Diisodecyl sebacate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.9 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):

50

Modified dose descriptor starting point:

NOAEC

Value:

392.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation was necessary.

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL derived from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF for subchronic (90-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) not applicable.

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker.

AF for the quality of the whole database:

2

Justification:

The available data on DIDS and good read-across compounds are adequate to derive the DNEL. DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.

AF for remaining uncertainties:

1

Justification:

No further 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:

15 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:

NOAEL

Value:

3 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As no data on effects of repeated dermal exposure to DIDS in humans or laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity study was considered a suitable alternative.

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.mg/kg/day DIDS.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF for subchronic (90-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling).

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker.

AF for the quality of the whole database:

2

Justification:

The available data on DIDS and good read-across compounds are adequate to derive the DNEL. DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.

AF for remaining uncertainties:

1

Justification:

No further 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

Acute toxicity

No acute toxicity data are available on DIDS in humans or laboratory animals.

Limited oral and inhalation, and reliable dermal, studies on good read-across substances (DIDA and DOS/DEHS) generally show low acute toxicity.

The weight of the evidence does not indicate that DIDS should be classified as acutely toxic via the oral, dermal or inhalation routes of exposure under the EU DSD or CLP regulations.

DNELs for acute toxicity should be derived if an acute toxicity hazard, leading to classification and labelling (e.g. under EU CLP regulations) has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures). This is not the case for DIDS. Consequently, no worker-DNELs for acute toxicity have been calculated.

Irritation/corrosivity

No skin irritation/corrosivity data are available on DIDS in humans or laboratory animals.

DIDA and DEHS were not irritating in reliablein vitroand laboratory animal studies, and a non-guideline study on DEHS did not indicate a potential for respiratory irritation.

The weight-of-evidence does not indicate that DIDS should be classified as a skin, eye or respiratory irritant under EU CLP regulations. Consequently, no worker-DNELs for irritation/corrosivity have been calculated.

Sensitisation

No skin sensitisation data are available on DIDS in humans or laboratory animals.

In limited studies on humans and laboratory animals, DIDS and DOS did not demonstrate a strong skin sensitising potential.

Although no relevant studies are available, DIDS is not expected to be a respiratory sensitiser, based on its predicted lack of skin sensitising potential and the limited possibility of respiratory exposure (low volatility) under normal conditions of use.

The weight-of-evidence does not indicate that DIDS should be classified as a skin or respiratory sensitiser under EU r CLP regulations. Consequently, no worker-DNELs for skin or respiratory sensitisation have been calculated.

Oral DNEL (repeated dose toxicity)

Not considered applicable for workers.

Inhalation DNEL (repeated dose toxicity)

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated inhalation exposure of DIDS.

 

Kidney toxicity was seen in male rats receiving 1000 mg/kg/day in an OECD Guideline 90-day toxicity study on DIDS, but not female rats. No significant effects were seen in either sex receiving 300 mg/kg/day DIDS.

Mode-of-action

DIDS is considered to have only threshold effects, as there is no convincing evidence that it possesses genotoxic potential. The lesion seen in male rat kidneys has the characteristics ofhyaline dropletnephropathy is most likely due to ana2mglobulin mode of action and is not relevant for humans. Immunohistopathology has not been carried out on the male rat kidney tissues so thea2mglobulin mode of action cannot be confirmed. As a consequence, the most conservative approach to risk assessment has been adopted by selecting the NOAEL in male rats as the starting point (300 mg/kg/day)

 

Modification of starting point

 

The corrected inhalation NOAEC for DIDS =

 

300 * (1/ sRV(a) *ABS oral-rat / ABS inhal-human (b) * 0.67 (c))

 

Where: (a) Standard respiratory volume (sRV) rat = 0.384 m³/kg

 (b) For oral route based on toxicokinetics data on DOA (EC number: 203-090-1 CAS number: 103-23-1)

ABS oral-rat = 75 % and ABS inhal-human = 100 %

 (c) correction for worker respiratory volume (conservative default for route to route)

 

= 300*1/0.384*75/100*0.67 = 392.6 mg/m³

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Workers are assumed to be exposed for 8 hr/day.

ECHA AFs for workers – inhalation DNEL (repeated dose toxicity)

 

Uncertainty	AF	Justification for AF
Interspecies differences	1	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) not applicable.
	2.5	Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.
Intraspecies differences	5	Default ECHA AF for (healthy) worker.
Differences in duration of exposure	2	Default ECHA AF for sub-chronic (90-day) to chronic extrapolation.
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL derived from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.
Quality of whole database	2	The available data on DIDS and good read-across compounds are adequate to derive the DNEL.DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.
Other AFs	1	None considered necessary.
Overall AF for worker	50

 

Worker (light activity) -DNEL (long-term for inhalation route-systemic)

 

=392.6 mg/m³/ 50 =7.9 mg/m³

 

Dermal DNEL (repeated dose toxicity)

Dose descriptor

There are no data available in humans or laboratory animals relating to the toxicity of DIDS following repeated dermal exposures. However, the repeated dose toxicity of DIDS has been investigated in an OECD Guideline 90-day oral toxicity study in rats. Kidney toxicity was seen in male rats receiving 1000 mg/kg/day in an OECD Guideline 90-day toxicity study on DIDS, but not female rats. No significant effects were seen in either sex receiving 300 mg/kg/day DIDS.

Mode-of-action

DIDS is considered to have only threshold effects, as there is no evidence that it possesses genotoxic potential. The lesion seen in male rat kidneys has the characteristics ofhyaline dropletnephropathy is most likely due to ana2mglobulin mode of action and is not relevant for humans. Immunohistopathology has not been carried out on the male rat kidney tissues so thea2mglobulin mode of action cannot be confirmed. As a consequence, the most conservative approach to risk assessment has been adopted by selecting the NOAEL in male rats as the starting point (300 mg/kg/day)

 

Modification of starting point

As no relevant data on effects of repeated dermal exposure to DIDS in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a 90-day oral toxicity study was considered a suitable alternative.

No data are available on the degree of absorption of DIDS. It is assumed that the degree of absorption by the oral is 100% and is 10% by the dermal route in both rats and humans. The starting point for the dermal NOAEL for DIDS in humans is therefore considered to be:

 300 x 100/10 =  3,000 mg/kg/day. 

ECHA AFs for workers – dermal DNEL (repeated dose toxicity)

Uncertainty	AF	Justification for AF
Interspecies differences	4	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
	2.5	Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	2	Default ECHA AF for sub chronic (90-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.
Quality of the whole database	2	The available data on DIDS and good read-across compounds are adequate to derive the DNEL. DIDS is, a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.
Other AFs	1	None considered necessary.
Overall AF for worker	200

Worker-DNEL (long-term for dermal route-systemic) = 3,000 mg/kg bw/day / 200 = 15.00 mg/kg bw/day

Genotoxicity

No test data are available on the genotoxic effects of DIDS. DIDA and DEHS did not demonstrate mutagenic activity in reliable bacterial reverse mutation assays. Equivocal evidence of mutagenicity was detected in a mouse lymphoma assay on DIDA at concentrations associated with cytotoxicity. Similarly, a chromosome aberration assay on human lymphocytes treated with DIDA also gave an equivocal result at cytotoxic concentrations. Noin vivoresults were available on DIDS, DIDA or DOS/DEHS. Overall, no convincing evidence of genotoxic activity was seen or is expected, as such DIDS does not warrant classification as mutagenic. Consequently, no worker-DN(M)ELs for genotoxicity have been calculated.

Carcinogenicity

No standard carcinogenicity studies are available on DIDS. Chronic testing is not a requirement at this tonnage level (100-1000 tpa). Based on structural considerations, no carcinogenic activity is expected for DIDS and it is not classified as genotoxic. Limited reassurance can be gleaned from the lack of carcinogenic activity seen in rats fed DOS at about 10 mg/kg bw/day in the diet for 19 months. The absence of carcinogenicity at this low dose indicates that DOS is not a potent carcinogen.

Presumably, any chronic DNEL should also be protective against carcinogenic effects, given that repeated dose testing (an OECD Guideline 90-day oral toxicity study with DIDS) produced no apparent pre-carcinogenic effects. Consequently, no worker-DN(M)ELs for carcinogenicity have been calculated.

Reproductive toxicity (fertility impairment and developmental toxicity)

 

The results of an OECD Guideline 90-day oral toxicity study (with detailed examination of the reproductive organs) and an OECD Guideline prenatal developmental toxicity study are available. No adverse effects on developmental toxicity endpoints were seen in the prenatal developmental toxicity study and no adverse histopathology was observed in the reproductive organs of either sex in the 90-day oral toxicity study. As a consequence, it was considered unnecessary to derive DNELs for effects on fertility or development.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.9 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

392.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation was necessary.

AF for dose response relationship:

1

Justification:

There are no data available in humans or laboratory animals relating to repeated inhalation exposure of DIDS.

Kidney toxicity was seen in male rats receiving 1000 mg/kg/day in an OECD Guideline 90-day toxicity study on DIDS, but not female rats. No significant effects were seen in either sex receiving 300 mg/kg/day DIDS.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF for subchronic (90-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) not applicable.

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population.

AF for the quality of the whole database:

2

Justification:

The available data on DIDS and good read-across compounds are adequate to derive the DNEL.. DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.)

AF for remaining uncertainties:

1

Justification:

No further 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:

7.5 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

3 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As no data on effects of repeated dermal exposure to DIDS in humans or laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity study was considered a suitable alternative.

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF for subchronic (90-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling).

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population.

AF for the quality of the whole database:

2

Justification:

The available data on DIDS and good read-across compounds are adequate to derive the DNEL. DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.

AF for remaining uncertainties:

1

Justification:

No further 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:

0.8 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:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is necessary.

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.

AF for differences in duration of exposure:

8

Justification:

AF for subacute (14-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling).

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population.

AF for the quality of the whole database:

2

Justification:

The available data on DIDS and good read-across compounds are adequate to derive the DNEL. DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.

AF for remaining uncertainties:

1

Justification:

Limited study performed on a very closely-related read-across compound (DIDA), and very briefly reported in the secondary literature.

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

Discussion

Acute toxicity

As explained in the worker DNEL section above, no acute hazard has been identified for DIDS, therefore a DNEL for acute toxicity is unnecessary as the long-term systemic general population DNEL will be sufficient to ensure that adverse effects do not occur.

Irritation/corrosivity

Based on the available data, DIDS would not be classified as a skin, eye or respiratory tract irritant. Consequently, no general population-DNELs for irritation/corrosivity have been calculated.

Sensitisation

Based on the available data, DIDS would not be classified as a skin or respiratory sensitiser and therefore, no general population-DNELs for skin or respiratory sensitisation have been calculated.

Oral DNEL (repeated dose toxicity)

Dose descriptor

Kidney toxicity was seen in male rats receiving 1000 mg/kg/day in an OECD Guideline 90-day toxicity study on DIDS, but not female rats. No significant effects were seen in either sex receiving 300 mg/kg/day DIDS.

Mode-of-action

DIDS is considered to have only threshold effects, as there is no convincing evidence that it possesses genotoxic potential. The lesion seen in male rat kidneys has the characteristics ofhyaline dropletnephropathy is most likely due to ana2mglobulin mode of action and is not relevant for humans. Immunohistopathology has not been carried out on the male rat kidney tissues so thea2mglobulin mode of action cannot be confirmed. As a consequence, the most conservative approach to risk assessment has been adopted by selecting the NOAEL in male rats as the starting point (300 mg/kg/day)

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. No modification of the starting point is necessary.

ECHA AFs for general population – oral DNEL (repeated dose toxicity)

 

Uncertainty	AF	Justification for AF
Interspecies differences	4	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
	2.5	Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	Default ECHA AF for sub chronic (90-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.
Quality of whole database	2	The available data on DIDS and good read-across compounds are adequate to derive the DNEL. DIDS is a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.
Other AFs	1	None considered necessary.
Overall AF for general population	400

General population-DNEL (long-term for oral route-systemic)= 300 mg/kg bw/day / 400 =0.8 mg/kg bw/day

Inhalation DNEL (repeated dose toxicity)

Dose descriptor

Kidney toxicity was seen in male rats receiving 1000 mg/kg/day in an OECD Guideline 90-day toxicity study on DIDS, but not female rats. No significant effects were seen in either sex receiving 300 mg/kg/day DIDS.

Mode-of-action

DIDS is considered to have only threshold effects, as there is no convincing evidence that it possesses genotoxic potential. The lesion seen in male rat kidneys has the characteristics ofhyaline dropletnephropathy is most likely due to ana2mglobulin mode of action and is not relevant for humans. Immunohistopathology has not been carried out on the male rat kidney tissues so thea2mglobulin mode of action cannot be confirmed. As a consequence, the most conservative approach to risk assessment has been adopted by selecting the NOAEL in male rats as the starting point (300 mg/kg/day)

Modification of starting point

 

The corrected inhalation NOAEC for DIDS =

 

300 * (1/ sRV(a) *ABS oral-rat / ABS inhal-human (b) * 0.67 (c))

 

Where: (a) Standard respiratory volume (sRV) rat = 0.384 m³/kg

 (b) For oral route based on toxicokinetics data on DOA (EC number: 203-090-1 CAS number: 103-23-1)

ABS oral-rat = 75 % and ABS inhal-human = 100 %

 (c) correction for worker respiratory volume (conservative default for route to route)

 

= 300*1/0.384*75/100*0.67 = 392.6 mg/m³

ECHA AFs for general population – inhalation DNEL (repeated dose toxicity)

 

Uncertainty	AF	Justification for AF
Interspecies differences	1	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) not applicable.
	2.5	Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.
Intraspecies differences	10	Default ECHA AF for general population.
Differences in duration of exposure	2	Default ECHA AF for subchronic (90-day) to chronic extrapolation.
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.
Quality of whole database	2	No human health effects data are available on DIDS, and testing is proposed. The available data on good read-across compounds are generally limited. DIDS is, however, a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.
Other AFs	1	Limited study performed on a closely-related read-across compound (DEHS, considered a worst-case surrogate for DIDS), and very briefly reported in the secondary literature.
Overall AF for general population	100

General population-DNEL (long-term for inhalation route-systemic) = 392.6 mg/m³/ 100 =3.9 mg/m³

Dermal DNEL (repeated dose toxicity)

Dose descriptor

There are no data available in humans or laboratory animals relating to the toxicity of DIDS following repeated dermal exposures. However, the repeated dose toxicity of DIDS has been investigated in an OECD Guideline 90-day oral toxicity study in rats. Kidney toxicity was seen in male rats receiving 1000 mg/kg/day in an OECD Guideline 90-day toxicity study on DIDS, but not female rats. No significant effects were seen in either sex receiving 300 mg/kg/day DIDS.

Mode-of-action

DIDS is considered to have only threshold effects, as there is no evidence that it possesses genotoxic potential. The lesion seen in male rat kidneys has the characteristics ofhyaline dropletnephropathy is most likely due to ana2mglobulin mode of action and is not relevant for humans. Immunohistopathology has not been carried out on the male rat kidney tissues so thea2mglobulin mode of action cannot be confirmed. As a consequence, the most conservative approach to risk assessment has been adopted by selecting the NOAEL in male rats as the starting point (300 mg/kg/day)

Modification of starting point

As no relevant data on effects of repeated dermal exposure to DIDS in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a 90-day oral toxicity study was considered a suitable alternative.

No data are available on the degree of absorption of DIDS. It is assumed that the degree of absorption by the oral is 100% and is 10% by the dermal route in both rats and humans. The starting point for the dermal NOAEL for DIDS in humans is therefore considered to be:

 300 x 100/10 =  3,000 mg/kg/day.  ECHA AFs for general population – dermal DNEL (repeated dose toxicity)

 

Uncertainty	AF	Justification for AF
Interspecies differences	4	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
	2.5	Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	Default ECHA AF for sub-chronic (90-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from an OECD Guideline 90-day oral toxicity study. No significant effects were observed in rats dosed with 300 mg/kg/day.
Quality of the whole database	2	No human health effects data are available on DIDS, and testing is proposed. The available data on good read-across compounds are generally limited. DIDS is, however, a simple diester that rapidly hydrolyses to a fatty acid and alcohol (as also suggested by the results of a ready biodegradability test). Its toxicological characteristics are well understood and accepted to be of low concern. Properties can therefore be predicted with reasonable confidence.
Other AFs	1	Limited study performed on a closely-related read-across compound (DEHS, considered a worst-case surrogate for DIDS), and very briefly reported in the secondary literature.
Overall AF for general population	400

General population DNEL (long-term for dermal route-systemic) = 3,000 mg/kg bw/day / 400 = 7.5 mg/kg bw/day

Genotoxicity

No general population DN(M)ELs for genotoxicity have been calculated as DIDS and its read-across compounds DIDA and DOS/DEHS have displayed no convincing evidence of genotoxic activity in a range ofin vitrotests.

Carcinogenicity

No general population DN(M)ELs for carcinogenicity have been calculated as no carcinogenic activity is expected for DIDS.

Reproductive toxicity (fertility impairment and developmental toxicity)

The results of an OECD Guideline 90-day oral toxicity study (with detailed examination of the reproductive organs) and an OECD Guideline prenatal developmental toxicity study are available. No adverse effects on developmental toxicity endpoints were seen in the prenatal developmental toxicity study and no adverse histopathology was observed in the reproductive organs of either sex in the 90-day oral toxicity study. As a consequence, it was considered unnecessary to derive DNELs for effects on fertility or development.