Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.86 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Acute toxicity

No acute toxicity data in humans are available. EDDS acid and its trisodium salt are of low acute toxicity in laboratory animal studies following oral, dermal and inhalation exposures. In reliable studies, acute oral LD50 values exceeded 2 g/kg bw in rats following gavage administration of EDDS acid (Brunt, 2002a) and its trisodium salt (Kynoch et al. 1989; Mahl, 1993a). In addition, acute dermal LD50s in excess of 2 g/kg bw in rats (Mahl, 1993b) and rabbits (Liggett and Allan, 1989) and an acute inhalation LC50 in rats in excess of 1490 mg/m³ air (Hardy and Jackson, 1989) were seen with trisodium EDDS.

Based on the available data, EDDS acid (and its trisodium salt) would not be classified as acutely toxic by the oral, inhalation or dermal routes according to the EU CLP or DSD regulations. DNELs for acute toxicity should be derived if an acute toxicity hazard, leading to classification and labeling (i.e. under EU CLP or DSD 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 is expected to be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNEL for acute toxicity has been calculated.

Irritation/corrosivity

In reliable studies, no evidence of irritation was observed when trisodium EDDS was applied for 4 h (under semi-occlusive conditions) to the intact skin of rabbits (Arcelin, 1993a; Liggett, 1989a) or following repeated exposure of the diluted material to the skin of the upper arm of a number of healthy volunteers (Pitts, 1993; Rybicki, 1993). The use of irritation data on a salt to predict the irritation potential of the equivalent acid is only reliable if large differences in pH are absent. The pH of a 10% w/w aqueous preparation of EDDS acid was determined to be 4.2 (Brunt, 2002b), thus EDDS acid is a relatively weak acid and would not be classified as corrosive to the eyes or skin on the basis of pH alone. In addition, in a guideline study, EDDS acid caused only moderate transient effects on the conjunctivae of rabbits [see below for further details], which would tend to support a conclusion that significant skin irritation is unlikely. In further support of this, the structurally-related acid EDTA caused, at worst, mild irritation to the skin of one rabbit following a 20-hr exposure to a 50% aqueous preparation (BASF, 1973). In summarising this early study, EU experts have concluded “that these findings do not warrant a classification and labelling for skin irritation” (EU, 2004a). Overall, the weight-of-evidence suggests that EDDS acid is likely to be, at most, only a slight skin irritant.

There is no information from humans on the potential for EDDS or its trisodium salt to cause eye irritation. However, in reliable studies with rabbits, instillation of EDDS acid caused only moderate transient effects on the conjunctivae (the iris and cornea were unaffected) (Brunt, 2002b) and instillation of trisodium EDDS produced, at worst, mild transient effects (Arcelin, 1993b; Liggett, 1989b).

There are no data in relation to respiratory tract irritation in humans or laboratory animals. However, due to their low vapour pressure and low skin and eye irritation potential, it is unlikely that EDDS acid (or its trisodium salt) would cause such an effect.

Based on the available data, EDDS acid would not be classified as a eye, skin or respiratory tract irritant under the EU CLP or DSD regulations. Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects. Consequently, no worker-DNEL for irritation/corrosivity has been calculated.

Sensitisation

In reliable studies, trisodium EDDS produced no sensitising potential when repeatedly applied to the clipped skin of guinea pigs (Arcelin, 1993c; Merriman, 1995) or to the skin of more than 100 healthy volunteers (Rybicki, 1993). There are no data relating to respiratory tract sensitisation in humans or laboratory animals. However, due to their low vapour pressure and lack of skin sensitisation potential, it is unlikely that EDDS acid or its trisodium salt would cause such an effect.

Based on the available data, EDDS would not be classified as a skin or respiratory tract sensitiser under EU CLP or DSD regulations and no worker-DNELs for skin or respiratory tract sensitisation have been calculated.

Oral DNEL (repeated dose toxicity)

Not considered applicable for workers.

 

Inhalation DNEL (repeated dose toxicity, systemic effects)

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated inhalation exposure to EDDS acid or its trisodium salt. However, several studies have investigated the repeated dose oral toxicity of trisodium EDDS in rodents and this has allowed the identification of the lowest, relevant NOAEL of 300 mg/kg bw/day from a reliable 90-day dietary study in rats which included a 28-day recovery period (Dotti et al. 1995). In this GLP study, conducted according to OECD Guideline 408 (available at the time), a slight transient reduction in body weight gain and effects on the pancreas (single cell death and fatty infiltration) were seen at higher doses (700 mg/kg bw/day and above). As these studies were conducted on the trisodium salt of EDDS, a correction for the difference in molecular weights is necessary. Trisodium EDDS has a molecular weight (MW) of 358 and EDDS acid has a MW of 292. Thus, a NOAEL of 300 mg/kg bw/day for trisodium EDDS corresponds to a NOAEL of 245 mg/kg bw/day for the free acid [300 x 292/358 = 245].

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess genotoxic potential (Bigger and Clarke, 1993; Jones et al. 1989; Putman, 1994; Putman and Curry, 1994; San and Wyman, 1993; Thompson, 2002).

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 EDDS acid or its trisodium salt 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,at least 5% of radiolabelled trisodium EDDS was considered absorbed after 72 h in male and female rats following a single gavage administration (Ferdinandi, 1995). Although there is no specific information for the inhalation route of exposure, it is unlikely that absorption of trisodium EDDS will be complete following inhalation exposure. However, a health precautionary approach is to assume 5% oral absorption and 100% inhalation absorption. Therefore, the starting point has been corrected by a factor of 20 (i.e. 245 mg/kg bw/day / 20 = 12.25 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 h/day (exposure of workers). Thus, 12.25 mg/kg bw/day / 0.38 m3/kg bw/day = 32.25 mg/m3 (8-h exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 32.25 mg/m3x (6.7 m3/ 10 m3) = 21.6 mg/m3 (8-h exposure of workers, light activity).

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

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

 

2.5

Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

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 subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL (slight reduction in body weight gain and pancreas effects) were not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

Overall AF for worker

 

25

Worker (light activity) -DNEL (long-term for inhalation route-systemic) = 21.6 mg/m3/ 25 = 0.86 mg/m3

Dermal DNEL(repeated dose toxicity, systemic effects)

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, several studies have investigated the repeated dose oral toxicity of trisodium EDDS in rodents and this has allowed the identification of the lowest, relevant NOAEL of 300 mg/kg bw/day from a 90-day dietary study in rats (Dotti et al. 1995). In this reliable study, reduced body weight gain and effects on the pancreas (single cell death and fatty infiltration) were seen at higher doses (700 mg/kg bw/day and above). As these studies were conducted on the trisodium salt of EDDS, a correction for the difference in molecular weights results in a NOAEL of 245 mg/kg bw/day.

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 EDDS acid or its trisodium salt 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.

In reliable studies, only about 11% of radiolabelled trisodium EDDS was considered absorbed after 72 h in male and female rats following dermal application and about 5% following single gavage(Ferdinandi, 1995). Therefore,it is appropriate to correct the starting point for differences in dermal (11%) and oral (5%) absorption, thus 245 mg/kg bw/day x (5 / 11) = 111.4 mg/kg bw/day.

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

 

 

2.5

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

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 subchronic (90-day) to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Default ECHA AF; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL (slight reduction in body weight gain and pancreas effects) were not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for worker

 

100

 

Worker-DNEL (long-term for dermal route-systemic) = 111.4 mg/kg bw/day / 100 = 1.1 mg/kg bw/day

Genotoxicity

No information is available on genotoxic effects in humans. In a reliable study, EDDS acid showed no evidence of mutagenic potential when tested at up to 5 mg/plate in a bacterial reverse mutation assay (Ames test) using five strains of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102, both in the presence and absence of S9 (Thompson, 2002). On the related material, trisodium EDDS also showed no mutagenic activity in Ames tests when tested at up to 5 mg/plate in five strains of S. typhimurium and two strains of E. coli, with and without S9 (Jones et al. 1989; San and Wyman, 1993) or at the tk locus in mouse lymphoma cells in an in vitro mammalian cell mutation assay when tested at up to about 5 mg/mL, with and without S9 (Bigger and Clarke, 1993).

In reliable studies, trisodium EDDS induced statistically significant increases in chromosome numbers and structural aberrations (although the latter effect was not considered biologically relevant) in cultured Chinese hamster ovary cells after a 42-h exposure in the absence of S9. No evidence of numerical or structural chromosome aberrations were seen after 6-h or 18-h exposures without S9, or after a 6-h incubation in the presence of S9. Overall, trisodium EDDS was considered to cause chromosome aberrations in this in vitro mammalian cytogenicity assay (Putman and Curry, 1994). However, no evidence of induction of numerical or structural chromosome aberrations was seen when trisodium EDDS was administered as a single oral dose at up to 2000 mg/kg bw in a bone marrow cytogenetic assay in male and female rats (Putman, 1994). Good-quality toxicokinetic studies (Powers, 1993a,b)have shown distribution of trisodium EDDS to the bone marrow.

Overall, therefore, the weight-of-evidence indicates that EDDS acid and its trisodium salt are not mutagenic and do not directly interact with DNA. Under EU CLP and DSD regulations, they would not be classified as mutagenic. Consequently, no worker-DN(M)ELs for genotoxicity have been calculated.

Carcinogenicity

No information on carcinogenic effects in humans are available and no laboratory animal data on EDDS acid or its simple salts were identified. In reliable long-term rodent cancer bioassays (conducted at the US National Cancer Institute), the structurally-related compound trisodium ethylenediaminetetraacetate (EDTA) showed no evidence of carcinogenic potential when fed to rats and mice in the diet for 2 years at up to 7500 ppm (about 375 and 1125 mg/kg bw/day, respectively) (NCI, 1977). Based on their structural similarity, it is expected that EDDS acid is also unlikely to induce tumourgenicity following long-term oral exposure at comparable doses. According to EU CLP and DSD regulations, EDDS acid (and its trisodium salt) would not be classified as carcinogenic based on the data described. AsEDDS acid (and its trisodium salt) are not considered to be genotoxic and are not expected to produce tumours in rodents at doses of 375 mg/kg bw/day and above following lifetime dietary exposure, it is considered that there would be no risk of tumour development associated with exposures lower than those required to produce chronic toxicity (i.e. a NOAEL of 300 mg/kg bw/day in a 90-day dietary rat study has been identified as the critical value). Consequently, the long-term worker-DNELs for repeated dose systemic effects are considered protective against potential carcinogenic effects.

Reproductive toxicity (fertility impairment and developmental toxicity)

Fertility DNEL

No information is available on fertility effects in humans. In a reliable one-generation reproduction study, no adverse effects on measures of fertility (and development or systemic toxicity) were seen in groups of rats administered trisodium EDDS by gavage at up to 700 mg/kg bw/day (considered the study NOAEL) for 70 days prior to mating, and throughout mating, pregnancy, lactation and weaning (York, 1999).

No 2-, 3- or multi-generation studies on EDDS acid, its simple salts, or EDTA were identified. However, data from a multi-generation study on rats with calcium disodium EDTA gave no evidence for adverse effects on reproductive performance and outcome at up to 250 mg/kg bw/day, considered the study NOAEL (Oser et al. 1963). In a limited and briefly reported 2-generation reproductive toxicity study, normal first and second litters were reported from rats fed disodium EDTA in the diet at up to about 500 mg/kg bw/day (considered the study NOAEL), while those animals of the highest dose (2500 mg/kg bw/day) failed to produce any litters. Data on the second generation were not available (Yang, 1952).

Overall, therefore, the NOAEL of 700 mg/kg bw/day from the one-generation reproduction study with trisodium EDDS will be used for the calculation of a fertility DNEL. Maternal toxicity was not observed in these reproductive toxicity studies at dose levels higher than those causing adverse effects in the general repeated dose toxicity studies indicating that there is no reason to suggest that pregnant women are more vulnerable to the effects of trisodium EDDS.

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 700 mg/kg bw/day has been seen in a one-generation reproduction study in rats following repeated dietary exposure. As these studies were conducted on the trisodium salt of EDDS, a correction for the difference in molecular weights is necessary. Thus, a NOAEL of 700 mg/kg bw/day for trisodium EDDS corresponds to a NOAEL of 571 mg/kg bw/day for the free acid [700 x 292/358 = 571].

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 an inhalation DNEL (fertility) from oral studies was considered suitable (no high first-pass metabolism has been reported or is expected).

As explained previously,only about 5% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following a single gavage administration(Ferdinandi, 1995). A health precautionary approach is to assume 100% absorption following inhalation exposure. Therefore, the starting point has been corrected to reflect 5% oral absorption and 100% inhalation absorption. Thus, 571 mg/kg bw/day / 20 = 29 mg/kg bw/day.

Workers are assumed to be exposed for 8 h/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 29 mg/kg bw/day / 0.38 m3/kg bw/day x (6.7 m3/ 10 m3) = 51 mg/m3(8-h exposure of workers, light activity).

ECHA AFs for workers – inhalation DNEL (fertility)

 

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

 

2.5

Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

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

1

No AF necessary as exposure for70 days prior to mating, and throughout mating, pregnancy and weaning

Dose response and endpoint specific/severity issues

1

Default ECHA AF; no adverse effects on fertility outcomes at highest tested dose in well-conducted one-generation reproductive toxicity study

Quality of whole database

2

ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high. However, as the 2-generation and multi-generation reproduction studies were carried out on a closely-related surrogate (the simple salts of EDTA) it was felt health precautionary to include an AF of 2.

Overall AF for worker

 

25

 

Worker (light activity)-DNEL (fertility)long-term for inhalation route-systemic = 51 mg/m3/ 25 = 2 mg/m3

Overall, as this inhalation DNEL(fertility) is higher than the inhalation DNEL for repeated dose effects (0.86 mg/m3), the long-term inhalation worker-DNEL for systemic effects is considered protective against 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 700 mg/kg bw/day [equivalent to about 571 mg EDDS acid/kg bw/day] has been seen in a one-generation reproduction study in rats following dietary exposure. 

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 studies was considered suitable (no high first-pass metabolism has been reported or is expected).

About 11% of radiolabelled trisodium EDDS was considered absorbed after 72 h in male and female rats following dermal application and about 5% following single gavage(Ferdinandi, 1995). Therefore,it is appropriate to correct the starting point for differences in dermal (11%) and oral (5%) absorption, thus 571 mg/kg bw/day x (5 / 11) = 260 mg/kg bw/day.

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

 

 

2.5

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

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

1

No AF necessary as exposure for70 days prior to mating, and throughout mating, pregnancy, lactation and weaning

Dose response and endpoint specific/severity issues

1

Default ECHA AF; no adverse effects on fertility outcomes at highest tested dose in well-conducted one-generation reproductive toxicity study

Quality of whole database

2

ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high. However, as the 2-generation and multi-generation reproduction studies were carried out on a closely-related surrogate (the simple salts of EDTA) it was felt health precautionary to include an AF of 2.

Overall AF for worker

 

100

 

Worker-DNEL (fertility)long-term for dermal route-systemic = 260 mg/kg bw/day / 100 = 2.6 mg/kg bw/day

Overall, as this dermal DNEL(fertility) is higher than the dermal DNEL for repeated dose effects (1.1 mg/kg bw/day), the long-term dermal worker-DNEL for systemic effects is considered protective of fertility impairment in workers.

Developmental

No information is available on developmental effects in humans. In a reliable study, a NOAEL of 551 mg/kg bw/day was derived for both maternal and developmental toxicity in rats given trisodium EDDS in the diet from day 6 to 15 of pregnancy (Denny, 1996a).Evidence of maternal toxicity (reduced body weight gain and food consumption) in the high-dose group (944 mg/kg bw/day) was observed. Also in the high dose group, mean gravid uterine weight was reduced, and there was a statistically significant increase in the number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio). Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures(Denny, 1996a). In another reliable study, NOAELs of 400 and 1000 mg/kg bw/day were derived for maternal and developmental toxicity, respectively, in groups of rats administered trisodium EDDS by oral gavage from day 6 to 15 of pregnancy (Denny, 1996b).

 

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 551 mg/kg bw/day has been seen in a reliable developmental toxicity study in rats following dietary exposure (Denny, 1996a). As these studies were conducted on the trisodium salt of EDDS, a correction for the difference in molecular weights is necessary. Thus, a NOAEL of 551 mg/kg bw/day for trisodium EDDS corresponds to a NOAEL of 450 mg/kg bw/day for the free acid [551 x 292/358 = 450].

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 an inhalation DNEL (developmental) from oral studies was considered suitable (no high first-pass metabolism has been reported or is expected).

Only about 5% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following a single gavage administration(Ferdinandi, 1995). A health precautionary approach is to assume 100% absorption following inhalation exposure. Therefore, the starting point has been corrected to reflect 5% oral absorption and 100% inhalation absorption (i.e. 450 mg/kg bw/day / 20 = 22.5 mg/kg bw/day).

Workers are assumed to be exposed for 8 h/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 22.5 mg/kg bw/day / 0.38 m3/kg bw/day x (6.7 m3/ 10 m3) = 39.7 mg/m3 (8-h exposure of workers, light activity).

ECHA AFs for workers – inhalation DNEL (development)

 

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

 

2.5

Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

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

1

No AF necessary as developmental study covers critical period of organogenesis

Dose response and endpoint specific/severity issues

2

Default ECHA AF; no adverse effects at 551 mg/kg bw/day (diet) or, in another developmental study in rats, at up to 1000 mg/kg bw/day (gavage). However, in the dietary study, an increase inthe number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio) was seen. Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for worker

 

25

 

Worker (light activity) -DNEL (development)long-term for inhalation route-systemic= 39.7 mg/m3/ 25 = 1.6 mg/m3.

Overall, as this inhalation DNEL(development) is higher than the inhalation DNEL for repeated dose effects (0.86 mg/m3), the long-term inhalation worker-DNEL for systemic effects is considered protective against developmental effects in pregnant 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 551 mg/kg bw/day [equivalent to about 450 mg EDDS acid/kg bw/day] has been seen in a reliable developmental toxicity study in rats following dietary exposure (Denny, 1996a). 

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 an dermal DNEL (developmental) from oral studies was considered suitable (no high first-pass metabolism has been reported or is expected).

In reliable studies, only about 11% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following dermal application compared to about 5% following single gavage(Ferdinandi, 1995). Therefore,it is appropriate to correct the starting point for differences in dermal (11%) and oral (5%) absorption, thus 450 mg/kg bw/day x (5 / 11) = 205 mg/kg bw/day.

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

 

 

2.5

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

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

1

No AF necessary as developmental study covers critical period of organogenesis

Dose response and endpoint specific/severity issues

2

Default ECHA AF; no adverse effects at 551 mg/kg bw/day (diet) or, in another developmental study in rats, at up to 1000 mg/kg bw/day (gavage). However, in the dietary study, an increase inthe number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio) was seen. Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for worker

 

100

 

Worker-DNEL (development)long-term for dermal route-systemic = 205 mg/kg bw/day / 100 = 2.1 mg/kg bw/day.

Overall, as this dermal DNEL(development) is higher than the dermal DNEL for repeated dose effects (1.1 mg/kg bw/day), the long-term dermal worker-DNEL for systemic effects is considered protective of developmental effects in pregnant workers.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.21 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.56 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.23 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Acute toxicity

As explained in the worker DNEL section above, EDDS acid and its trisodium salt are of low acute toxicity in laboratory animal studies following oral, dermal and inhalation exposures and would not be classified as acutely toxic under the EU CLP or DSD regulations. Therefore, a DNEL for such effects is not considered necessary 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, EDDS acid would not likely be classified as skin, eye or respiratory tract irritants under the EU CLP or DSD regulations. Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects. Consequently, no general population-DNEL for irritation/corrosivity has been calculated.

Sensitisation

Based on the available data, EDDS acid and its trisodium salt would not be classified as skin or respiratory sensitisers under the EU CLP or DSD regulations. Therefore, no general population-DNELs for skin or respiratory sensitisation have been calculated.

 

Oral DNEL (repeated dose toxicity, systemic effects)

Dose descriptor

No data are available on repeated dose oral toxicity effects in humans. However,several studies have investigated the repeated dose oral toxicity of trisodium EDDS in rodents and this has allowed the identification of the lowest, relevant NOAEL of 300 mg/kg bw/day from a 90-day dietary study in rats, which included a 28-day recovery period (Dotti et al. 1995). In this GLP study, conducted according to OECD Guideline 408 (available at the time), a slight transient reduction in body weight gain was seen in males during the last 3 weeks of treatmentat 700 mg/kg bw/day (and above) and in the pancreas (at these doses) there was an increased incidence of single cell death and fatty infiltration, the latter of which was still present in the top dose group (1000 mg/kg bw/day) at the end of the recovery period (Dotti et al. 1995).

As these studies were conducted on the trisodium salt of EDDS, a correction for the difference in molecular weights is necessary. Trisodium EDDS has a molecular weight (MW) of 358 and EDDS acid has a MW of 292. Thus, a NOAEL of 300 mg/kg bw/day for trisodium EDDS corresponds to a NOAEL of 245 mg/kg bw/day for the free acid [300 x 292/358 = 245].

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess genotoxic potential (Bigger and Clarke, 1993; Jones et al. 1989; Putman, 1994; Putman and Curry, 1994; San and Wyman, 1993; Thompson, 2002).

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.General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

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

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

2.5

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

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

1

No AF necessary as developmental study covers critical period of organogenesis

Dose response and endpoint specific/severity issues

2

Default ECHA AF; no adverse effects at 551 mg/kg bw/day (diet) or, in another developmental study in rats, at up to 1000 mg/kg bw/day (gavage). However, in the dietary study, an increase inthe number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio) was seen. Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for general population

 

200

 

General population-DNEL (long-term for oral route-systemic)= 245 mg/kg bw/day / 200 = 1.23 mg/kg bw/day

Inhalation DNEL (repeated dose toxicity, systemic effects)

Dose descriptor

There are no data available in humans or laboratory animals relating to repeated inhalation exposure. Several studies have investigated the repeated dose oral toxicity of trisodium EDDS in rodents and this has allowed the identification of a NOAEL of 300 mg/kg bw/day from a reliable 90-day dietary study in rats (Dotti et al. 1995).

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 EDDS acid or its trisodium salt 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).

Only about 5% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following a single gavage administration(Ferdinandi, 1995). A health precautionary approach is to assume 100% absorption following inhalation. Therefore, the starting point has been corrected to reflect 5% oral absorption and 100% inhalation absorption. Thus, 245 mg/kg bw/day / 20 = 12.3 mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited 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 the corresponding air concentration using a standard breathing volume for the rat of 1.15 m3/kg bw for 24 h/day. Thus, 12.3 mg/kg bw/day / 1.15 m3/kg bw/day = 10.7 mg/m3(24-h exposure of the general population).

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

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

2.5

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

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

2

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

Dose response and endpoint specific/severity issues

1

Default ECHA AF; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL (slight reduction in body weight gain and pancreas effects) were not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for general population

 

50

 

General population-DNEL(long-term for inhalation route-systemic) = 10.7 mg/m3/ 50 = 0.21 mg/m3

 

Dermal DNEL(repeated dose toxicity, systemic effects)

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.Several studies have investigated the repeated dose oral toxicity of trisodium EDDS in rodents and this has allowed the identification of a NOAEL of 300 mg/kg bw/day from a reliable 90-day dietary study in rats (Dotti et al. 1995). As these studies were conducted on the trisodium salt of EDDS, a correction for the difference in molecular weights results in a NOAEL of 245 mg/kg bw/day.

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 EDDS acid or its trisodium salt 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.

In reliable studies, only about 11% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following dermal application and about 5% following single gavage(Ferdinandi, 1995). Therefore,it is appropriate to correct the starting point for differences in dermal (11%) and oral (5%) absorption, thus 245 mg/kg bw/day x (5 / 11) = 111.4 mg/kg bw/day

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – dermal DNEL (repeated dose toxicity, systemic effects)

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

2.5

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

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

2

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

Dose response and endpoint specific/severity issues

1

Default ECHA AF; human health relevant NOAEL from well-conducted 90-day dietary study. Effects at the LOAEL (slight reduction in body weight gain and pancreas effects) were not considered severe

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for general population

 

200

 

General population-DNEL (long-term for dermal route-systemic) = 111.4 mg/kg bw/day / 200 =0.56 mg/kg bw/day

Genotoxicity

The weight-of-evidence indicates that EDDS acid (and its trisodium salt) are not mutagenic and do not directly interact with DNA. Under EU CLP and DSD regulations, they would not be classified as mutagenic. Consequently, general population-DN(M)ELs for genotoxicity have not been calculated.

Carcinogenicity

No information on carcinogenic effects in humans are available and no laboratory animal data on EDDS acid or its simple salts were identified.However, no evidence of carcinogenic potential was seen when the structurally-related compound trisodium EDTA was fed to rats and mice in the diet for 2 years at up to about 375 and 1125 mg/kg bw/day, respectively (NCI, 1977). Based on their structural similarity, it is expected that EDDS acid is also unlikely to induce tumourgenicity following long-term oral exposure at comparable doses. According to EU CLP and DSD regulations, EDDS acid (and its trisodium salt) would not be classified as carcinogenic based on the available data. AsEDDS acid (and its trisodium salt) are not considered to be genotoxic and are not expected to produce tumours in rodents at doses of 375 mg/kg bw/day and above following lifetime dietary exposure, it is considered that there would be no risk of tumour development associated with exposures lower than those required to produce chronic toxicity (i.e. a NOAEL of 300 mg/kg bw/day in a 90-day dietary rat study has been identified as the critical value). Consequently, the long-term worker-DNELs for repeated dose systemic effects are considered protective against potential carcinogenic effects.

 

Reproductive toxicity (fertility impairment and developmental toxicity)

Fertility DNEL

No information is available on fertility effects in humans. In a reliable one-generation reproduction study, no adverse effects on measures of fertility (and development or systemic toxicity) were seen in groups of rats administered trisodium EDDS by gavage at up to 700 mg/kg bw/day (considered the study NOAEL) for70 days prior to mating, and throughout mating, pregnancy, lactation and weaning(York, 1999).

No 2-, 3- or multi-generation studies on EDDS acid, its simple salts, or EDTA were identified. However, data from a multi-generation study on rats with calcium disodium EDTA gave no evidence for adverse effects on reproductive performance and outcome at up to 250 mg/kg bw/day, considered the study NOAEL (Oser et al. 1963). In a limited and briefly reported 2-generation reproductive toxicity study, normal first and second litters were reported from rats fed disodium EDTA in the diet at up to about 500 mg/kg bw/day (considered the study NOAEL), while those animals of the highest dose (2500 mg/kg bw/day) failed to produce any litters. Data on the second generation were not available (Yang, 1952).

Overall, therefore, the NOAEL of 700 mg/kg bw/day from the one-generation reproduction study with trisodium EDDS will be used for the calculation of a fertility DNEL. Maternal toxicity was not observed in these reproductive toxicity studies at dose levels higher than those causing adverse effects in the general repeated dose toxicity studies indicating that there is no reason to suggest that pregnant women are more vulnerable to the effects of trisodium EDDS.

Oral DNEL (fertility)

Dose descriptor

There are no data available in humans relating to fertility effects following repeated oral exposure. However, as explained above, a NOAEL of 700 mg/kg bw/day [equivalent to about 571 mg EDDS acid/kg bw/day] has been seen in a one-generation reproduction study in rats following repeated dietary exposure. 

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – oral DNEL (fertility)

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

 

2.5

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

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

1

No AF necessary as exposure for70 days prior to mating, and throughout mating, pregnancy and weaning

Dose response and endpoint specific/severity issues

1

Default ECHA AF; no adverse effects on fertility outcomes at highest tested dose in well-conducted one-generation reproductive toxicity study

Quality of whole database

2

ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high. However, as the 2-generation and multi-generation reproduction studies were carried out on a closely-related surrogate (the simple salts of EDTA) it was felt health precautionary to include an AF of 2.

Overall AF for general population

 

200

 

General population-DNEL (fertility)long-term for oral route-systemic= 571 mg/kg bw/day/ 200 = 2.9mg/kg bw/day

Overall, as this oral DNEL(fertility) is higher than the oral DNEL for repeated dose effects (1.23 mg/kg bw/day), the long-term oral general population-DNEL for systemic effects is considered protective of fertility impairment.

 

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 700 mg/kg bw/day [equivalent to about 571 mg EDDS acid/kg bw/day] has been seen in a one-generation reproduction study in rats following repeated dietary exposure. 

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 an inhalation DNEL (fertility) from oral studies was considered suitable (no high first-pass metabolism has been reported or is expected).

Only about 5% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following a single gavage administration(Ferdinandi, 1995). A health precautionary approach is to assume 100% absorption following inhalation. Therefore, the starting point has been corrected to reflect 5% oral absorption and 100% inhalation absorption. Thus, 571 mg/kg bw/day / 20 = 28.6 mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m3/kg bw for 24 h/day. Thus, 28.6 mg/kg bw/day / 1.15 m3/kg bw/day = 24.9 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

 

 

 

2.5

Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

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

1

No AF necessary as exposure for70 days prior to mating, and throughout mating, pregnancy and weaning

Dose response and endpoint specific/severity issues

1

Default ECHA AF; no adverse effects on fertility outcomes at highest tested dose in well-conducted one-generation reproductive toxicity study

Quality of whole database

2

ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high. However, as the 2-generation and multi-generation reproduction studies were carried out on a closely-related surrogate (the simple salts of EDTA) it was felt health precautionary to include an AF of 2.

Overall AF for general population

 

50

 

General population-DNEL (fertility)long-term for inhalation route-systemic= 24.9 mg/m3/ 50 = 0.5 mg/m3.

Overall, as this inhalation DNEL (fertility) is higher than the inhalation DNEL for repeated dose effects (0.21 mg/m3), the long-term inhalation general population-DNEL for systemic effects is considered protective against fertility impairment.

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 700 mg/kg bw/day [equivalent to about 571 mg EDDS acid/kg bw/day] has been seen in a one-generation reproduction study in rats following dietary exposure. 

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 studies was considered suitable (no high first-pass metabolism has been reported or is expected).

About 11% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following dermal application and about 5% following single gavage(Ferdinandi, 1995). Therefore,it is appropriate to correct the starting point for differences in dermal (11%) and oral (5%) absorption, thus 571 mg/kg bw/day x (5 / 11) = 259.6 mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – dermal DNEL (fertility)

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

2.5

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

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

1

No AF necessary as exposure for70 days prior to mating, and throughout mating, pregnancy, lactation and weaning

Dose response and endpoint specific/severity issues

1

Default ECHA AF; no adverse effects on fertility outcomes at highest tested dose in well-conducted one-generation reproductive toxicity study

Quality of whole database

2

ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high. However, as the 2-generation and multi-generation reproduction studies were carried out on a closely-related surrogate (the simple salts of EDTA) it was felt health precautionary to include an AF of 2.

Overall AF for general population

 

200

 

General population-DNEL (fertility)long-term for dermal route-systemic= 259.6 mg/kg bw/day / 200 = 1.3 mg/kg bw/day.

Overall, as this dermal DNEL(fertility) is higher than the dermal DNEL for repeated dose effects (0.56 mg/kg bw/day), the long-term dermal general population-DNEL for systemic effects is considered protective against fertility impairment.

Development DNEL

No information is available on developmental effects in humans. In a reliable study, a NOAEL of 551 mg/kg bw/day was derived for both maternal and developmental toxicity in rats given trisodium EDDS in the diet from day 6 to 15 of pregnancy (Denny, 1996a).Evidence of maternal toxicity (reduced body weight gain and food consumption) in the high-dose group (944 mg/kg bw/day) was observed. Also in the high dose group, mean gravid uterine weight was reduced, and there was a statistically significant increase in the number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio). Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures(Denny, 1996a). In another reliable study, NOAELs of 400 and 1000 mg/kg bw/day were derived for maternal and developmental toxicity, respectively, in groups of rats administered trisodium EDDS by oral gavage from day 6 to 15 of pregnancy (Denny, 1996b).

Oral DNEL (development)

Dose descriptor

There are no data available in humans relating to developmental effects following repeated oral exposure. A NOAEL of 551 mg/kg bw/day [equivalent to about 450 mg EDDS acid/kg bw/day] has been seen in a reliable developmental toxicity study in rats following dietary exposure covering the critical period of organogenesis (Denny, 1996a).

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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. General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – oral DNEL (development)

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

2.5

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

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

1

No AF necessary as developmental study covers critical period of organogenesis

Dose response and endpoint specific/severity issues

2

Default ECHA AF; no adverse effects at 551 mg/kg bw/day (diet) or, in another developmental study in rats, at up to 1000 mg/kg bw/day (gavage). However, in the dietary study, an increase inthe number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio) was seen. Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for general population

 

200

 

General population-DNEL (development)long-term for oral route-systemic = 450mg/kg bw/day / 200 = 2.25 mg/kg bw/day.

Overall, as this oral DNEL(development) is higher than the oral DNEL for repeated dose effects (1.23 mg/kg bw/day), the long-term oral general population-DNEL for systemic effects is considered protective against developmental effects.

 

Inhalation DNEL (development)

Dose descriptor

There are no data available in humans or laboratory animals relating to developmental effects following repeated inhalation exposure. A NOAEL of 551 mg/kg bw/day [equivalent to about 450 mg EDDS acid/kg bw/day] has been seen in a reliable developmental toxicity study in rats following dietary exposure (Denny, 1996a). 

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 an inhalation DNEL (developmental) from oral studies was considered suitable (no high first-pass metabolism has been reported or is expected).

Only about 5% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following a single gavage administration(Ferdinandi, 1995). A health precautionary approach is to assume 100% absorption following inhalation. Therefore, the starting point has been corrected to reflect 5% oral absorption and 100% inhalation absorption (i.e. 450 mg/kg bw/day / 20 = 22.5 mg/kg bw/day).

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m3/kg bw for 24 h/day. Thus, 22.5 mg/kg bw/day / 1.15 m3/kg bw/day = 19.6 mg/m3(24-h exposure of the general population).

ECHA AFs for general population – inhalation DNEL (development)

Uncertainty

AF

Justification for AF

Interspecies differences

1

 

 

 

2.5

Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above

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

1

No AF necessary as developmental study covers critical period of organogenesis

Dose response and endpoint specific/severity issues

2

Default ECHA AF; no adverse effects at 551 mg/kg bw/day (diet) or, in another developmental study in rats, at up to 1000 mg/kg bw/day (gavage). However, in the dietary study, an increase inthe number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio) was seen. Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for general population

 

50

 

General population-DNEL (development)long-term for inhalation route-systemic= 19.6 mg/m3/ 50 = 0.4 mg/m3.

Overall, as this inhalation DNEL(development) is higher than the inhalation DNEL for repeated dose effects (0.21 mg/m3), the long-term inhalation general population-DNEL for systemic effects is considered protective of developmental effects.

Dermal DNEL (development)

Dose descriptor

There are no data available in humans or laboratory animals relating to developmental effects following repeated inhalation exposure. A NOAEL of 551 mg/kg bw/day [equivalent to about 450 mg EDDS acid/kg bw/day] has been seen in a reliable developmental toxicity study in rats following dietary exposure (Denny, 1996a).

Mode-of-action

EDDS acid and its trisodium salt are considered to have only threshold effects, as the weight-of-evidence indicates that they do not possess 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 (developmental) from oral studies was considered suitable (no high first-pass metabolism has been reported or is expected).

Only about 11% of radiolabelled trisodium EDDS was considered absorbed after 72 h in rats following dermal application compared to about 5% following single gavage(Ferdinandi, 1995). Therefore,it is appropriate to correct the starting point for differences in dermal (11%) and oral (5%) absorption, thus 450 mg/kg bw/day x (5 / 11) = 205 mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – dermal DNEL (development)

Uncertainty

AF

Justification for AF

Interspecies differences

4

 

 

2.5

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

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

1

No AF necessary as developmental study covers critical period of organogenesis

Dose response and endpoint specific/severity issues

2

Default ECHA AF; no adverse effects at 551 mg/kg bw/day (diet) or, in another developmental study in rats, at up to 1000 mg/kg bw/day (gavage). However, in the dietary study, an increase inthe number of early resorptions and postimplantational losses (which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio) was seen. Foetuses in the high-dose group had a diverse range of external, visceral and/or skeletal malformations and developmental variations, affecting all the major organs and skeletal structures

Quality of whole database

1

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

Overall AF for general population

 

200

 

General population-DNEL (development)long-term for dermal route-systemic = 205 mg/kg bw/day / 200 = 1.03 mg/kg bw/day.

Overall, as this dermal DNEL(development) is higher than the dermal DNEL for repeated dose effects (0.56 mg/kg bw/day), the long-term dermal general population-DNEL for systemic effects is considered protective against developmental effects.