific Target Organ Toxicity following Repeated Exposure (STOT RE) Category 2.
The European CLP (EC 1272/2008 as amended) classification of ethylene glycol was qualitatively determined to be STOT RE Category 2 (oral, kidney) as the effect concentrations in the available animal studies do not trigger CLP classification, yet kidney effects have been reported in humans following chronic exposure to ethylene glycol. Following a precautionary approach, BHET will similarly be classified as STOT RE Category 2 (oral, kidney).
Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance. The most conservative chronic NOAEL value was 150 mg/kg bw/day for ethylene glycol or 2.4 mmol/kg bw/day. Therefore, the concentration for further safety assessment of BHET will be 2.4 mmol/kg bw/day or 307 mg/kg bw/day.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 307 mg/kg bw/day
- Study duration:
- chronic
- Experimental exposure time per week (hours/week):
- 168
- Species:
- rat
- System:
- urinary
- Organ:
- kidney
Additional information
The primary adverse effect of lifetime (2-year) high doses of terephthalic acid to rats was almost completely restricted to the urinary tract. Terephthalic acid induced bladder stones were seen in the high dose (1 000 mg/kg bw/day) female group. Bladder calculi cannot occur unless the solubility of the stone components were exceeded. Based on urinary solubility of Ca-terephthalate, normal human urine would become saturated with Ca-terephthalate at a terephthalic acid concertation of approximately 8 to 16 mM. The concentration of terephthalic acid that would need to be absorbed to produce this effect in humans is approximately 2 400 mg/kg bw/day. The 2-year LOAEL for female rats due to bladder calculi formation was 1 000 mg/kg bw/day (6.0 mmol/kg bw/day).
The chronic toxicity of ethylene glycol was assessed in rats. Groups of Fischer 344 rats were fed diets yielding approximate dosages of 40, 200, or 1 000 mg/kg b/day of ethylene glycol for two years. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. The LOAEL of 1 000 mg/kg bw/day and the NOAEL of 200 mg/kg bw/day for repeated oral toxicity were reported. A one-year repeated oral dose study exposed Wistar Han rats to 40, 150, 300, or 400 mg/kg bw/day ethylene glycol in feed. The NOAEL in Wistar rats was determined to be 150 mg/kg bw/day, and the LOAEL was 300 mg/kg day/day for renal toxicity in the Wistar rats for 1 year of exposure in diet. All sub-chronic and chronic oral studies in rats appear to converge in a NOAEL around 150 mg/kg bw/day. The LOAEL and NOAEL values determined for ethylene glycol do not trigger the European CLP classification; however, due to the potential of oxalate nephrosis following oral exposure, ethylene glycol has been classified as Specific Target Organ Toxicity following Repeated Exposure (STOT RE) Category 2.
The European CLP (EC 1272/2008 as amended) classification of ethylene glycol was qualitatively determined to be STOT RE Category 2 (oral, kidney) as the effect concentrations in the available animal studies do not trigger CLP classification, yet kidney effects have been reported in humans following chronic exposure to ethylene glycol. Following a precautionary approach, BHET will similarly be classified as STOT RE Category 2 (oral, kidney).
Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance. The most conservative chronic NOAEL value was 150 mg/kg bw/day for ethylene glycol or 2.4 mmol/kg bw/day. Therefore, the concentration for further safety assessment of BHET will be 2.4 mmol/kg bw/day or 307 mg/kg bw/day.
Justification for classification or non-classification
The CLP classification of ethane-1,2-diol (203-473-3; 107-21-1) was qualitatively determined to be STOT RE Category 2 (oral, kidney) as the effect concentrations in the available animal studies do not trigger European CLP (EC 1272/2008 as amended) classification, yet kidney effects have been reported in humans following chronic exposure to ethane-1,2-diol. Following a precautionary approach, BHET (959-26-2; 213-497-6) will similarly be classified as STOT RE Category 2 (oral, kidney).
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