Bis(hydroxyethyl) terephthalate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

BHET is non-mutagenic.

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

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

Type of assay:

bacterial reverse mutation assay

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

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Key result

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Key result

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Key result

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Conclusions:

As both terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) are non-mutagenic according to in vitro S. typimurium assays, it was predicted that BHET will not be mutagenic according to an in vitro gene mutation assay in bacteria.

Executive summary:

A total of 34 chemicals were tested using the Salmonella typhimurium test system developed by Ames and his colleagues; terephthalic acid was one of these 34 chemicals. S. typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 were exposed to terephthalic acid by the pre-incubation method both in the presence and absence of Aroclor 1254-induced S9. The doses tested were 100, 333, 1 000, 3 333, 10 000 µg/plate. Terephthalic acid was non-mutagenic under the conditions of this assay. Following a standard Salmonella plate assay, ethylene glycol was assessed by exposing S. typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 both in the presence and absence of Aroclor 12-54-induced S9 at a maximum concentration of 10 000 µg/plate. Ethylene glycol was non-mutagenic under the conditions of this assay. Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, as both terephthalic acid and ethylene glycol are non-mutagenic according to in vitro S. typhimurium assays, it was predicted that BHET will not be mutagenic according to an in vitro gene mutation assay in bacteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

BHET is non-mutagenic.

Link to relevant study records

Reference

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

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:

data waiving: 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.

Key result

Sex:

male/female

Genotoxicity:

negative

Toxicity:

not specified

Vehicle controls validity:

not specified

Negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

Based on a mammalian erythrocyte micronucleus assay, terephthalic acid (202-830-0; 100-21-0) is not genotoxic.

Based on a rodent dominant lethal mutagenesis assay, ethane-1,2-diol (203-473-3; 107-21-1) is not genotoxic.

Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET was predicted to be non-genotoxic.

Conclusions:

BHET is predicted to be non-genotoxic.

Executive summary:

The cytogenicity of terephthalic acid was assessed in a GLP-compliant assay according to OECD 474. Male and female ICR mice were exposed by intraperitoneal injection to 200, 400, or 800 mg/kg terephthalic acid. The incidence of micronuclei did not differ from the vehicle control. The assay was considered valid. Terephthalic acid was reported as negative under the conditions of this mammalian erythrocyte micronucleus test. The mammalian germ cell gene mutation potential of ethylene glycol was assessed in a rodent dominant lethal mutagenesis assay. The F2 males from a three-generation reduction study were exposed in utero and up to 155 days of age prior to being mated with untreated females. The concentrations assessed were 40, 200 and 1 000 mg/kg bw/day. Reproductive parameters, including the percentage of pregnant rats, total number of early fetal deaths per pregnant female, and median number of fetal deaths were unaffected by ethylene glycol treatment. Treatment of male rats with ethylene glycol in the diet during gestation, up to mating and subsequent mating to untreated females over 3 weeks produced no indication of a dominant lethal mutagenic effect. Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET was predicted to be non-genotoxic.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Gene mutation in bacteria, in vitro (REACH Annex VII 8.4.1)

A total of 34 chemicals were tested using the Salmonella typhimurium test system developed by Ames and his colleagues; terephthalic acid was one of these 34 chemicals. S. typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 were exposed to terephthalic acid by the pre-incubation method both in the presence and absence of Aroclor 1254-induced S9. The doses tested were 100, 333, 1 000, 3 333, 10 000 µg/plate. Terephthalic acid was non-mutagenic under the conditions of this assay. Following a standard Salmonella plate assay, ethylene glycol was assessed by exposing S. typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 both in the presence and absence of Aroclor 12-54-induced S9 at a maximum concentration of 10 000 µg/plate. Ethylene glycol was non-mutagenic under the conditions of this assay. Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, as both terephthalic acid and ethylene glycol are non-mutagenic according to in vitro S. typhimurium assays, it was predicted that BHET will not be mutagenic according to an in vitro gene mutation assay in bacteria.

Somatic cell genotoxicity, in vivo (REACH Annex XI, 8.4)

The cytogenicity of terephthalic acid was assessed in a GLP-compliant assay according to OECD 474. Male and female ICR mice were exposed by intraperitoneal injection to 200, 400, or 800 mg/kg terephthalic acid. The incidence of micronuclei did not differ from the vehicle control. The assay was considered valid. Terephthalic acid was reported as negative under the conditions of this mammalian erythrocyte micronucleus test. The mammalian germ cell gene mutation potential of ethylene glycol was assessed in a rodent dominant lethal mutagenesis assay. The F2 males from a three-generation reduction study were exposed in utero and up to 155 days of age prior to being mated with untreated females. The concentrations assessed were 40, 200 and 1 000 mg/kg bw/day. Reproductive parameters, including the percentage of pregnant rats, total number of early fetal deaths per pregnant female, and median number of fetal deaths were unaffected by ethylene glycol treatment. Treatment of male rats with ethylene glycol in the diet during gestation, up to mating and subsequent mating to untreated females over 3 weeks produced no indication of a dominant lethal mutagenic effect. Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET was predicted to be non-genotoxic.

Justification for classification or non-classification

Both of the source substances, terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1), do not meet the criteria for classification as a mutagen according to European CLP (EC No 1272/2008 as amended).  Information on the source substances are considered to be directly applicable to BHET (959-26-2; 213-497-6).  Therefore, BHET does not meet the criteria for classification as a mutagen according to CLP.