1-(N,N-bis(2-hydroxyethyl)amino)propan-2-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.18 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

88.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

As no data on effects of repeated inhalation exposure to DEIPA in humans or laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative (no high first-pass metabolism has been reported or is expected).

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-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); already considered in correcting starting point above

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:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

AF for remaining uncertainties:

1

Justification:

Not required

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:

0.33 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-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:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

AF for remaining uncertainties:

1

Justification:

Not required

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

Workers

Acute toxicity

No acute toxicity data in humans are available on DEIPA.

 

DEIPA is of low acute toxicity in laboratory animal studies. Good quality guideline studies have been conducted (to GLP) via the dermal and oral routes, while an early, poorly-reported study is available on toxicity via inhalation. No mortalities, and very few clinical treatment-related signs of toxicity, were seen in rats given 2000 mg/kg bw by gavage (Stebbins and Brooks, 1999a). Similarly, no mortalities or signs of systemic toxicity were seen within two weeks of a 24-hour dermal treatment of 2000 mg/kg bw in rabbits (Stebbins and Brooks, 1999b), and no mortalities were seen in 6 male rats exposed to DEIPA saturated air (at 16.4 mg/L) for 7 hours (Vaughn et al. 1975). Repeated dose toxicity studies (including reproductive toxicity studies), where available, provide no relevant (dose-response) information on acute toxicity. Based on the available data, DEIPA would not be classified as acutely toxic under the EU 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). As no acute hazard has been identified, then a DNEL for acute toxicity is unnecessary as the long-term DNEL for systemic effects will normally be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNELs for acute toxicity have been calculated.

 

Irritation/corrosivity

No irritation/corrosivity data on DEIPA are available in humans.

 

In a guideline study conducted to GLP, DEIPA produced no signs of dermal irritation when applied undiluted to the clipped skin of rabbits, under occlusion, for 4 hours (Stebbins and Brooks, 1999c). Only transient skin effects were reported in a reliable acute dermal toxicity study on rats given 2000 mg/kg bw (Stebbins and Brooks, 1999b). Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects on the skin. The animal data indicate that DEIPA is not a skin irritant, and that classification for skin irritation or corrosion under EU CLP regulations is not warranted.

 

In an OECD guideline eye irritation study, conducted to GLP, slight to moderate irritation was seen following instillation of undiluted DEIPA (0.1 ml) to the eyes of rabbits. By 48 hours post exposure, only slight irritation was seen. All effects had resolved by day 8 (Stebbins and Brooks, 1999d). Based on the results of this reliable study, DEIPA does not warrant classification and labelling for eye irritation or corrosion under the EU CLP regulations.

No reliable respiratory tract irritation information is available. However, exposure of the respiratory system is not anticipated under normal conditions of use, due to its low volatility. In addition, the lack of irritation in the available reliable skin and eye irritation studies suggest that even if exposure of the respiratory tract were to occur, then respiratory irritation is unlikely.

 

Based on the available data, DEIPA would not be classified as a skin, eye or respiratory tract irritant under the EU CLP regulations. Consequently, no worker-DNELs for irritation/corrosivity have been calculated.

 

Sensitisation

No skin sensitisation data on DEIPA are available in humans.

 

A good-quality guideline study has been conducted (to GLP) to assess the skin sensitising potential of DEIPA. In a guinea pig maximisation test, no evidence of skin sensitisation was observed in any of the 20 test animals (Glaza, 1999).

 

Although no laboratory animal studies are available, DEIPA is not expected to be a respiratory sensitiser based on its lack of skin sensitising potential and the limited possibility of respiratory exposure (based on its physico-chemical properties) under normal conditions of use.

 

Based on the available data, DEIPA would not be classified as a skin or respiratory sensitiser under EU 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. However, the oral toxicity of DEIPA has been investigated in a reliable 28-day gavage study in rats, allowing the identification of a NOAEL of 100 mg/kg bw/day (Stebbins and Zablotny, 1999).

 

Mode-of-action

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

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

 

As no data on effects of repeated inhalation exposure to DEIPA in humans or laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative (no high first-pass metabolism has been reported or is expected).

 

In the absence of route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). In this instance, there is no human or laboratory animal data on the toxicokinetics of DEIPA (with estimates, based on physicochemical data, of 100% absorption predicted via the oral, dermal and inhalation routes). The default factor of 2 has been applied to the starting point, as a health precautionary measure. The corrected NOAEL is therefore 50 mg/kg bw/day.

 

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

 

Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to this corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m³/kg bw for 8 hr/day (exposure of workers). Thus, 50 mg/kg bw/day / 0.38 m³/kg bw/day = 131.6 mg/m³(8-hr exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 50 mg/kg bw/day / 0.38 m³/kg bw x (6.7 m³/ 10 m³) = 88.2 mg/m³ (8-hr exposure of workers, light activity).

 

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); already considered in correcting starting point above
	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	6	Default ECHA AF for subacute (28-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for worker	75

 

Worker (light activity)-DNEL (long-term for inhalation route-systemic) = 88.2 mg/m³/ 75 = 1.18 mg/m³

 

Dermal DNEL (repeated dose toxicity)

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated dermal exposure which are suitable as the basis from which to calculate a dermal DNEL.However, the oral toxicity of DEIPA has been investigated in a reliable 28-day study in rats treated by gavage, allowing the identification of a NOAEL of 100 mg/kg bw/day (Stebbins and Zablotny, 1999).

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

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

 

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

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. As no data are available on the toxicokinetics of DEIPA (with 100% absorption assumed through both the dermal and oral routes, based on physical-chemical data) no correction of the NOAEL is required.

 

Workers are assumed to be exposed for 8 h/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	6	Default ECHA AF for subacute (28-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day were not considered severe
Quality of the whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high
Overall AF for worker	300

 

Worker-DNEL (long-term for dermal route-systemic) = 100 mg/kg bw/day / 300 = 0.33 mg/kg bw/day

 

Genotoxicity

No information is available on the genotoxic effects of DEIPA in humans.

DEIPA showed no convincing evidence of mutagenic activity in a reliable Ames test at up to 5000 μg/plate, in the presence and absence of S9 (Mecchi, 1999).

In a reliable chromosome aberration study, no biologically significant increase in the incidence of aberrant cells was reported in rat lymphocytes exposed to DEIPA at up to 1632 μg/ml for 4 hr with and without S9, or for 24 hr without S9 (Linscombe et al., 1999).

No gene mutation data in mammalian cells were identified for DEIPA. However, no reproducible, statistically significant increases in gene mutations were seen when the closely-related compound TIPA was tested (at up to 5000 μg/ml; with and without S9) in a reliable in vitro CHO/HGPRT forward gene mutation assay (Sitek Research Laboratories, 1993).

Overall, the available data indicate that DEIPA is not mutagenic and does not directly interact with DNA. Under EU DSD or CLP regulations, DEIPA does not warrant classification as mutagenic. Consequently, no worker-DN(M) ELs for genotoxicity have been calculated.

 

Carcinogenicity

No information on carcinogenic effects in humans or laboratory animals is available. Chronic testing is not a requirement at this tonnage level (100-1000 tpa). DEIPA is not expected to be genotoxic in vivo. Presumably any chronic DNEL (based on a NOAEL of 100 mg/kg bw/day seen in a 28-day oral rat study) should also be protective against carcinogenic effects, given that the critical effect was hyperplasia in the stomach seen at 1000 mg/kg bw/day which resolved within a 2-week recovery period.

 

Reproductive toxicity (fertility impairment and developmental toxicity)

 

Fertility impairment

No information is available on fertility effects in humans.

 

While there are no standard laboratory animal fertility studies available on DEIPA, no adverse effects on the reproductive organs and tissues were seen in rats treated orally for 28 days with up to 1000 mg/kg bw/day (Stebbins and Zablotny, 1999).

 

A guideline reproduction study in rats has been performed (to GLP) on TIPA, a structurally closely-related compound (read-across surrogate). Parental rats were fed TIPA for 5 wk in the diet at up to 7500 ppm prior to pairing and throughout mating, gestation and lactation. Their offspring were continued on the diet for 90-days. No observable effects on reproductive performance, development, or on signs of systemic toxicity were seen in any group. The NOAEL was determined to be 600 mg/kg bw/day, the highest dose tested (Mullin, 1988).

 

Inhalation DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility effects following repeated inhalation exposure. However, as explained above, a NOAEL of 600 mg/kg bw/day has been seen in a reproduction study involving oral administration of TIPA, a structurally closely-related compound.

 

Mode-of-action

 

DEIPA and TIPA are considered to have only threshold effects, as the weight-of-evidence indicates that they lack genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a inhalation DNEL(fertility) from oral fertility studies was considered suitable (no high first-pass metabolism has been reported or is expected).

 

In the absence of route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). In this instance, there is no human or laboratory animal data on the absorption of DEIPA or TIPA following inhalation exposure, so the default factor of 2 has been applied to the starting point as a health precautionary measure. The corrected NOAEL is therefore 300 mg/kg bw/day.

 

The oral dose for the rat is converted to the corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m³/kg bw for 8 h/day (exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 300 mg/kg bw/day / 0.38 m³/kg bw x (6.7 m³/ 10 m³) = 529 mg/m³ (8-h exposure of workers, light activity).

 

ECHA AFs for workers – inhalation DNEL (fertility)

Interspecies differences	1	Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above
	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	ECHA AF: Parental rats were treated prior to pairing and throughout mating, gestation and lactation. Their offspring were continued on the diet for 90-days. This study therefore comprises the most sensitive phases under consideration for fertility, and post weaning development and maturation. The ability of this study to detect the reproductive capacity of the offspring was limited to microscopic examination of the reproductive organs (i.e. a second generation was not produced).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted reproduction study. No effects were seen at the highest tested dose.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Other AFs	2	ECHA AF: Study was performed on a closely-related read-across compound (TIPA).
Overall AF for worker	50

 

Worker (light activity)-DNEL(fertility) long-term for inhalation route = 529 mg/m³/ 50 = 10.6 mg/m³

 

Overall, therefore, as this inhalation DNEL(fertility) is higher than the inhalation DNEL for repeated dose effects (1.18 mg/m³), the long-term inhalation worker-DNEL for repeated dose effects is considered protective of fertility impairment in workers.

 

Dermal DNEL (fertility)

Dose descriptor

 

There are no data available in humans or laboratory animals relating to fertility effects following repeated dermal exposure. However, as explained above, a NOAEL of 600 mg/kg bw/day was reported in a reliable fertility study on rats with TIPA.

 

Mode-of-action

 

DEIPA and TIPA are considered to have only threshold effects, as the weight-of-evidence indicates that they lack genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (fertility) from oral fertility studies was considered suitable.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. As no data are available on the absorption of DEIPA (with 100% absorption assumed through both the dermal and oral routes, based on physical-chemical data) no correction of the NOAEL is required.No data are available on the absorption of TIPA following inhalation, so it is assumed that the same default factors apply.

 

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

 

ECHA AFs for workers – dermal DNEL (fertility)

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	ECHA AF: Parental rats were treated prior to pairing and throughout mating, gestation and lactation. Their offspring were continued on the diet for 90-days. This study therefore comprises the most sensitive phases under consideration for fertility, and post weaning development and maturation. The ability of this study to detect the reproductive capacity of the offspring was limited to microscopic examination of the reproductive organs (i.e. a second generation was not produced).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted reproduction study. No observed adverse effects at highest tested dose
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high
Other AFs	2	Study was performed on a closely-related read-across compound (TIPA).
Overall AF for worker	200

 

Worker-DNEL (fertility) long-term for dermal route = 600 mg/kg bw/day / 200 = 3 mg/kg bw/day

 

Overall, therefore, as this dermal DNEL(fertility) is higher than the dermal DNEL for repeated dose effects (0.33 mg/kg bw/day), the long-term dermal worker-DNEL for repeated dose effects is considered protective of fertility impairment in workers.

 

Developmental toxicity

No information is available on the developmental effects of DEIPA in humans.

 

In a reliable developmental toxicity study, rats were treated with DEIPA at 0, 100, 300 or 1000 mg/kg bw/day on gestation days (GD) 6 to 20. Foetuses were examined on GD 21. Increased relative and absolute kidney weights were seen in dams given 1000 mg/kg bw/day. Skeletal variations, exhibited as delayed ossification of several skull bones in foetuses of dams given at least 300 mg/kg bw/day, were seen. No increased incidences of malformations or lethality were seen in foetuses at any dose level (Marty and Zablotny, 2001). In a preliminary screening study, DEIPA given at up to 1000 mg/kg bw/day on GD 6 to 20 by gavage produced no treatment-related maternal toxicity or embryo/foetal lethality in rats (Zablotny et al., 2001).

 

Inhalation DNEL (development)

Dose descriptor

 

There are no data available in humans or laboratory animals relating to developmental effects following repeated inhalation exposure. However, as explained above, a NOAEL of 100 mg/kg bw/day has been seen in a guideline developmental toxicity study involving oral administration of DEIPA.

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a inhalation DNEL(development) from an oral developmental toxicity study was considered suitable (no high first-pass metabolism has been reported or is expected).

 

Without route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). In this instance, there is no human or laboratory animal data on the absorption of DEIPA (with estimates, based on physicochemical data, of 100% absorption predicted via the oral, dermal and inhalation routes). The default factor of 2 has been applied to the starting point, as a health precautionary measure. The corrected NOAEL is therefore 50 mg/kg bw/day.

 

The oral dose for the rat is converted to the corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m³/kg bw for 8 h/day (exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 50 mg/kg bw/day / 0.38 m³/kg bw x (6.7 m³/ 10 m³) = 88.2 mg/m³ (8-h exposure of workers, light activity).

 

ECHA AFs for workers – inhalation DNEL (development)

Interspecies differences	1	Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above
	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	ECHA AF: Animals treated on GD 6-20, providing a robust assessment of prenatal developmental toxicity (as this covers the critical period of organogenesis), but not of postnatal effects (either as a result of prenatal or lactational exposure).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted developmental toxicity study. Effects at higher doses (300 or 1000 mg/kg bw/day) were not considered severe.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for worker	25

 

Worker (light activity)-DNEL(development)long-term for inhalation route = 88.2 mg/m³/ 25 = 3.5 mg/m³

Overall, therefore, as this inhalation DNEL(development) is greater than the inhalation DNEL for repeated dose effects (1.18 mg/m³), the long-term inhalation worker-DNEL for repeated dose toxicity is considered protective of developmental effects in the offspring of workers.

 

Dermal DNEL (development)

Dose descriptor

 

There are no data available in humans or laboratory animals relating to developmental effects following repeated dermal exposure. However, as explained above, a NOAEL of 100 mg/kg bw/day has been seen in a guideline developmental toxicity study involving oral administration of DEIPA .

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.Route-to-route extrapolation to calculate a dermal DNEL (development) from oral developmental toxicity study was considered suitable.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. As no data are available on the toxicokinetics of DEIPA (with 100% absorption assumed through both the dermal and oral routes, based on physical-chemical data), no correction of the NOAEL is required.

 

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

 

ECHA AFs for workers – dermal DNEL(development)

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	ECHA AF: Animals treated on GD 6-20, providing a robust assessment of prenatal developmental toxicity (as this covers the critical period of organogenesis), but not of postnatal effects (either as a result of prenatal or lactational exposure).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted developmental toxicity study. Effects at higher doses (300 or 1000 mg/kg bw/day) were not considered severe.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high
Overall AF for worker	100

 

Worker-DNEL(development)long-term for dermal route= 100 mg/kg bw/day / 100 = 1 mg/kg bw/day

 

Overall, therefore, as this dermal DNEL(development) is higher than the dermal DNEL for repeated dose effects (0.33 mg/kg bw/day), the long-term dermal worker-DNEL for repeated dose toxicity is considered protective of developmental effects in the offspring of workers.

 

References

ECHA (2012b). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7a: Endpoint specific guidance. Version 2.0. November 2012.http://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

As no relevant data on effects of repeated inhalation exposure to DEIPA in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from repeated dose oral toxicity studies was considered a suitable alternative

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-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); already considered in correcting starting point above

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 (including children and the elderly)

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

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:

0.17 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-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:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high

AF for remaining uncertainties:

1

Justification:

Not required

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:

0.17 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-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:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

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

General population

Discussion

 

Acute toxicity

 

As explained in the worker DNEL section above, no acute hazard has been identified for DEIPA, 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, DEIPA 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, DEIPA 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

 

No data are available on repeated dose oral toxicity effects in humans, but the oral toxicity of DEIPA has been investigated in a reliable 28-day study in rats treated by gavage, allowing the identification of a NOAEL of 100 mg/kg bw/day (Stebbins and Zablotny, 1999).

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

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	6	Default ECHA AF for subacute (28-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day were not considered severe
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for general population	600

 

General population-DNEL (long-term for oral route-systemic)= 100 mg/kg bw/day / 600 = 0.17 mg/kg bw/day

 

Inhalation DNEL (repeated dose toxicity)

 

Dose descriptor

 

There are no data available in humans or laboratory animals relating to repeated inhalation exposure to DEIPA. However, a reliable 28-day oral gavage study has investigated the repeated dose oral toxicity of DEIPA in rats and this has allowed the identification of a NOAEL of 100 mg/kg bw/day (Stebbins and Zablotny, 1999).

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

As no data on effects of repeated inhalation exposure to DEIPA in humans or laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative (no high first-pass metabolism has been reported or is expected).

In the absence of route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 is recommended (which assumes 50% absorption for oral exposure, and 100% for inhalation). The corrected NOAEL is therefore 50 mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 hr/day, 7 d/wk). No consumer exposure is expected.

Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to this corresponding air concentration using a standard breathing volume for the rat of 1.15 m³/kg bw for 24 hr/day. Thus, 50 mg/kg bw/day / 1.15 m³/kg bw/day = 43.5 mg/m³ (24-h exposure of the general population).

 

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); already considered in correcting starting point above
	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 (including children and the elderly)
Differences in duration of exposure	6	Default ECHA/ AF for subacute (28-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day were not considered severe
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for general population	150

 

General population-DNEL (long-term for inhalation route-systemic) = 43.5 mg/m³/ 150 = 0.3 mg/m³

 

Dermal DNEL(repeated dose toxicity)

 

Dose descriptor

 

No data are available in humans or laboratory animals relating to repeated dermal exposure to DEIPA which are suitable as the basis from which to calculate a dermal DNEL. However, a reliable 28-day study has investigated the repeated dose oral toxicity of DEIPA in rats and this has allowed the identification of a NOAEL of 100 mg/kg bw/day (Stebbins and Zablotny, 1999).

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL from repeated dose oral toxicity studies was considered suitable.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). No consumer exposure is expected.

 

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	6	Default ECHA AF for subacute (28-day) to chronic extrapolation
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from a well-conducted 28-day gavage study. Effects at LOAEL of 1000 mg/kg bw/day (inflammation, hyperplasia and hyperkeratosis of the non-glandular mucosa of the stomach, resolving within a 2-week recovery period) were not considered severe
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for general population	600

 

General population-DNEL (long-term for dermal route-systemic) = 100 mg/kg bw/day / 600 = 0.17 mg/kg bw/day

 

Genotoxicity

 

The weight-of-evidence indicates that DEIPA does not have genotoxic potential, and would not be classified as mutagenic. Consequently, no general population-DN(M)ELs for genotoxicity have been calculated.

 

Carcinogenicity

 

No carcinogenicity data on DEIPA are available from studies on humans or laboratory animals, and DEIPA is not expected to be genotoxicin vivo. Presumably any chronic DNEL (based on a NOAEL of 100 mg/kg bw/day seen in a 28-day oral rat study) should also be protective against carcinogenic effects, given that the critical effect was hyperplasia in the stomach seen at 1000 mg/kg bw/day which resolved within a 2-week recovery period.

 

Reproductive toxicity (fertility impairment and developmental toxicity)

 

Fertility impairment

 

No information is available on fertility effects in humans.

 

While there are no standard laboratory animal fertility studies available on DEIPA, no adverse effects on the reproductive organs and tissues were seen in rats treated orally for 28 days with up to 1000 mg/kg bw/day (Stebbins and Zablotny, 1999). In addition, a NOAEL of 600 mg/kg bw/day (the highest dose tested) was reported in a reproduction guideline dietary study on TIPA, a structurally-related read-across compound (Mullin, 1988).

 

Oral DNEL(fertility)

 

Dose descriptor

 

No standard data are available in humans or laboratory animals relating to fertility effects of DEIPA following repeated oral exposure. However, as explained above, a NOAEL of 600 mg/kg bw/day has been seen in a reproduction study involving oral administration of TIPA, a closely-related compound.

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

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(fertility)

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	ECHA AF: Parental rats were treated prior to pairing and throughout mating, gestation and lactation. Their offspring were continued on the diet for 90-days. This study therefore comprises the most sensitive phases under consideration for fertility, and post weaning development and maturation. The ability of this study to detect the reproductive capacity of the offspring was limited to microscopic examination of the reproductive organs (i. e. a second generation was not produced).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted one-generation study. No effects were seen at the highest tested dose.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Other AFs	2	ECHA AF: Study was performed on a closely-related read-across compound (TIPA).
Overall AF for general population	400

 

General population-DNEL(fertility) long-term for oral route = 600 mg/kg bw/day / 400 = 1.5 mg/kg bw/day

 

As this oral DNEL (fertility) is higher than the oral DNEL for repeated dose effects (0.17 mg/kg bw/day), the long-term oral DNEL for repeated dose toxicity is considered protective of fertility impairment in the general population.

 

Inhalation DNEL (fertility)

 

Dose descriptor

 

There are no data available in humans or laboratory animals relating to fertility effects following repeated inhalation exposure. However, in a reproduction oral study on TIPA, a NOAEL of 600 mg/kg bw/day for effects on fertility was seen.

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.Route-to-route extrapolation to calculate a inhalation DNEL(fertility) from repeated dose oral toxicity studies was considered suitable (no high first-pass metabolism has been reported or is expected).

 

In the absence of route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). The corrected NOAEL is therefore 300 mg/kg bw/day.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). No consumer exposure is expected.

 

Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to this corresponding air concentration using a standard breathing volume for the rat of 1.15 m³/kg bw for 24 h/day. Thus, 300 mg/kg bw/day / 1.15 m³/kg bw/day = 260.9 mg/m³ (24-h exposure of the general population).

 

ECHA AFs for general population – inhalation DNEL (fertility)

Uncertainty	AF	Justification for AF
Interspecies differences	1	Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above
	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	ECHA AF: Parental rats were treated prior to pairing and throughout mating, gestation and lactation. Their offspring were continued on the diet for 90-days. This study therefore comprises the most sensitive phases under consideration for fertility, and post weaning development and maturation. The ability of this study to detect the reproductive capacity of the offspring was limited to microscopic examination of the reproductive organs (i.e. a second generation was not produced).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted one-generation study. No effects were seen at the highest tested dose.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Other AFs	2	ECHA AF: Study was performed on a closely-related read-across compound (TIPA).
Overall AF for general population	100

 

General population-DNEL (fertility) long-term for inhalation route = 260.9 mg/m³/ 100 = 2.6 mg/m³

 

As this inhalation DNEL(fertility) is higher than the inhalation DNEL for repeated dose effects (0.3 mg/m³), the long-term inhalation DNEL for repeated dose toxicity is considered protective of fertility impairment in the general population.

 

Dermal DNEL (fertility)

 

Dose descriptor

 

There are no data available in humans or laboratory animals relating to fertility effects following repeated dermal exposure. However, in a reproduction oral study on TIPA, a NOAEL of 600 mg/kg bw/day for effects on fertility was seen.

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (fertility) from repeated dose oral toxicity studies was considered suitable.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. As such, no correction of the NOAEL is required.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). No consumer exposure is expected.

 

ECHA AFs for general population – dermal DNEL (fertility)

 

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	ECHA AF: Parental rats were treated prior to pairing and throughout mating, gestation and lactation. Their offspring were continued on the diet for 90-days. This study therefore comprises the most sensitive phases under consideration for fertility, and post weaning development and maturation. The ability of this study to detect the reproductive capacity of the offspring was limited to microscopic examination of the reproductive organs (i.e. a second generation was not produced).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted one-generation study. No effects were seen at the highest tested dose.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Other AFs	2	ECHA AF: Study was performed on a closely-related read-across compound (TIPA).
Overall AF for general population	400

 

General population-DNEL(fertility) long-term for dermal route = 600 mg/kg bw/day / 400 = 1.5 mg/kg bw/day

 

As this dermal DNEL (fertility) is higher than the dermal DNEL for repeated dose effects (0.17 mg/kg bw/day), the long-term dermal DNEL for repeated dose toxicity is considered protective of fertility impairment in the general population.

 

Developmental toxicity

A NOAEL of 100 mg/kg bw/day was reported in a reliable developmental toxicity study on rats treated from GD 6 to 20 with DEIPA via gavage. Skeletal variations, exhibited as delayed ossification of several skull bones in foetuses of dams given at least 300 mg/kg bw/day, were seen (Marty and Zablotny, 2001).

 

Oral DNEL (development)

 

Dose descriptor

 

As explained in the worker DNEL section above, a good quality prenatal developmental toxicity study is available on DEIPA, with pregnant rats treated from GD 6 to 20 via oral gavage. A NOAEL of 100 mg/kg bw/day was observed.

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

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 (development)

Interspecies differences	4	Default ECHA AF for rats 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	ECHA AF: Animals treated on GD 6-20, providing a robust assessment of prenatal developmental toxicity (as this covers the critical period of organogenesis), but not of postnatal effects (either as a result of prenatal or lactational exposure).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted developmental toxicity study. Effects at higher doses (300 or 1000 mg/kg bw/day) were not considered severe.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for general population	200

 

General population-DNEL(development) long-term for oral route = 100 mg/kg bw/day / 200 = 0.5 mg/kg bw/day

 

Overall, therefore, as this oral DNEL(development) is more than the oral DNEL for repeated dose effects (0.17 mg/kg bw/day), the long-term oral DNEL for repeated dose toxicity is considered protective of developmental effects on the offspring of the general population.

 

Inhalation DNEL (development)

 

Dose descriptor

There are no data available in humans or laboratory animals relating to developmental effects following repeated inhalation exposure. However, as explained above, a NOAEL of 100 mg/kg bw/day has been seen in a guideline developmental toxicity study involving oral administration of DEIPA.

 

Mode-of-action

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a inhalation DNEL(development) from an oral developmental toxicity study was considered suitable (no high first-pass metabolism has been reported or is expected).

 

Without route-specific information on absorption for both the starting route (oral) and end route (inhalation), a default factor of 2 should be used (which assumes 50% absorption for oral exposure, and 100% for inhalation). The corrected NOAEL is therefore 50 mg/kg bw/day.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). No consumer exposure is expected.

 

Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to this corresponding air concentration using a standard breathing volume for the rat of 1.15 m³/kg bw for 24 h/day. Thus, 50 mg/kg bw/day / 1.15 m³/kg bw/day = 43.5 mg/m³(24-h exposure of the general population).

 

ECHA AFs for general population – inhalation DNEL (development)

Interspecies differences	1	Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above
	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	ECHA AF: Animals treated on GD 6-20, providing a robust assessment of prenatal developmental toxicity (as this covers the critical period of organogenesis), but not of postnatal effects (either as a result of prenatal or lactational exposure).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted developmental toxicity study. Effects at higher doses (300 or 1000 mg/kg bw/day) were not considered severe.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
Overall AF for general population	50

 

General population-DNEL(development) long-term for inhalation route = 43.5 mg/m³/ 50 = 0.87 mg/m³

Overall, therefore, as this inhalation DNEL(development) is more than the inhalation DNEL for repeated dose effects (0.3 mg/m³), the long-term inhalation DNEL for repeated dose toxicity is considered protective of developmental effects on the general population.

 

Dermal DNEL (development)

 

Dose descriptor

 

There are no data available in humans or laboratory animals relating to developmental effects following repeated dermal exposure. However, as explained above, a NOAEL of 100 mg/kg bw/day has been seen in a guideline developmental toxicity study involving oral administration of DEIPA.

 

Mode-of-action

 

DEIPA is considered to have only threshold effects, as the weight-of-evidence indicates that it lacks genotoxic potential.

 

Modification of starting point

 

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.Route-to-route extrapolation to calculate a dermal DNEL (development) from oral developmental toxicity study was considered suitable.

 

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation. As such, no correction of the NOAEL is required.

 

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). No consumer exposure is expected.

 

ECHA AFs for general population – dermal DNEL(development)

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	ECHA AF: Animals treated on GD 6-20, providing a robust assessment of prenatal developmental toxicity (as this covers the critical period of organogenesis), but not of postnatal effects (either as a result of prenatal or lactational exposure).
Dose response and endpoint specific/severity issues	1	Default ECHA AF; NOAEL from well-conducted developmental toxicity study. Effects at higher doses (300 or 1000 mg/kg bw/day) were not considered severe.
Quality of whole database	1	ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high
Overall AF for general population	200

 

General population-DNEL(development) long-term for dermal route = 100 mg/kg bw/day / 200 = 0.5 mg/kg bw/day

 

Overall, therefore, as this dermal DNEL(development) is higher than the dermal DNEL for repeated dose effects (0.17 mg/kg bw/day), the long-term dermal DNEL for repeated dose toxicity is considered protective of developmental effects on the offspring of the general population.

 

References

ECHA (2012b). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7a: Endpoint specific guidance. Version 2.0. November 2012.http://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf