Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.58 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

EXPOSURE DNEL DERIVATIONS FOR EASTMANTM168 PLASTICIZER

(CAS No. 6422-86-2)

 

 

I. Introduction

 

Bis(2-ethylhexyl) terephthalate (EastmanTM168 Plasticizer; diocyl terephthalate; DOTP) is used as a plasticizer in PVC plastic articles and surface coatings. It is not currently listed as a hazardous substance in the Annex I of Directive 67/548/EEC. Similarly, it is not listed in Annex VI to EC Regulation 1272/2008. It is not a mutagen, carcinogen, or reproductive hazard. There are no published OEL values available for this material. Summarized in Table 1 are the critical preliminary DNEL values derived forbis(2-ethylhexyl) terephthalate.

 

Table 1: Critical Preliminary DNEL Values for Bis(2-Ethylhexyl) Terephthalate

 

Exposure Pattern

DNEL

Workers

General Population

Acute – inhalation, systemic

not calculated1

N/A

Acute – inhalation, local

not calculated

 

N/A

Acute – dermal, systemic

not calculated

 

N/A

Acute – dermal, local

not calculated2

 

N/A

Acute – oral, systemic

not relevant3

 

N/A

Long-term – inhalation, systemic

23.2 mg/m3

 

N/A

Long-term – inhalation, local

not relevant4

 

N/A

Long-term – dermal, systemic

6.58 mg/kg bwt/day

 

N/A

Long-term – dermal, local

No data

 

N/A

Long-term – oral, systemic

not relevant3

 

N/A

1 Chapter 8 of the REACH TGD (Appendix R.8-8) indicates that acute exposure DNEL values are not normally required. Additionally, the lack of acute oral, inhalation or dermal toxicity would indicatebis(2-ethylhexyl) terephthalateis non-hazardous under acute exposure scenarios.

2 Qualitative assessment based on results of skin irritation testing.

3 It is assumed that there will be no acute or long-term oral exposures tobis(2-ethylhexyl) terephthalatein worker populations or acute oral exposures in consumer populations.

4 Eye and respiratory irritation thresholds are assumed to exceed thresholds for chronic systemic effects.


 

Summarized in Table 2 is the critical toxicological study and endpoint identified forbis(2-ethylhexyl) terephthalate.

 

Table 2: Dose descriptors for key studies of toxicological concern

Endpoint

Descriptor

Key Reference

Associated Effects/Comments

Repeated Dose Toxicity

Oral (diet)

NOAEL = 79 mg/kg bwt/day (males)

Chase, K.R.(2005). Eastman 168 Plasticizer Carcinogenicity Study by Dietary Administration to F-344 Rats for 104 Weeks.Report KOD/030, Huntingdon Life Science Ltd. for Eastman Chemical Company.

 

Toxicity limited to low weight gain and food conversion efficiency in male and female rats and ocular changes in female rats.

 

 

II. Descriptions and Rationale for DNEL Derivations

 

1.        Acute toxicity

 

Bis(2-ethylhexyl) terephthalateis of low acute oral toxicity in experimental animals with LD50values ranging above >3200 mg/kg in experimental animals. In rats, there were no mortalities or treatment related adverse effects following 6-hour/day inhalation exposures over a 10-day period to 0.0718 mg/Lbis(2-ethylhexyl) terephthalate. In this latter study, the 0.0718 mg/L exposure concentration was the highest attainable after passing a high airflow through heated material (95°C). Based on the physical properties ofbis(2-ethylhexyl) terephthalate, significant inhalation exposure is unlikely. The acute dermal toxicity ofbis(2-ethylhexyl) terephthalatein guinea pigs is low with an LD50value of >20 ml/kg bwt (19,680 mg/kg bwt). The Technical Guidance Document (TGD, Chapter R.8) indicates that a DNEL for acute toxicity should be derived if an acute hazard has been identified and there is a potential for high peak exposures. Bis(2-ethylhexyl) terephthalateis not hazardous following acute oral, dermal exposures, or inhalation exposures.

 

1.1      Irritation/sensitization

 

Based on experimental results from animal and human testing,bis(2-ethylhexyl) terephthalateis not rated as a skin or eye irritant or a skin sensitizer. Limited results from acute inhalation toxicity testing indicate thatbis(2-ethylhexyl) terephthalatehas a low potential to cause respiratory tract irritation.

 

2.       Repeat dose toxicity

 

The repeated-dose toxicity ofbis(2-ethylhexyl) terephthalateis generally low. Administration ofbis(2-ethylhexyl) terephthalatein the diet of male and female rats for 21 days at concentrations of 0.1, 0.5, 1.0, 1.2 and 2.5% lead to effects on lipid metabolism and only slight peroxisome proliferation at the highest dose level. At the highest dose level there were significant decreases in food consumption and body weight gain and a variety of adverse clinical signs. Altered lipid matabolism and hepatic peroxisomes may have been related to reduced feed intake and not a direct consequence ofbis(2-ethylhexyl) terephthalateexposure. The NOEL in the latter study was 0.5% (equivalent to 505 and 487 mg/kg bwt/day, males and females respectively). In a 90-day study in male and female rats, administration ofbis(2-ethylhexyl) terephthalateat up to 1% in the diet (equivalent to 561 and 617 mg/kg bwt/day, males and females) produced minor hematological changes and increases in liver weights. Gross or microscopic lesions did not accompany liver weight changes or corresponding changes in clinical chemistry parameters. The NOEL for systemic effects in the 90-day study was considered to be 277 mg/kg bwt/day (males) and 309 mg/kg bwt/day (females). In 2-year toxicology and carcinogenicity studies in rats, exposure to levels in the diet of 1500, 6000 or 12000 ppm again produced increases in relative liver weights at the highest dose level tested, but these changes again occurred in the absence of gross or macroscopic lesions or corresponding changes in clinical chemistry parameters. In the 2-year studies, a NOEL of 1500 ppm (corresponding to 79 and 102 mg/kg bwt/day, males and females respectively) was assigned based on low weight gains and food conversion efficiencies and on ocular changes in females receiving the higher dose levels. 

 

3.        Genotoxicity/carcinogenicity

 

Bis(2-ethylhexyl) terephthalatewas negative when testedin vitroin the Ames test at plate incorporation levels up to 10,000mg/plate, either with or without metabolic activation. Urine from male rats dosed for 15 consecutive days with 2000 mg/kg bwt/day ofbis(2-ethylhexyl) terephthalateshowed no mutagenic response in the Ames test, either with or without metabolic activation. Bis(2-ethylhexyl) terephthalatedid not produce chromosomal aberrations in CHO cells when tested up to 1000 nL/mL and was not mutagenic in the CHO/HGPRT mutation assay at concentrations up to 20 nL/mL, either with or without metabolic activation. A specializedin vivostudy conducted in pregnant Sprague-Dawley rats by gavage administration ofbis(2-ethylhexyl) terephthalate(500 mg/kg bwt/day) on gestational days 12 through 19 showed no changes in gene expression in fetal testes.

 

4.        Reproductive/developmental toxicity

 

In a 13-week oral toxicity study conducted in male and female Sprague-Dawley rats exposed to 0, 0.1, 0.5 or 1.0% ofbis(2-ethylhexyl) terephthalatein the diet (equivalent to 561 mg/kg bw/day in males and 617 mg/kg bw/day in females at the 1% dose level), there were no adverse effects on weight of testes or ovaries nor on testes, epididymides, male accessory sex glands, ovaries, uterus, vagina, fallopian tubes, or male and female mammary glands. In a feeding study of shorter duration, there were similarly no adverse effects on testicular weight or gross/microscopic pathology in male Fischer 344 rats receiving up to 2.5% (equivalent to 2104 mg/kg bw/day) ofbis(2-ethylhexyl) terephthalatein the diet for 21 days. In a 2-year oral study conducted with male and female rats provided diets containing up to 10000 ppmbis(2-ethylhexyl) terephthalate(equivalent to 666 and 901 mg/kg bw/day in males and females, respectively), there were no adverse effects on reproductive organs in either sex. In a two-generation reproductive toxicity study conducted in male and female rats, there were no adverse effects on sexual function, fertility or reproductive organs in either sex receiving up to 10000 ppm in the diet. Although some developmental toxicity (lower body and organ weights) was evident at 6000 and 10000 ppm in the diet, this occurred in the presence of maternal toxicity. In a prenatal developmental toxicity study, female mice were exposed to test diets containing up to 7000 ppm ofbis(2-ethylhexyl) terephthalate(equivalent to 1382 mg/kg bw/day) during gestation days 0-18. There were no adverse effects on any reproductive parameters. There were also no adverse effect on live litter size, fetal body weight or sex ratio and there were no increases in the incidence of external, skeletal or visceral malformations or variations, even at maternally toxic doses. In a similar study in which pregnant Sprague-Dawley rats were exposed to up to 10000 ppm di (2-ethylhexyl) terephthalate in the diet from gestation days 0-20, there were no adverse effects on reproductive organs and no significant differences in numbers of early or late resorptions, corpora lutea, viable fetuses per litter, implantation sites, or pre- or post-implantation loss among any of the groups. Fetal sex ratios were also unaffected.

 

III. Mode of Action Considerations

 

For the critical study identified in Table 2, a threshold mode of action was assumed.

 

IV. Modification of Relevant Dose Descriptors to the Correct Starting Point

 

Summarized in Table 3 are corrected dose descriptors derived from those in Table 2 (see Guidance Document, Chapter R.8, Appendix R.8-2).

 

Table 3: Corrected dose descriptors for the key study of toxicological concern

 

Endpoint

Most relevant dose descriptors

Corrected dose descriptors

(Worker)

 

Local

Systemic

Local

Systemic

Repeated Dose Toxicity

-oral

NC

NOAEL = 79 mg/kg bwt/day

NC

NC

-dermal

NC

(use oral data)

NC

NOELderm,corr= 79 mg/kg bwt/day

-inhalation

NC

(use oral data)

NC

NOELinh, corr= 69.7 mg/m3

NC - not calculated

 

1.        Endpoint toxicity in rats

 

In the case of worker exposures, the oral route of exposure was not considered. For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed (see Guidance Document, Chaper R.8, Appendix R.8-2). A first-pass effect was discounted for the purposes of these calculations.

 

Oral:

 

For the extrapolation from rats to humans, equivalent bioavailability was assumed (see Guidance Document, Section R.8.4.2, page 24). Thus, no modification of the dose descriptor was used. 

 

Dermal:

 

Complete absorption of the test material by both the oral and dermal routes was assumed. Thus, dermal exposure to the same amount of test material would produce an equivalent internal dose. Differences in metabolism, distribution and elimination were not considered and thus no further correction was applied (see Guidance Document, Section R.8.4.2, page 25). Thus, the corrected dose descriptor for the worker population is 79 mg/kg bwt/day.

 

Inhalation:

 

In the case of worker exposures, 50% absorption of the test material by the oral versus the inhalation route was assumed (see Guidance Document, Chapter R.8, Appendix R.8.4.2, page 25). The rat repeated-dose oral NOEL value was divided by 0.38 m3/kg bwt to yield an equivalent air concentration for an 8-hour exposure (see Guidance Document, Chapter R.8, Appendix R.8-2, page 65). This value was further corrected to account for increased metabolic rate (and inhalation volume) in the case of light work versus basal metabolism (multiplicative factor of 6.7 m3/10 m3, or 0.67).

 

(NOELoralX 0.50)¸0.38 m3/kg bwt = 39.5 mg/kg bwt¸0.38 m3/kg bwt = 104 mg/m3

 

104 mg/m3X 0.67 = 69.7 mg/m3= NOELinh,corr

 

V. Application of Assessment Factors to the Corrected Dose Descriptors

 

Summarized in Table 4 are endpoint-specific DNEL values for worker exposures to bis(2-ethylhexyl) terephthalate derived from the corrected dose descriptors found in Table 3.

 

Table 4: Endpoint-specific DNEL values for bis(2-ethylhexyl) terephthalate

 

Endpoint

Corrected dose descriptor

Overall AF[1]

Endpoint-specific worker DNELs

 

Local

Systemic

 

Local

Systemic

Repeated-Dose Toxicity

-oral

NC

NC

NC

NC

NC

-dermal

NC

NOAELderm, corr= 79 mg/kg bwt/day

12

NC

6.58 mg/kg bwt/day

-inhalation

NC

NOAELinh, corr= 69.7 mg/m3

3

NC

23.2 mg/m3

NC - not calculated

 

 

Dermal:

 

In the case of worker exposure, an allometric scaling (AS) factor of 4 (for differences in metabolic rate) was assigned. In addition, an AF value of 3 (intraspecies, sensitive worker) was also assigned. No further assessment factors were applied. These values are summarized in Table 6.

 

 

Table 6: LongTerm Systemic DNEL Assessment Factors (Dermal)

 

Uncertainty

AF

(worker)

AF

 (gen. pop.)

Justification

Establishment of NOAEL

1

N/A

default AF; clear NOAEL assigned

Duration of exposure

1

N/A

Based on a 2-year chronic study in rats

Interspecies differences

4

N/A

default allometric scaling factor (rat)

Intraspecies differences

3

N/A

default AF

Overall AF

12

N/A

 

 

 

Inhalation:

 

Allometric scaling was already performed in the previous step (corrected dose descriptor) and no further factors were applied. In the case of worker exposure, an AF value of 3 (intraspecies, sensitive worker) was assigned. No further assessment factors were applied. These values are summarized in Table 7.

 

Table 7: LongTerm Systemic DNEL Assessment Factors (Inhalation)

 

Uncertainty

AF

(worker)

AF

 (gen. pop.)

Justification

Establishment of NOAEL

1

N/A

default AF; clear NOAEL assigned

Duration of exposure

1

N/A

Based on a 2-year chronic study in rats

Interspecies differences

1

N/A

allometric scaling not applicable

Intraspecies differences

3

N/A

default AF

Overall AF

3

N/A

 

 

 

SUMMARY

 

Based on calculated DNEL values, those derived from the NOEL value for toxicity in rats from chronic dietary studies were found to be the most protective for worker population exposures. These are summarized in Table 1 at the beginning of this document.

 


[1]Overall assessment factors were assigned based on the guidelines provided in ECETOC Technical Report 86, Derivation of Assessment Factors for Human Health Risk Assessment, Brussels, February 2003.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.86 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.95 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.95 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

EXPOSURE DNEL DERIVATIONS FOR EASTMANTM168 PLASTICIZER

(CAS No. 6422-86-2)

 

 

I. Introduction

 

Bis(2-ethylhexyl) terephthalate (EastmanTM168 Plasticizer; diocyl terephthalate; DOTP) is used as a plasticizer in PVC plastic articles and surface coatings. It is not currently listed as a hazardous substance in the Annex I of Directive 67/548/EEC. Similarly, it is not listed in Annex VI to EC Regulation 1272/2008. It is not a mutagen, carcinogen, or reproductive hazard. There are no published OEL values available for this material. Summarized in Table 1 are the critical preliminary DNEL values derived forbis(2-ethylhexyl) terephthalate.

 

Table 1: Critical Preliminary DNEL Values for Bis(2-Ethylhexyl) Terephthalate

 

Exposure Pattern

DNEL

Workers

General Population

Acute – inhalation, systemic

N/A

not calculated

Acute – inhalation, local

 

N/A

not calculated

Acute – dermal, systemic

 

N/A

not calculated

Acute – dermal, local

 

N/A

not calculated

Acute – oral, systemic

 

N/A

not relevant3

Long-term – inhalation, systemic

 

N/A

6.86 mg/m3

Long-term – inhalation, local

 

N/A

not relevant4

Long-term – dermal, systemic

 

N/A

3.95 mg/kg/day

Long-term – dermal, local

 

N/A

No data

Long-term – oral, systemic

 

N/A

3.95 mg/kg/day

1 Chapter 8 of the REACH TGD (Appendix R.8-8) indicates that acute exposure DNEL values are not normally required. Additionally, the lack of acute oral, inhalation or dermal toxicity would indicatebis(2-ethylhexyl) terephthalateis non-hazardous under acute exposure scenarios.

2 Qualitative assessment based on results of skin irritation testing.

3 It is assumed that there will be no acute or long-term oral exposures tobis(2-ethylhexyl) terephthalatein worker populations or acute oral exposures in consumer populations.

4 Eye and respiratory irritation thresholds are assumed to exceed thresholds for chronic systemic effects.


 

Summarized in Table 2 is the critical toxicological study and endpoint identified forbis(2-ethylhexyl) terephthalate.

 

Table 2: Dose descriptors for key studies of toxicological concern

Endpoint

Descriptor

Key Reference

Associated Effects/Comments

Repeated Dose Toxicity

Oral (diet)

NOAEL = 79 mg/kg bwt/day (males)

Chase, K.R.(2005). Eastman 168 Plasticizer Carcinogenicity Study by Dietary Administration to F-344 Rats for 104 Weeks.Report KOD/030, Huntingdon Life Science Ltd. for Eastman Chemical Company.

 

Toxicity limited to low weight gain and food conversion efficiency in male and female rats and ocular changes in female rats.

 

 

II. Descriptions and Rationale for DNEL Derivations

 

1.        Acute toxicity

 

Bis(2-ethylhexyl) terephthalateis of low acute oral toxicity in experimental animals with LD50values ranging above >3200 mg/kg in experimental animals. In rats, there were no mortalities or treatment related adverse effects following 6-hour/day inhalation exposures over a 10-day period to 0.0718 mg/Lbis(2-ethylhexyl) terephthalate. In this latter study, the 0.0718 mg/L exposure concentration was the highest attainable after passing a high airflow through heated material (95°C). Based on the physical properties ofbis(2-ethylhexyl) terephthalate, significant inhalation exposure is unlikely. The acute dermal toxicity ofbis(2-ethylhexyl) terephthalatein guinea pigs is low with an LD50value of >20 ml/kg bwt (19,680 mg/kg bwt). The Technical Guidance Document (TGD, Chapter R.8) indicates that a DNEL for acute toxicity should be derived if an acute hazard has been identified and there is a potential for high peak exposures. Bis(2-ethylhexyl) terephthalateis not hazardous following acute oral, dermal exposures, or inhalation exposures.

 

1.1      Irritation/sensitization

 

Based on experimental results from animal and human testing,bis(2-ethylhexyl) terephthalateis not rated as a skin or eye irritant or a skin sensitizer. Limited results from acute inhalation toxicity testing indicate thatbis(2-ethylhexyl) terephthalatehas a low potential to cause respiratory tract irritation.

 

2.       Repeat dose toxicity

 

The repeated-dose toxicity ofbis(2-ethylhexyl) terephthalateis generally low. Administration ofbis(2-ethylhexyl) terephthalatein the diet of male and female rats for 21 days at concentrations of 0.1, 0.5, 1.0, 1.2 and 2.5% lead to effects on lipid metabolism and only slight peroxisome proliferation at the highest dose level. At the highest dose level there were significant decreases in food consumption and body weight gain and a variety of adverse clinical signs. Altered lipid matabolism and hepatic peroxisomes may have been related to reduced feed intake and not a direct consequence ofbis(2-ethylhexyl) terephthalateexposure. The NOEL in the latter study was 0.5% (equivalent to 505 and 487 mg/kg bwt/day, males and females respectively). In a 90-day study in male and female rats, administration ofbis(2-ethylhexyl) terephthalateat up to 1% in the diet (equivalent to 561 and 617 mg/kg bwt/day, males and females) produced minor hematological changes and increases in liver weights. Gross or microscopic lesions did not accompany liver weight changes or corresponding changes in clinical chemistry parameters. The NOEL for systemic effects in the 90-day study was considered to be 277 mg/kg bwt/day (males) and 309 mg/kg bwt/day (females). In 2-year toxicology and carcinogenicity studies in rats, exposure to levels in the diet of 1500, 6000 or 12000 ppm again produced increases in relative liver weights at the highest dose level tested, but these changes again occurred in the absence of gross or macroscopic lesions or corresponding changes in clinical chemistry parameters. In the 2-year studies, a NOEL of 1500 ppm (corresponding to 79 and 102 mg/kg bwt/day, males and females respectively) was assigned based on low weight gains and food conversion efficiencies and on ocular changes in females receiving the higher dose levels. 

 

3.        Genotoxicity/carcinogenicity

 

Bis(2-ethylhexyl) terephthalatewas negative when testedin vitroin the Ames test at plate incorporation levels up to 10,000mg/plate, either with or without metabolic activation. Urine from male rats dosed for 15 consecutive days with 2000 mg/kg bwt/day ofbis(2-ethylhexyl) terephthalateshowed no mutagenic response in the Ames test, either with or without metabolic activation. Bis(2-ethylhexyl) terephthalatedid not produce chromosomal aberrations in CHO cells when tested up to 1000 nL/mL and was not mutagenic in the CHO/HGPRT mutation assay at concentrations up to 20 nL/mL, either with or without metabolic activation. A specializedin vivostudy conducted in pregnant Sprague-Dawley rats by gavage administration ofbis(2-ethylhexyl) terephthalate(500 mg/kg bwt/day) on gestational days 12 through 19 showed no changes in gene expression in fetal testes.

 

4.        Reproductive/developmental toxicity

 

In a 13-week oral toxicity study conducted in male and female Sprague-Dawley rats exposed to 0, 0.1, 0.5 or 1.0% ofbis(2-ethylhexyl) terephthalatein the diet (equivalent to 561 mg/kg bw/day in males and 617 mg/kg bw/day in females at the 1% dose level), there were no adverse effects on weight of testes or ovaries nor on testes, epididymides, male accessory sex glands, ovaries, uterus, vagina, fallopian tubes, or male and female mammary glands. In a feeding study of shorter duration, there were similarly no adverse effects on testicular weight or gross/microscopic pathology in male Fischer 344 rats receiving up to 2.5% (equivalent to 2104 mg/kg bw/day) ofbis(2-ethylhexyl) terephthalatein the diet for 21 days. In a 2-year oral study conducted with male and female rats provided diets containing up to 10000 ppmbis(2-ethylhexyl) terephthalate(equivalent to 666 and 901 mg/kg bw/day in males and females, respectively), there were no adverse effects on reproductive organs in either sex. In a two-generation reproductive toxicity study conducted in male and female rats, there were no adverse effects on sexual function, fertility or reproductive organs in either sex receiving up to 10000 ppm in the diet. Although some developmental toxicity (lower body and organ weights) was evident at 6000 and 10000 ppm in the diet, this occurred in the presence of maternal toxicity. In a prenatal developmental toxicity study, female mice were exposed to test diets containing up to 7000 ppm ofbis(2-ethylhexyl) terephthalate(equivalent to 1382 mg/kg bw/day) during gestation days 0-18. There were no adverse effects on any reproductive parameters. There were also no adverse effect on live litter size, fetal body weight or sex ratio and there were no increases in the incidence of external, skeletal or visceral malformations or variations, even at maternally toxic doses. In a similar study in which pregnant Sprague-Dawley rats were exposed to up to 10000 ppm di (2-ethylhexyl) terephthalate in the diet from gestation days 0-20, there were no adverse effects on reproductive organs and no significant differences in numbers of early or late resorptions, corpora lutea, viable fetuses per litter, implantation sites, or pre- or post-implantation loss among any of the groups. Fetal sex ratios were also unaffected.

 

III. Mode of Action Considerations

 

For the critical study identified in Table 2, a threshold mode of action was assumed.

 

IV. Modification of Relevant Dose Descriptors to the Correct Starting Point

 

Summarized in Table 3 are corrected dose descriptors derived from those in Table 2 (see Guidance Document, Chapter R.8, Appendix R.8-2).

 

Table 3: Corrected dose descriptors for the key study of toxicological concern

 

Endpoint

Most relevant dose descriptors

Corrected dose descriptors

(General Population)

Repeated Dose Toxicity

-oral

NC

NOAEL = 79 mg/kg bwt/day

NC

NOELoral, corr= 79 mg/kg bwt

-dermal

NC

(use oral data)

NC

NOELderm, corr= 79 mg/kg bwt/day

-inhalation

NC

(use oral data)

NC

NOELinh, corr= 34.3 mg/m3

NC - not calculated

 

1.        Endpoint toxicity in rats

 

In the case of general population exposures, the oral route of exposure was considered. For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed (see Guidance Document, Chaper R.8, Appendix R.8-2). A first-pass effect was discounted for the purposes of these calculations.

 

Oral:

 

For the extrapolation from rats to humans, equivalent bioavailability was assumed (see Guidance Document, Section R.8.4.2, page 24). Thus, no modification of the dose descriptor was used. In the case of general population oral exposure, the corrected dose descriptor is 79 mg/kg bwt/day.

 

Dermal:

 

Complete absorption of the test material by both the oral and dermal routes was assumed. Thus, dermal exposure to the same amount of test material would produce an equivalent internal dose. Differences in metabolism, distribution and elimination were not considered and thus no further correction was applied (see Guidance Document, Section R.8.4.2, page 25). Thus, the corrected dose descriptor for the general population is 79 mg/kg bwt/day.

 

Inhalation:

 

In the case of exposure to the general population, 50% absorption of the test material by the oral versus the inhalation route was also assumed (see Guidance Document, Chapter R.8, Appendix R.8.4.2, page 25). The rat repeated-dose oral NOEL value was divided by 1.15 m3/kg bwt to yield an equivalent air concentration for continuous exposure (see Guidance Document, Chapter R.8, Appendix R.8-2, page 64). No further correction factors were applied.

 

(NOELoralX 0.50)¸1.15 m3/kg bwt = 39.5 mg/kg bwt/day¸1.15 m3/kg bwt =

 

34.3 mg/m3= NOELinh,corr

 

V. Application of Assessment Factors to the Corrected Dose Descriptors

 

Summarized in Table 4 are endpoint-specific DNEL values for general population exposures to bis(2-ethylhexyl) terephthalate derived from the corrected dose descriptors found in Table 3.

 

Table 4: Endpoint-specific DNEL values for bis(2-ethylhexyl) terephthalate

 

Endpoint

Corrected dose descriptor

Overall AF[1]

 

Endpoint-specific general population DNELs

 

Local

Systemic

 

Local

Systemic

Repeated-Dose Toxicity

-oral

NC

NOAELoral, corr= 79 mg/kg bwt/day

20

NC

3.95 mg/kg bwt/day

-dermal

NC

NOAELderm, corr= 79 mg/kg bwt/day

20

NC

3.95 mg/kg bwt/day

-inhalation

NC

NOAELinh, corr= 34.3 mg/m3

5

NC

6.86 mg/m3

NC - not calculated

 

Oral:

 

Given the assumption of equivalent bioavailability between oral exposures in rats and humans, an allometric scaling (AS) factor of 4 (for differences in metabolic rate) was assigned. In addition, an AF value of 5 (intraspecies, sensitive individual) was also assigned. No further assessment factors were applied. These values are summarized in the Table 5.


 

Table 5: General Population Long Term Systemic DNEL Assessment Factors (Oral)

 

Uncertainty

AF

(gen. pop.)

Justification

Establishment of NOAEL

1

default AF; clear NOAEL assigned

Duration of exposure

1

Based on a 2-year chronic study in rats

Interspecies differences

4

default allometric scaling factor (rat)

Intraspecies differences

5

default AF

Overall AF

20

 

*Note: Both a 2-generation reproductive/developmental toxicity study and a lifespan toxicity/carcinogenicity study were available.

 

Dermal:

 

In the case of exposure to the general population, an allometric scaling (AS) factor of 4 (for differences in metabolic rate) was assigned. In addition, an AF value of 5 (intraspecies, sensitive individual) was also assigned. No further assessment factors were applied. These values are summarized in Table 6.

 

Table 6: LongTerm Systemic DNEL Assessment Factors (Dermal)

 

Uncertainty

AF

(worker)

AF

 (gen. pop.)

Justification

Establishment of NOAEL

N/A

1

default AF; clear NOAEL assigned

Duration of exposure

 

N/A

1

Based on a 2-year chronic study in rats

Interspecies differences

 

N/A

4

default allometric scaling factor (rat)

Intraspecies differences

 

N/A

5

default AF

Overall AF

 

N/A

20

 

 

 

Inhalation:

 

In the case of exposure to the general population, an AF value of 5 (intraspecies, sensitive individual) was assigned. No further assessment factors were applied. These values are summarized in Table 7.


 

Table 7: LongTerm Systemic DNEL Assessment Factors (Inhalation)

 

Uncertainty

AF

(worker)

AF

 (gen. pop.)

Justification

Establishment of NOAEL

 

N/A

1

default AF; clear NOAEL assigned

Duration of exposure

 

N/A

1

Based on a 2-year chronic study in rats

Interspecies differences

 

N/A

1

allometric scaling not applicable

Intraspecies differences

 

N/A

5

default AF

Overall AF

 

N/A

5

 

 

 

SUMMARY

 

Based on calculated DNEL values, those derived from the NOEL value for toxicity in rats from chronic dietary studies were found to be the most protective for general population exposures. These are summarized in Table 1 at the beginning of this document.

 


[1]Overall assessment factors were assigned based on the guidelines provided in ECETOC Technical Report 86, Derivation of Assessment Factors for Human Health Risk Assessment, Brussels, February 2003.