Bis(hydroxyethyl) terephthalate

Endpoint summary

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

Reference

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.

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

Reference

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.

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).