Isophthalic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 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):

200

Modified dose descriptor starting point:

LOAEC

Value:

1 760 mg/m³

Explanation for the modification of the dose descriptor starting point:

Subchronic oral LOAEL of 500 mg/kg bw/day identified as PoD for derivation of inhalation dose descriptor starting point. The inhalation PoD was 250 mg/kg bw/d and the LOAEC was 1760 mg/m3.

AF for dose response relationship:

2

Justification:

Starting point derived from an oral LOAEL, default value of 2 used for assessment factor.

AF for differences in duration of exposure:

2

Justification:

Endpoint based on subchronic exposure data and extrapolated for long term DNEL using standard adjustment factor

AF for interspecies differences (allometric scaling):

1

Justification:

use of an allometric scaling factor is not appropriate where route to route extrapolation is used since the species differences are accounted for in the breathing rate adjustments in the calculation.

AF for other interspecies differences:

10

Justification:

default value for toxicokinetic and toxicodynamic interspecies differences and includes factor of 4 to reflect the allometry adjustments

AF for intraspecies differences:

5

Justification:

default factor for all intraspecies differences

AF for the quality of the whole database:

1

Justification:

good quality database from oral and inhalation exposure studies in rats

AF for remaining uncertainties:

1

Justification:

default factor for no other identified 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:

25 mg/kg bw/day

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):

200

Modified dose descriptor starting point:

LOAEL

Value:

5 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Subchronic oral LOAEL of 500 mg/kg bw/day identified as PoD for derivation of dermal dose descriptor starting point. Dermal absorption of 10% assumed based on default value.

AF for dose response relationship:

2

Justification:

Starting point derived from an oral LOAEL, default value of 2 used for assessment factor.

AF for differences in duration of exposure:

2

Justification:

Endpoint based on subchronic exposure data and extrapolated for long term DNEL using standard adjustment factor

AF for interspecies differences (allometric scaling):

4

Justification:

standard allometric scaling factor for rats

AF for other interspecies differences:

2.5

Justification:

default value for toxicokinetic and toxicodynamic interspecies differences

AF for intraspecies differences:

5

Justification:

default factor for all intraspecies differences

AF for the quality of the whole database:

1

Justification:

default factor for good quality database

AF for remaining uncertainties:

1

Justification:

default factor for no other identified 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

No specific studies on the toxicokinetics of isophthalic acid are available, however in accordance with REACH guidance an adequate assessment of the toxicokinetic properties of the substance can be made using theoretical considerations and data from other toxicity studies, including studies on structurally similar materials. Consequently, data from studies on the structural isomer terephthalic acid (TPA) have been used in this assessment.

 

The absorption of IPA is shown to be rapid and extensive following oral and inhalation exposure; dermal absorption is predicted (based on theoretical considerations) to be less rapid and less extensive. Based on a molecular weight of 166 g/mol and a log Kow of -2.34, the dermal absorption of IPA is likely to be relatively low. Moffitet al. (1975) report no significant dermal absorption of the closely-related isomer terephthalic acid (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 another related compound dimethylterephthalate is reported. As a conservative approach, a dermal absorption value of 10% for IPA will be used for risk assessment purposes.

 

The toxicokinetics of TPA have been investigated in a number of investigative studies and a guideline compliant mouse study. The results of these studies can also be used to elucidate the likely toxicokinetic behaviour of IPA. Following oral administration, terephthalic acid is rapidly absorbed and is excreted rapidly and predominantly in the urine as the sulphate conjugate. The weight of evidence indicates that there is little potential for bioaccumulation.

 

Although no specific toxicokinetic studies are available for IPA, similar toxicokinetic behaviour (to TPA) is predicted, i.e., rapid absorption, wide distribution, and rapid excretion primarily in the urine. This assessment is consistent with the available data obtained in an oral repeated dose experiment in which blood and urine levels of IPA were measured at various intervals during a 13-week toxicity study. Because metabolites were not measured in this study, it is not clear whether or not IPA is excreted in the urine as the sulphate conjugate, although it is possible based on its structural similarity to TPA. Rapid clearance of IPA from the body was also observed in a repeated dose inhalation study in which blood levels were not detected in blood one week following the last exposure. Like TPA, the weight of evidence also indicates that there is little potential for bioaccumulation.

 

Acute toxicity

Studies indicate that isophthalic acid is of very low toxicity by the oral, inhalation and dermal routes. Acute oral LD50 values of >5000, 10900 and 13000 mg/kg bw are reported. An inhalation LC50 of >11370 mg/m³ is reported. A dermal LD50 of >2000 mg/kg bw is also reported.

 

Irritation

Isophthalic acid was found to be a minimal skin irritant and a mild eye irritant in studies in the rabbit. Classification of the substance as a skin or eye irritant is not required.

 

Sensitisation

The results of a Buehler study do not indicate that classification as a skin sensitiser is required.

 

Repeated dose toxicity

The substance was found to be of low toxicity in a 90-day dietary rat study and in a 28-day rat inhalation study. Effects in the dietary study were limited to urolithiasis and secondary effects; findings were more marked in males. No clear or significant effects of treatment were seen in the inhalation study at the highest exposure concentration of 9.59 mg/m³. A minimal NOAEL of 0.5% (5000 ppm, equivalent to 500 mg/kg bw/d) can be derived for the dietary toxicity study.

 

Genetic toxicity

The genotoxicity of isophthalic acid has been adequately investigated in an appropriate battery of studiesin vitroandin vivo, in accordance with REACH guidance. A positive result was reported in one of two Ames tests; however negative results are reported in two studies of mammalian cell mutation and in a study of clastogenicity in vitro. A negative Ames test with the structural isomer terephthalic acid (TPA) is also available (DuPont, 1979).

Negative results inin vivostudiesinvestigating mutational and chromosomal endpoints are available for the read-across substance terephthalic acid, leading to the conclusion that isophthalic acid is not genotoxicin vivo.

 

Carcinogenicity

Urinary tract carcinogenicity can be predicted for isophthalic acid based on read-across from the substance terephthalic acid which is both structurally related and has a comparable toxicological profile. This effect is considered to have a threshold mode of action and is of limited relevance to the human risk assessment. Studies do not identify any non-neoplastic urinary tract effects at lower dose levels than those casuing urinary tract carcinogenicity.

 

Reproductive toxicity

No evidence of reproductive toxicity was seen in a two-generation study performed with the read-across substance terephthalic acid at dose levels of up to 2000 mg/kg bw/d. No evidence of developmental toxicity was seen at the highest exposure concentration of 9.07 mg/m3 in an inhalation study with isophthalic acid performed in the rat.

 

DNEL derivation

IPA is of low acute toxicity, is not an irritant or sensitiser and is not mutagenic or a reproductive toxin. The critical effects of IPA toxicity are those seen on the urinary tract associated with urolithiasis. A minimal LOAEL of 500 mg/kg bw/d was seen for this effect in a 90-day dietary toxicity study. By read-across to the chemically and toxicologically comparable substance terephthalic acid (TPA), it can be predicted that the chronic administration of IPA will result in urinary tract carcinogenicity. This high dose effect is considered to have a threshold mode of action and is of limited relevance to human risk assessment. It can additionally be argued that rodents are more susceptible to this type of effect for physiological and anatomical reasons. The results of a 28 -day inhalation study with IPA did not identify any local or systemic effects at the highest exposure concentration.

 

The minimal LOAEL of 500 mg/kg bw/d is therefore considered to be the relevant point of departure (PoD) for DNEL derivation.

Using a conservative assumption of 10% dermal absorption, a dermal PoD of 5000 mg/kg bw/d is derived.

Following the default assumption that inhalation absorption = 2 x oral absorption, an inhalation PoD of 250 mg/kg bw/d is derived.

The use of assessment factors according to REACH guidance is considered below:

Intraspecies differences (allometric scaling): a default assessment factor of 4 is used as the PoD is derived from a rat study

Intraspecies differences (remaining differences): a default assessment factor of 2.5 is used

Interspecies differences: a default assessment factor of 5 is used

Duration: an additional assessment factor of 2 is used long-term DNEL values as the PoD is derived from a sub-chronic study

Dose-response: an additional assessment factor of 2 is used as the PoD is a minimal LOAEC

Database quality: a default assessment factor of 1 is used

An overall assessment factor of 100 [4*2.5*5*1*2*1] is therefore used for the derivation of short-term DNEL values

An overall assessment factor of 200 [4*2.5*5*2*2*1] is therefore used for the derivation of long-term DNEL values

 

Acute / short-term exposure - systemic effects

 

Dermal DNEL

 

The derivation of dermal DNEL values assumes 10% dermal absorption. Applying the overall assessment factor of 100 to the dermal PoD of 5000 mg/kg bw/d gives a DNEL value of 50 mg/kg bw/d.

 

Inhalation DNEL

 

The derivation of inhalation DNEL values assumes that the extent of inhalation absorption is twice that of oral absorption. Applying the overall assessment factor of 100 to the inhalation PoD of 250 mg/kg bw/d gives a DNEL value of 17.5 mg/m³(assuming a bodyweight of 70 kg and a breathing rate of 10 m³/8h).

 

Acute / short-term exposure - local effects

 

Dermal DNEL

 

IPA is not a skin irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

 

Inhalation DNEL

 

IPA is not a respiratory irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

 

Long-term exposure - systemic effects

 

Dermal DNEL

 

The derivation of dermal DNEL values assumes 10% dermal absorption. Applying the overall assessment factor of 200 to the dermal PoD of 5000 mg/kg bw/d gives a DNEL value of 25 mg/kg bw/d.

 

Inhalation DNEL

 

The derivation of inhalation DNEL values assumes that the extent of inhalation absorption is twice that of oral absorption. Applying the overall assessment factor of 200 to the inhalation PoD of 250 mg/kg bw/d gives a DNEL value of 8.8 mg/m³(assuming a bodyweight of 70 kg and a breathing rate of 10 m³/8h).

 

Long-term exposure - local effects

 

Dermal DNEL

 

IPA is not a skin irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

 

Inhalation DNEL

IPA is not a respiratory irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.2 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):

400

Modified dose descriptor starting point:

LOAEC

Value:

880 mg/m³

Explanation for the modification of the dose descriptor starting point:

Subchronic oral LOAEL of 500 mg/kg bw/day identified as PoD for derivation of inhalation dose descriptor starting point. The inhalation PoD was 250 mg/kg bw/d and the LOAEC was 880 mg/m3.

AF for dose response relationship:

2

Justification:

Starting point derived from an oral LOAEL, default value of 2 used for assessment factor.

AF for differences in duration of exposure:

2

Justification:

Endpoint based on subchronic exposure data and extrapolated for long term DNEL using standard adjustment factor

AF for interspecies differences (allometric scaling):

1

Justification:

use of an allometric scaling factor is not appropriate where route to route extrapolation is used since the species differences are accounted for in the breathing rate adjustments in the calculation.

AF for other interspecies differences:

10

Justification:

default value for toxicokinetic and toxicodynamic interspecies differences, includes factor of 4 for allometry

AF for intraspecies differences:

10

Justification:

default factor for all intraspecies differences

AF for the quality of the whole database:

1

Justification:

good quality database from oral rat studies with reliable supporting information

AF for remaining uncertainties:

1

Justification:

default factor for no other identified 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:

12.5 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):

400

Modified dose descriptor starting point:

LOAEL

Value:

5 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Subchronic oral LOAEL of 500 mg/kg bw/day identified as PoD for derivation of dermal dose descriptor starting point. Dermal absorption of 10% assumed based on default value.

AF for dose response relationship:

2

Justification:

Starting point derived from an oral LOAEL, default value of 2 used for assessment factor.

AF for differences in duration of exposure:

2

Justification:

Endpoint based on subchronic exposure data and extrapolated for long term DNEL using standard adjustment factor

AF for interspecies differences (allometric scaling):

4

Justification:

standard allometric scaling factor for rats

AF for other interspecies differences:

2.5

Justification:

default value for toxicokinetic and toxicodynamic interspecies differences

AF for intraspecies differences:

10

Justification:

default factor for all intraspecies differences

AF for the quality of the whole database:

1

Justification:

good quality database from oral rat studies

AF for remaining uncertainties:

1

Justification:

default factor for no other identified 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:

1.3 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):

400

Modified dose descriptor starting point:

LOAEL

Value:

520 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL derived from an oral subchronic exposure study , no route to route extrapolation required

AF for dose response relationship:

2

Justification:

Starting point derived from an oral LOAEL, default value of 2 used for assessment

AF for differences in duration of exposure:

2

Justification:

Endpoint based on subchronic exposure data and extrapolated for long term DNEL using standard adjustment factor

AF for interspecies differences (allometric scaling):

4

Justification:

standard allometric scaling factor for rats

AF for other interspecies differences:

2.5

Justification:

default value for toxicokinetic and toxicodynamic interspecies differences

AF for intraspecies differences:

10

Justification:

default factor for all intraspecies differences

AF for the quality of the whole database:

1

Justification:

good quality database from oral rat studies

AF for remaining uncertainties:

1

Justification:

default factor for no other identified 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

DNEL derivation

IPA is of low acute toxicity, is not an irritant or sensitiser and is not mutagenic or a reproductive toxin. The critical effects of IPA toxicity are those seen on the urinary tract associated with urolithiasis. A minimal LOAEL of 500 mg/kg bw/d was seen for this effect in a 90 -day dietary toxicity study. By read-across to the chemically and toxicologically comparable substance terephthalic acid (TPA), it can be predicted that the chronic administration of IPA will result in urinary tract carcinogenicity. This high dose effect is considered to have a threshold mode of action and is of limited relevance to human risk assessment. It can additionally be argued that rodents are more susceptible to this type of effect for physiological and anatomical reasons. The results of a 28 -day inhalation study with IPA did not identify any local or systemic effects at the highest exposure concentration.

The minimal LOAEL of 500 mg/kg bw/d is therefore considered to be the relevant point of departure (PoD) for DNEL derivation.

Following a conservative assumption of 10% dermal absorption, a dermal PoD of 5000 mg/kg bw/d is derived.

Following the default assumption that inhalation absorption = 2 x oral absorption, an inhalation PoD of 250 mg/kg bw/d is derived.

The use of assessment factors according to REACH guidance is considered below:

Intraspecies differences (allometric scaling): a default assessment factor of 4 is used as the PoD is derived from a rat study

Intraspecies differences (remaining differences): a default assessment factor of 2.5 is used

Interspecies differences: a default assessment factor of 10 is used

Duration: an additional assessment factor of 2 is used long-term DNEL values as the PoD is derived from a sub-chronic study

Dose-response: an additional assessment factor of 2 is used as the PoD is a minimal LOAEC

Database quality: a default assessment factor of 1 is used

An overall assessment factor of 200 [4*2.5*10*1*2*1] is therefore used for the derivation of short-term DNEL values

An overall assessment factor of 400 [4*2.5*10*2*2*1] is therefore used for the derivation of long-term DNEL values

Acute / short-term exposure - systemic effects

Dermal DNEL

The derivation of dermal DNEL values assumes 10% dermal absorption. Applying the overall assessment factor of 200 to the dermal PoD of 5000 mg/kg bw/d gives a DNEL value of 25 mg/kg bw/d.

Inhalation DNEL

The derivation of inhalation DNEL values assumes that the extent of inhalation absorption is twice that of oral absorption. Applying the overall assessment factor of 200 to the inhalation PoD of 250 mg/kg bw/d gives a DNEL value of 4.4 mg/m³ (assuming a bodyweight of 70 kg and a breathing rate of 20 m³/24h).

Oral DNEL

Applying the overall assessment factor of 200 to the PoD of 500 mg/kg bw/d gives a DNEL value of 2.5 mg/kg bw/d.

Acute / short-term exposure - local effects

Dermal DNEL

IPA is not a skin irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

Inhalation DNEL

IPA is not a respiratory irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

Long-term exposure - systemic effects

Dermal DNEL

The derivation of dermal DNEL values assumes 10% dermal absorption. Applying the overall assessment factor of 400 to the dermal PoD of 5000 mg/kg bw/d gives a DNEL value of 12.5 mg/kg bw/d.

Inhalation DNEL

The derivation of inhalation DNEL values assumes that the extent of inhalation absorption is twice that of oral absorption. Applying the overall assessment factor of 400 to the inhalation PoD of 250 mg/kg bw/d gives a DNEL value of 2.2 mg/m³ (assuming a bodyweight of 70 kg and a breathing rate of 20 m³/24h).

Oral DNEL

Applying the overall assessment factor of 400 to the PoD of 500 mg/kg bw/d gives a DNEL value of 1.3 mg/kg bw/d.

 

Long-term exposure - local effects

Dermal DNEL

IPA is not a skin irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.

Inhalation DNEL

IPA is not a respiratory irritant or sensitiser; no dose-response data are available. A quantitative dose descriptor is not available and no DNEL can be derived.