Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
187 mg/m³
Explanation for the modification of the dose descriptor starting point:
A corrected starting point of 187 mg/m3 is derived from the oral PoD of 125 mg/kg bw/d, following correction for respiratory volume and activity and assuming oral absorption of 85% and inhalation absorption of 100%.
AF for dose response relationship:
1
Justification:
Default value; PoD is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Although this endpoint is derived from a sub-chronic study, it lower than (or comparable to) endpoints from carcinogenicity studies and therefore represents a conservative position.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric differences are already accounted for
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
Default value: a comprehensive toxicological dataset is available
AF for remaining uncertainties:
1
Justification:
Default value: no remaining uncertainties
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:
21 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):
50
Modified dose descriptor starting point:
NOAEL
Value:
1 063 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
.A corrected starting point of 1063 mg/kg bw/d is derived from the oral PoD of 125 mg/kg bw/d and assuming oral absorption of 85% and dermal absorption of 10%.
AF for dose response relationship:
1
Justification:
Default value; PoD is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Although this endpoint is derived from a sub-chronic study, it lower than (or comparable to) endpoints from carcinogenicity studies and therefore represents a conservative position.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (NOAEL from a rat study)
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value (workers)
AF for the quality of the whole database:
1
Justification:
Default value: a comprehensive toxicological dataset is available
AF for remaining uncertainties:
1
Justification:
Default value: no remaining uncertainties
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

Toxicokinetics

The toxicokinetics of terephthalic acid have been investigated in a number of studies. Following oral administration, terephthalic acid is found to be rapidly and extensively absorbed and is excreted predominantly in the urine as the sulphate conjugate. Studies in vitro also demonstrate a lack of phase 1 metabolism. There is no potential for bioaccumulation. TPA was transported to the foetus after administration of the compound to pregnant rats; however, the concentrations in foetal tissues were low relative to the corresponding maternal tissues, indicating that rapid maternal urinary excretion is an effective protective mechanism.

Oral absorption of terephthalic acid is reported to be up to 85% in studies with adequate recovery; this value is therefore used for the purposes of DNEL derivation. In the absence of any information, inhalation absorption is assumed to be 100%. 

Moffit et al (1975) report no significant dermal absorption of radiolabelled TPA in the rat following a single or repeated dermal application of 80 mg. In contrast, dermal absorption of 11% of a single dose and 13% of a repeated dose of the related compound dimethylterephthalate is reported. As a conservative approach, a dermal absorption value of 10% for TPA is used for DNEL derivation.

Acute toxicity

Terephthalic acid is of low acute toxicity by all routes investigated.

Irritation / corrosion

In vivo studies for skin irritation and eye irritation show that terephthalic acid is not corrosive but is a mild skin and eye irritant. Classification is not required for skin or eye irritation according to CLP criteria.

Sensitisation

No data are available for terephthalic acid, however no evidence of skin sensitisation was noted in a Buehler study with the read-across compound (structural isomer) isophthalic acid (IPA). The OECD QSAR Toolbox does not report any structural alerts for protein binding activity (relevant for skin sensitisation) for TPA or IPA, TPA is therefore assumed not to be a skin sensitiser on the basis of read-across.

Repeated dose toxicity

The critical effect of oral exposure is urolithiasis, the formation of urinary calculi and secondary effects on the urinary system including inflammation, hyperplasia, haematuria and increased kidney weights. Reduced weight gain and mortality is also seen at the highest dose levels tested. NOAELs are based on effects on the bladder, with the exception of the 90-day study of Ledoux (19822), which reports the lowest NOAEL (based on bodyweight effects).

An older 28 -day inhalation study (Leach & Hatoum, 1987) did not show any systemic toxicity at concentration levels of up to 3 mg/m3, however this study did report local microscopic effects (minimal degradation) on the tracheal lining at all exposure concentrations. This effect was specifically investigated in a more recent study (Fuhst, 2008) which included assessment of higher exposure concentrations. No systemic toxicity and no local effects were reported in this study at exposure levels of up to 10.05 mg/m3. The findings in the 1987 study are therefore considered to be artefactual.

Genetic toxicity

No evidence of mutagenicity was seen in a guideline-comparable Ames test (DuPont, 1979). A clastogenicity study with terephthalic acid in human lymphocytes (Fox, 2006) reports a positive result in the absence of metabolic activation; however, negative results in studies with sodium terephthalate (Fox, 2006; 2007) indicate that the terephthalate anion itself is not clastogenic and that findings in the study with terephthalic acid may therefore be due to the acidity of the test substance. The results of a mouse lymphoma assay (Riach & Willington, 1994) with the read-across substance isoterephthalic acid report a weak and non-reproducible positive response associated with marked cytotoxicity and pH changes in the culture medium. The biological significance of this effect is doubtful. No evidence of UDS was seen in a study in the rat liver at the limit dose of 2000 mg/kg bw (Fox, 2006). No evidence of clastogenicity was seen in a mouse bone marrow micronucleus assay (intraperitoneal dosing) at dose levels sufficient to cause toxicity (Gudi & Krsmanovic, 2001).  Although the results of the studies in mammalian cells vitro are not universally negative, finding are considered likely to be due to pH changes caused by the acidic test substance and are associated with marked toxicity. The clear negative results in the two higher tier assays in vivo demonstrate that the substance is not genotoxic. The available data on the genetic toxicity of TPA was reviewed by the independent UK Government Committee on Mutagenicity (COM). The COM concluded, on the basis of the data available, that the two in vivo studies of genotoxicity performed with TPA were adequate and negative and indicated that terephthalic acid is not an in vivo mutagen. The COM further concluded that the available evidence supported their previous conclusion of a non-genotoxic mechanism for the bladder tumours seen in the rat carcinogenicity study.

Carcinogenicity

Evidence of carcinogenicity was seen in a chronic rat study (Preache, 1983; Ackerman, 1983) in which female rats had an increased incidence of transitional cell adenomas and carcinomas at the highest dose level equivalent to approximately 1000 mg/kg bw/d. Findings are associated with urolithiasis. Several other effects were noted in this study (retinal degeneration and uterine adenocarcinomas), but could not be attributed to treatment as they were seen with similar incidence across all treated and control groups. Similar findings were reported in the study of Gross (1974), in which bladder tumour incidences were increased at dietary dose levels of 2% and 5% (equivalent to approximately 1000 mg/kg bw/d and 2500 mg/kg bw/d, respectively). A NOAEL of 1% (equivalent to approximately 500 mg/kg bw/d) was derived for this study.

Numerous mechanistic studies have been performed in order to characterise the mode of action of the carcinogenicity of TPA in the rat. It is clear that the urinary tract is the target organ for the toxicity of TPA following repeated oral administration, with marked effects apparent in the sub-chronic studies. Toxicity is characterised by urolithiasis; studies have reported urinary sediment and calculus formation and have demonstrated that stones are formed largely of calcium terephthalate. The precipitation of urinary calcium terephthalate occurs at concentrations exceeding the limit of solubility and is pH dependent. Studies in which TPA was co-administered with sodium hydrogencarbonate demonstrate the absence of urinary effects due to the greater solubility of calcium terephthalate in less acidic urine. Urolithiasis causes local irritation of the transitional epithelia, resulting in inflammation and hyperplasia. Findings are associated with haematuria, effects on kidney weight, reduced bodyweight and food consumption and (in extreme cases) mortality. Chronic hyperplasia of the transitional epithelium in rodent studies can result in the development of papillomas, adenomas and carcinomas in the urinary bladder. The development of bladder tumours in the chronic rat toxicity studies is secondary to calculi formation and can be considered a threshold effect; this is supported by the fact that carcinogenicity is only seen at high dose levels. Humans are generally considered to be less sensitive than rats to urolithiasis for anatomical reasons; it is possible that urolithiasis could occur in exposed humans; however it is extremely unlikely that humans could be exposed to the levels of TPA of the magnitude used in the rat toxicity studies, or for similarly long periods.

Reproductive toxicity

In a one-generation screening study (Ledoux et al, 1982), administration of TPA in the diet up to 5% did not affect reproduction or fertility parameters in CD and Wistar rats. In a modern, GLP- and guideline-compliant proprietary study (Milburn (2003), dietary administration of 20000 ppm terephthalic acid for two successive generations of Wistar-derived rats did not result in any effects on reproductive performance. In contrast to these studies, Cui et al (2004) reports damage to spermatogenic cells and Sertoli cells (observed by electron microscopy), testicular sperm head counts, daily sperm production, and activity of sorbitol dehydrogenase (SDH) following the administration of TPA at a dietary concentration of 5% to male SD rats. Sperm motility was significantly reduced in all treated groups (0.2-5.0%), in a dose dependent manner.  The findings of this study are not considered to be of clear significance, given the clear absence of functional reproductive effects in the one-generation screening study and the two-generation study and also in the clear absence of effects on sperm parameters in the multi-generation study.

Developmental toxicity

No evidence of developmental toxicity was seen in an inhalation study in rats exposed to TPA at levels of up to 10 mg/m3 (Ryan et al, 1990).

Overview of NOAEL values

Study

NOAEL

LOAEL

Findings at LOAEL

Williams (1955)

90-day rat study

1%

3.2%

Urinary tract injury; urolithiasis

Vogin (1972)

90-day rat study

-

3%

Bladder pathology; urolithiasis

Kohn (1970)

15-week rat study

1.6%

5%

Reduced weight gain

Bladder pathology; urolithiasis

Ledoux (1982)

90-day rat study

0.125%

0.5%

Reduced weight gain

Bladder pathology at 5%

Preache (1983)

Ackerman (1983)

Rat carcinogenicity study

142 mg/kg bw/d

1000 mg/kg bw/d

Bladder carcinogenicity

Gross (1974)

EPA (1984)

Rat carcinogenicity study 

1%

2%

Bladder carcinogenicity

Milburn (2003)

Multi-generation study

20000 ppm (reproductive)

5000 ppm (parental)

5000 ppm (offspring)

-

 

-

Reduced weight gain Reduced weight gain

Ledoux (1982)

One-generation study

5% (reproductive)

0.5% (parental)

0.5% (offspring)

-

2%

2%

-

Mortality (?)

Urolithiasis

Leach & Hatoum (1987)

28-day inhalation

-

0.5 mg/m3

Local irritation

Fuhst (2008)

28-day inhalation

10.05 mg/m3

-

-

The lowest NOAEL is the NOAEL of 0.125% (125 mg/kg bw/d) from the 90-day study of Ledoux (1982), based on bodyweight effects at higher dose levels. This NOAEL is notably lower than those from studies of comparable duration and studies of longer duration. Furthermore, other studies are consistent in identifying urolithiasis and associated histopathology of the urinary bladder as the critical effects of terephthalic acid toxicity, with bodyweight effects only seen at higher dietary concentrations. Nevertheless, the NOAEL of 125 mg/kg bw/d is comparable to the NOAEL for carcinogenicity (142 mg/kg bw/d) and is therefore used as a conservative point of departure (PoD) for DNEL derivation.

DNEL derivation

The relevant PoD for DNEL derivation is the lowest NOAEL of 0.125% (125 mg/kg bw/d). Although this endpoint is derived from a sub-chronic study, it lower than (or comparable to) endpoints from carcinogenicity studies and therefore represents a conservative position.

Worker DNELs

Inhalation: systemic effects

Long-term DNEL

A corrected starting point of 187 mg/m3 is derived from the oral PoD of 125 mg/kg bw/d, following correction for respiratory volume and activity and assuming oral absorption of 85% and inhalation absorption of 100%. Assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainty) results in an overall assessment factor of 12.5. Applying the overall assessment factor to the corrected starting point results in a DNEL of 15 mg/m3.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified for acute toxicity. A short-term DNEL is therefore not derived.

Inhalation: local effects

Long-term DNEL

The more reliable repeated exposure inhalation toxicity study did not identify any local effects at the highest exposure concentration. A local DNEL is therefore not derived.

Short-term DNEL

The acute inhalation toxicity study did not identify any local effects. A local DNEL is therefore not derived.

Dermal: systemic effects

Long-term DNEL

A corrected starting point of 1063 mg/kg bw/d is derived from the oral PoD of 125 mg/kg bw/d and assuming oral absorption of 85% and dermal absorption of 10%. Assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainty) results in an overall assessment factor of 50. Applying the overall assessment factor to the corrected starting point results in a DNEL of 21 mg/kg bw/d.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified for acute toxicity. A short-term DNEL is therefore not derived.

Dermal: local effects

Long-term DNEL

No hazard is identified. Terephthalic acid is not classified as a skin irritant. A long-term DNEL is therefore not derived.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified as a skin irritant. A short-term DNEL is therefore not derived.

Heck & Tyl (1985) used urinary electrolyte results from a study of dietary terephthalic acid in weanling F344 rats, pharmacokinetics and trans-placental transport data from the study of Wolkowski-Tyl et al (1982) to evaluate the equilibria involved in calcium terephthalate bladder stone formation. The thermodynamic solubility parameters of calcium terephthalate in weanling F344 rat urine at various concentrations were calculated From these data, and using the average ionic strength and average electrolyte concentrations of human urine and a 1.54 L/day urinary output, the authors calculated that a urinary concentration of 8 mM terephthalic acid would be required for saturation of adult human urine with calcium terephthalate; this urinary concentration was calculated to correspond to a daily intake of 2.0 g TPA (equivalent to 29 mg/kg bw/d assuming a bodyweight of 70 kg. The DNEL values derived above are lower than this value and are therefore protective with respect to the critical aspect of terephthalic acid toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
92 mg/m³
Explanation for the modification of the dose descriptor starting point:
A corrected starting point of 187 mg/m3 is derived from the oral PoD of 125 mg/kg bw/d, following correction for respiratory volume and activity and assuming oral absorption of 85% and inhalation absorption of 100%.
AF for dose response relationship:
1
Justification:
Default value; PoD is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Although this endpoint is derived from a sub-chronic study, it lower than (or comparable to) endpoints from carcinogenicity studies and therefore represents a conservative position
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric differences are already accounted for
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Default value: comprehensive toxicological dataset
AF for remaining uncertainties:
1
Justification:
Default value: no remaining uncertainties
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:
11 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
1 063 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A corrected starting point of 1063 mg/kg bw/d is derived from the oral PoD of 125 mg/kg bw/d and assuming oral absorption of 85% and dermal absorption of 10%.
AF for dose response relationship:
1
Justification:
Default value: starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Although this endpoint is derived from a sub-chronic study, it lower than (or comparable to) endpoints from carcinogenicity studies and therefore represents a conservative position.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (NOAEL from a rat study)
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Default value: comprehensive toxicological dataset
AF for remaining uncertainties:
1
Justification:
Default value: no remaining uncertainties
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:
1.25 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Correction of the starting point is not required as the starting point is derived from an oral study
AF for dose response relationship:
1
Justification:
Default value: starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Although this endpoint is derived from a sub-chronic study, it lower than (or comparable to) endpoints from carcinogenicity studies and therefore represents a conservative position.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (NOAEL from a rat study)
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Default value: a comprehensive toxicological dataset is available
AF for remaining uncertainties:
1
Justification:
Default value: no remaining uncertainties
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

Overview of relevant NOAELS

Study

NOAEL

LOAEL

Findings at LOAEL

Williams (1955)

90-day rat study

1%

3.2%

Urinary tract injury; urolithiasis

Vogin (1972)

90-day rat study

-

3%

Bladder pathology; urolithiasis

Kohn (1970)

15-week rat study

1.6%

5%

Reduced weight gain

Bladder pathology; urolithiasis

Ledoux (1982)

90-day rat study

0.125%

0.5%

Reduced weight gain

Bladder pathology at 5%

Preache (1983)

Ackerman (1983)

Rat carcinogenicity study

142 mg/kg bw/d

1000 mg/kg bw/d

Bladder carcinogenicity

Gross (1974)

EPA (1984)

Rat carcinogenicity study 

1%

2%

Bladder carcinogenicity

Milburn (2003)

Multi-generation study

20000 ppm (reproductive)

5000 ppm (parental)

5000 ppm (offspring)

-

 

-

Reduced weight gain Reduced weight gain

Ledoux (1982)

One-generation study

5% (reproductive)

0.5% (parental)

0.5% (offspring)

-

2%

2%

-

Mortality (?)

Urolithiasis

Leach & Hatoum (1987)

28-day inhalation

-

0.5 mg/m3

Local irritation

Fuhst (2008)

28-day inhalation

10.05 mg/m3

-

-

 

 The lowest NOAEL is the NOAEL of 0.125% (125 mg/kg bw/d) from the 90-day study of Ledoux (1982), based on bodyweight effects at higher dose levels. This NOAEL is notably lower than those from studies of comparable duration and studies of longer duration. Furthermore, other studies are consistent in identifying urolithiasis and associated histopathology of the urinary bladder as the critical effects of terephthalic acid toxicity, with bodyweight effects only seen at higher dietary concentrations. Nevertheless, the NOAEL of 125 mg/kg bw/d is comparable to the NOAEL for carcinogenicity (142 mg/kg bw/d) and is therefore used as a conservative point of departure (PoD) for DNEL derivation.


General Population DNELs

Inhalation: systemic effects

Long-term DNEL

A corrected starting point of 92 mg/m3 is derived from the oral PoD of 125 mg/kg bw/d, following correction for respiratory volume and assuming oral absorption of 85% and inhalation absorption of 100%. Assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainty) results in an overall assessment factor of 25. Applying the overall assessment factor to the corrected starting point results in a DNEL of 4 mg/m3.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified for acute toxicity. A short-term DNEL is therefore not derived.

Inhalation: local effects

Long-term DNEL

The more reliable repeated exposure inhalation toxicity study did not identify any local effects at the highest exposure concentration. A local DNEL is therefore not derived.

Short-term DNEL

The acute inhalation toxicity study did not identify any local effects. A local DNEL is therefore not derived.

Dermal: systemic effects

Long-term DNEL

A corrected starting point of 1063 mg/kg bw/d is derived from the oral PoD of 125 mg/kg bw/d and assuming oral absorption of 85% and dermal absorption of 10%. Assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainty) results in an overall assessment factor of 100. Applying the overall assessment factor to the corrected starting point results in a DNEL of 11 mg/kg bw/d.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified for acute toxicity. A short-term DNEL is therefore not derived.

Dermal: local effects

Long-term DNEL

No hazard is identified. Terephthalic acid is not classified as a skin irritant. A long-term DNEL is therefore not derived.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified as a skin irritant. A short-term DNEL is therefore not derived.

Oral: systemic effects

Long-term DNEL

Correction of the starting point is not required as the starting point is derived from an oral study. Assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainty) results in an overall assessment factor of 100. Applying the overall assessment factor to the starting point results in a DNEL of 1.25 mg/kg bw/d.

Short-term DNEL

No hazard is identified. Terephthalic acid is not classified for acute toxicity. A short-term DNEL is therefore not derived.

Heck & Tyl (1985) used urinary electrolyte results from a study of dietary terephthalic acid in weanling F344 rats, pharmacokinetics and trans-placental transport data from the study of Wolkowski-Tyl et al (1982) to evaluate the equilibria involved in calcium terephthalate bladder stone formation. The thermodynamic solubility parameters of calcium terephthalate in weanling F344 rat urine at various concentrations were calculated From these data, and using the average ionic strength and average electrolyte concentrations of human urine and a 1.54 L/day urinary output, the authors calculated that a urinary concentration of 8 mM terephthalic acid would be required for saturation of adult human urine with calcium terephthalate; this urinary concentration was calculated to correspond to a daily intake of 2.0 g TPA (equivalent to 29 mg/kg bw/d assuming a bodyweight of 70 kg. The DNEL values derived above are lower than this value and are therefore protective with respect to the critical aspect of terephthalic acid toxicity.