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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
34.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
AF for differences in duration of exposure:
2
AF for intraspecies differences:
3
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for intraspecies differences:
3
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Dibutyl terephthalate is currently not listed as a harmful substance in the Annex I of the EU Dangerous Substance Directive 67/548/EEC or in Annex VI to EC Regulation 1272/2008. It is not a Category 1 or 2 mutagen, carcinogen, or reproductive hazard; thus, DNEL/DMEL values for these endpoints were not derived. There is no published IOEL (Indicative Occupational Exposure Limit) value or other relevant exposure limit value available for this material. 

Summarized in the following table are the critical toxicological studies and values identified for dibutyl terephthalate.

Dose descriptors for key studies (starting points) of toxicological concern

 

Descriptor

 

Level

 

Key Reference

 

Associated Effects/Comments

Repeated Dose Toxicity

NOAEL (rat)

235 mg/kg bwt/day

ECETOC, 2003

CNS Effects; corrected for metabolism to yield 2 equiv. ofn-butanol

Sat. conc. for calcium terephthalic acid in human urine

48.6 mg/kg bwt/day

Wolkowski and Tyl, 1982

Effects of urolithiasis; corrected for molecular weight of dibutyl terephthalate and assuming 1 equiv. of TPA formed from metabolism

 

Descriptions and Rationale for DNEL Derivations

Metabolism and Toxicokinetic Considerations

Dibutyl terephthalate is rapidly and completely metabolized ton-butanol and terephthalic acid eitherin vivoorin vitro. Thus, the toxicity of dibutyl terephthalate is presumed to be dictated by the toxicities of then-butanol (BA) and terephthalic acid (TPA) metabolites.

1.       Acute toxicity

There is adequate acute toxicity information available for dibutyl terephthalate. The acute oral toxicity of dibutyl terephthalate is low with a LD50value reported in female rats >/= 2000 mg/kg bwt. The acute dermal toxicity of dibutyl terephthalate is also low with no deaths reported in male or female rats administered a single limit dose of the undiluted material under occluded contact for 24 hours. The acute dermal LD50value for dibutyl terephthalate was ≥ 2000 mg/kg bw in male and female rats. There were no significant clinical signs, body weight changes or pathological effects noted in either the oral or dermal acute toxicity studies.

Dibutyl terephthalate is a high boiling liquid with an extremely low vapor pressure at room temperature. Based on these physical properties of dibutyl terephthalate, the potential for significant inhalation exposure is limited. In addition, based on the absence of mortality or other signs to suggest systemic toxicity when a limit dose of 2000 mg/kg bwt was administered to rats by the oral or dermal routes, dibutyl terephthalate is also expected to present a low toxicity hazard by the inhalation route.

1.1    Irritation/sensitization

In two key studies in humans and in a supporting animal study, dibutyl terephthalate was not a skin irritant. Anin vitroeye irritation assay indicated a minimal potential for eye irritation for the undiluted material. Anin vivoeye irritation study in rabbits with the undiluted material indicated only minimal effects (conjunctival redness). Although the results of a LLNA in mice with undiluted dibutyl terephthalate indicated a potential for skin sensitization, a human repeated insult patch test on 208 volunteers indicated only a slight to moderate reaction in a single individual with no response in the other 207 volunteers. The test material is not judged to be a skin sensitizer.

Dibutyl terephthalate is not expected to cause respiratory irritation or sensitization.

2.      Repeat dose toxicity

There are no repeated dose toxicity studies available for dibutyl terephthalate. Rapidin vivoconversion to terephthalic acid (TPA) andn-butanol (BA) is anticipated, thus repeated dose toxicity information for these metabolites should substitute for toxicity information for the parent material.

Male and female rats were administered BA daily by gavage at 0, 30, 125 or 500 mg/kg bwt/day for either 6 or 13 weeks (ECETOC, 2003). There were no treatment related mortalities. Ataxia and hypoactivity (lasting less than 1 h) were observed immediately after dosing in both sexes of the high-dose group during the final 6 weeks of dosing. There were no other significant treatment related effects reported in this study. The NOAEL reported for this study was 125 mg/kg bwt/day. This value was used as the starting point for the calculation of DNEL values after correcting for the metabolism of dibutyl terephthalate which yields 2 equivalents of BA for each equivalent of the diester (278.34 / 2 x 74.12 or 1.88x). Thus the starting point for the calculation is 235 mg/kg bwt/day.

Information is available concerning the repeated dose toxicity of TPA following administration in the diet or following inhalation exposures. The critical effect following repeated oral exposures is urolithiasis, the formation of urinary tract calculi and secondary effects on the urinary system including inflammation, hyperplasia, hematuria and increased kidney weights. At high dose levels, mortality is observed. In a key study, TPA was administered in the diet to male and female Wistar and CD rats for 90 days at concentrations of 0, 0.03, 0.125, 0.5, 2.20 and 5.0% (Ledouxet al.,1982). TPA-administration resulted in a decrease in urinary pH. Chronic inflammatory lesions of the bladder and urethra were observed in treated rats, with the highest incidence occurring in rats fed 5% TPA. Some small strain differences were present, but it was concluded that there were no substantial difference in TPA toxicity between CD and Wistar rats. Based on reduced body weights, the NOAEL can be considered to be 0.125% TPA in the diet (125 mg/kg bwt/day).

No effects were observed in groups of male and female Sprague-Dawley rats exposed by inhalation to terephthalic acid for 4 weeks (6 hours/day, 5 days/week) at concentrations of 1.03, 2.93 or 10.05 mg/m3(analytical). There were no significant effects noted in this inhalation study.

In numerous mechanistic studies conducted on TPA, it is clear that the effects on the bladder and urinary system are due to urolithiasis. It also is clear that at levels below which calcium terephthalate becomes insoluble, bladder calculi and stone formation are avoided as well as the effects of urolithiasis. Based on the work of Wolkowski and Tyl (1982), a urinary concentration of 8 mM terephthalic acid corresponds to saturation in an adult human. This is equivalent to an intake of 2.0 g of TPA daily or 29 mg/kg bwt/day based on a 70 kg human. Assuming complete metabolism of dibutyl terephthalate to TPA, and after correction based on molecular weight (278.35 / 166.13 or 1.675x), the corresponding starting value for the calculation of DNEL values for dibutyl terephthalate is 48.6 mg/kg bwt/day.

3.       Genotoxicity/carcinogenicity

The mutagenic/genotoxic potential of dibutyl terephthalate has been characterized in a series of well conducted bacterial and mammalianin vitromutagenicity tests. It was negative in an Ames bacterial reverse mutation assay, at concentrations up to 5000 μg/plate in the presence or absence of metabolic activation. There were no increases in chromosomal aberrations in anin vitroassay with CHO cells, either in the presence or absence of metabolic activation, even at dose levels causing clear cytotoxicity. In anin vitrocell mutation assay using mouse lymphoma L5178Y cells, there was no increase in mutation frequency at the thymidine kinase locus at concentrations up to 350 μg/mL in the absence of metabolic activation or up to 700.0 μg/mL in the presence of activation. Both of these dose levels caused clear cytotoxicity.

Dibutyl terephthalate has not been tested for carcinogenicity.

4.       Reproductive/developmental toxicity

There are no reproduction/developmental toxicity studies available for dibutyl terephthalate. In a drinking water developmental toxicity study with BA, concentrations of 0.2, 1.0 or 5.0% (316, 1454 or 5654 mg/kg/day) were administered to rats on days 0 through 20 of pregnancy. Developmental effects were observed at the highest exposure concentration and consisted of lowered fetal weights and significant increases in the incidence of fetuses with skeletal variations at 5.0%. There were no significant increases in the incidence of fetuses with external, skeletal and internal abnormalities. Thus, BA was not judged to be a selective developmental toxicant.  Based on the significant decreases in maternal body weight gain and fetal weight, it is concluded that the no observed adverse effect levels (NOAELs) of BA for both dams and fetuses in this study was 1.0% (1454 mg/kg/day).

Groups of pregnant rats were exposed by inhalation to BA for 7 hours/day on days 1 through 19 of pregnancy at nominal concentrations of 0, 10.8, 18.5 and 24.7 mg/L (0, 3500, 6000, 8000 ppm). Narcosis was the primary clinical sign observed in dams at the highest exposure concentration. Two of 18 treated dams died at the highest exposure concentration. Body weights and food consumption decreased at the highest exposure concentration in dams. Fetal effects were minimal and included and included slightly decreased fetal weights at the two highest exposure concentrations. The NOAEL for maternal effects and fetal toxicity (decreased liter weights) was the 10.8 mg/L concentration. Based on the lack of overt teratogenicity, the 24.7 mg/L concentration was the NOAEL for teratogenicity.

Groups of pregnant rats were exposed by inhalation to TPA for 6 hours/day on gestation days 6 through 15 at nominal exposure concentrations of 0.0, 1.0, 5.0 and 10.0 mg/m³. There was no evidence of developmental toxicity up to the highest exposure concentration tested.

Mode of Action Considerations

For the critical studies identified, a threshold mode of action was assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point

Summarized in the Table 25 are corrected dose descriptors for worker exposures (see Guidance Document, Chapter R.8, Appendix R.8-2).

1.       Endpoint: subchronic 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, Chapter R.8, Appendix R.8-2). A first-pass effect was discounted for the purposes of these calculations.

Dermal:

Due to a lack of dermal absorption data for dibutyl terephthalate, 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 is 235 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 NOAEL 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, Example 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).

(NOAELoralX 0.50) / 0.38 m3/kg bwt = 309 mg/m3

309 mg/m3X 0.67 = 207 mg/m3= NOAELinh, corr

 

2.       Endpoint: threshold for urolithiasis effects in humans

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.

Dermal:

Due to a lack of dermal absorption data for dibutyl terephthalate, 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 is 48.6 mg/kg bwt/day.

Inhalation:

In the case of worker exposures and with a lack of experimental data, 100% absorption of the test material by the inhalation route was assumed. The calculated threshold human effect value for urolithiasis for the inhalation route was calculated based on a 70 kg human and a 10 m3/person/8 hour breathing volume (see Guidance Document, Chapter R.8, Example R.8-2, page 65).

NOAELoralX 70 kg bwt / 10 m3/person/8 hour = 340 mg/m3

Application of Assessment Factors to the Corrected Dose Descriptors

Summarized in Table 25 are endpoint-specific DNEL values for worker exposures to dibutyl terephthalate derived from the corrected dose descriptors.

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.

1.       Endpoint: subchronic toxicity in rats

dermal:

An AF of 4 was applied to the corrected dose descriptor for dermal long-term (repeated dose) systemic effects in workers (interspecies differences, allometric scaling). In addition, an AF of 2 (subchronic to chronic) and an intraspecies (sensitive worker) AF of 3 were applied. The overall AF obtained was 24.

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 of 2 (subchronic to chronic) and an AF value of 3 (intraspecies, sensitive worker) was assigned to give an overall AF of 6.

2.       Endpoint: threshold for urolithiasis effects in humans

dermal:

Since the starting effect was based on a threshold dose in humans, no additional allometric scaling factor was applied. Given also that the effect is considered a threshold level, below which no relevant toxicity will occur, an additional subchronic to chronic assessment factor was not applied. An intraspecies (sensitive worker) AF of 3 were applied. The overall AF obtained was 3.

inhalation:

Allometric scaling was not applied since the starting effect was based on a threshold dose in humans. Given also that the effect is considered a threshold level, below which no relevant toxicity will occur, an additional subchronic to chronic assessment factor was not applied. An intraspecies (sensitive worker) AF of 3 were applied. The overall AF obtained was 3.

SUMMARY

DNEL values based on a subchronic rat toxicity study (CNS effects) proved to be most conservative. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
AF for differences in duration of exposure:
2
AF for intraspecies differences:
5
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
Value:
235 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
4
AF for differences in duration of exposure:
2
AF for intraspecies differences:
5
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
Value:
235 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
4
AF for differences in duration of exposure:
2
AF for other interspecies differences:
5
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Dose descriptors for key studies (starting points) of toxicological concern

 

Descriptor

Level

Key Reference

Associated Effects/Comments

Repeated Dose Toxicity

NOAEL (rat)

235 mg/kg bwt/day

ECETOC, 2003

CNS Effects; corrected for metabolism to yield 2 equiv. ofn-butanol

Sat. conc. for calcium terephthalic acid in human urine

48.6 mg/kg bwt/day

Wolkowski and Tyl, 1982

Effects of urolithiasis; corrected for molecular weight of dibutyl terephthalate and assuming 1 equiv. of TPA formed from metabolism

 

Corrected Dose Descriptors (General Population)

1.       Endpoint: subchronic toxicity in rats

For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed (see Guidance Document, Chapter 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 235 mg/kg bwt/day.

Dermal:

Due to a lack of dermal absorption data for dibutyl terephthalate, 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 235 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, Example R.8-2, page 64). 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.

(NOAELoralX 0.50) / 1.15 m3/kg bwt = 102 mg/m3= NOAELinh, corr

2.       Endpoint: threshold for urolithiasis effects in humans

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 48.6 mg/kg bwt/day.

Dermal:

Due to a lack of dermal absorption data for dibutyl terephthalate, 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 48.6 mg/kg bwt/day.

Inhalation:

In the case of exposure to the general population, 100% absorption of the test material by the inhalation route was assumed. The calculated threshold human effect value for urolithiasis for the inhalation route was calculated based on a 70 kg human and a 20 m3/person/24 hour breathing volume (see Guidance Document, Chapter R.8, Example R.8-1, page 64).

NOAELoralX 70 kg bwt / 20 m3/person/24 hour = 170 mg/m3

 

Application of Assessment Factors (General Population)

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.

1.       Endpoint: subchronic toxicity in rats

oral:

An AF of 4 was applied to the corrected dose descriptor for oral long-term (repeated dose) systemic effects in the general population (interspecies differences, allometric scaling). In addition, an AF of 2 (subchronic to chronic) and an intraspecies (sensitive worker) AF of 5 were applied. The overall AF obtained was 40.

dermal:

An AF of 4 was applied to the corrected dose descriptor for oral long-term (repeated dose) systemic effects in the general population (interspecies differences, allometric scaling). In addition, an AF of 2 (subchronic to chronic) and an intraspecies (sensitive person) AF of 5 were applied. The overall AF obtained was 40.

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 of 2 (subchronic to chronic) and an AF value of 5 (intraspecies, sensitive person) was assigned to give an overall AF of 10.

2.       Endpoint: threshold for urolithiasis effects in humans

oral:

Since the starting effect was based on a threshold dose in humans, no additional allometric scaling factor was applied. Given also that the effect is considered a threshold level, below which no relevant toxicity will occur, an additional subchronic to chronic assessment factor was not applied. An intraspecies (sensitive person) AF of 5 was applied. The overall AF obtained was 5.

dermal:

Since the starting effect was based on a threshold dose in humans, no additional allometric scaling factor was applied. Given also that the effect is considered a threshold level, below which no relevant toxicity will occur, an additional subchronic to chronic assessment factor was not applied. An intraspecies (sensitive person) AF of 5 was applied. The overall AF obtained was 5.

inhalation:

Allometric scaling was not applied since the starting effect was based on a threshold dose in humans. Given also that the effect is considered a threshold level, below which no relevant toxicity will occur, an additional subchronic to chronic assessment factor was not applied. An intraspecies (sensitive person) AF of 5 were applied. The overall AF obtained was 5.

SUMMARY

DNEL values based on a subchronic rat toxicity study (CNS effects) proved to be most conservative.