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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Diss Factsheets

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
Reference
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.

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).