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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.987 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
24.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified.
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

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.” Additionally, Manual for the Simple European Calculator Of DNELs (SECO DNEL Tool 1.0., 2016) was instructed.

Available dose descriptors:

For o,o-Fe(Na)EDDHA, the following dose descriptors are available:

Acute/short-term exposure - systemic effects

According to REACH regulation and the ECHA guidance (Chapter R.8), a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, the source substance UVCB Fe(Na)EDDHA displays low acute toxicity as evidenced by LD50 values of >2000 mg/kg bw determined in rats for both the oral ((CIBA-GEIGY, 1993; Report No. 931140) and the dermal route (Hempstock, 1996, Report No. 003/082; CIBA-GEIGY, 1993, Report No. 931141), and a LC50 value of > 4200 mg/m³ determined in rats for the inhalation route (CIBA-GEIGY, 1993, Report No. 931142). Therefore, the target substance o,o-Fe(Na)EDDHA is not subject to classification for acute toxicity according to Regulation 1272/2008/EC, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, the source substance UVCB Fe(Na)EDDHA is not subject to classification for skin, eye and/or respiratory irritation (and sensitisation) and skin sensitisation and therefore no worker DNEL for local effects following acute/short-term or long-term exposure is derived. The long-term dermal DNEL for systemic effects covers sufficiently local effects.This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".

Long-term exposure – systemic effects (dermal DNEL)

For the dermal route, the NOAEL of 100 mg/kg bw/day from the key subacute repeated dose dermal toxicity study (CIBA-GEIGY, 1996, Report No. 941103) is regarded as the relevant dose descriptor for systemic effects associated with long-term exposure to the source substance Fe(Na)EDDHA. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted.

Long-term exposure – systemic effects (inhalation DNEL)

For the inhalation route, the NOAEL of 10 mg/kg bw/day from the key subchronic oral toxicity study (Novartis Crop Protection AG, 1998) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to FeNaEDDHA. NOAEL of 10 mg/kg bw was estimated from the LOAEL (please refer to the respective section of the UCLID file or to section “Repeated dose toxicity” for more detailed information), while NOEL of 5 mg/kg bw was established by the study director (Novartis Crop Protection AG, 1998).

In this study, treatment with the test item resulted in lower food intake and impaired body weight development of rats treated at 200 mg/kg bw/day. Reversible effects on the red blood cell (normochromic anaemia) and white blood cell parameters, and higher values of platelets and prothrombin activity were noted at 50 and/or 200 mg/kg bw/day. In addition, there were changes of blood chemistry and urine parameters concerning the liver and kidneys. The body weight relative heart weight was increased in males at 200 mg/kg bw/day.

Modification of the starting point:

DNELs are derived based on the available toxicity data for the source substance UVCB Fe(Na)EDDHA, reflecting the routes, the duration and the frequency of exposure.

Bioavailability (absorption)

There is no substance-specific experimental information on absorption by the oral, dermal and inhalation routes available. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies conducted with the source substance UVCB Fe(Na)EDDHA. Due to the negative logPowand high water solubility, absorption by oral route is considered to be low for the target substance since physico-chemical properties of the substance are not in range suggestive of absorption from the gastro-intestinal tract (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). However, due to systemic effects observed in the 28-day and 90-day studies, and the NOAEL of 10 mg/kg bw, it is considered that oral absorption should be set to 100% for the purposes of DNEL derivation. The oral absorption is considered to be the same in animals and in humans (worst-case).

No significant dermal absorption is expected for the substance (molecular weight of 435.17 g/mol, negative log Powof and water solubility of 20 g/L point to a very poor absorption through the skin). According to the TGD, Part I, Appendix VI and ECHA guidance on toxicokinetic(ChapterR7.C., 2014), 10% of dermal absorption should be considered in this case. Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of the target chemical in humans is available.

Absorption by inhalation is considered to be negligible (low vapour pressure) and not to be higher than absorption by oral route. However, 100% absorption is assumed for inhalation route (worst case) for the purposes of DNEL derivation and is considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOAEC for systemic effects. The following formula was used: corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Exposure conditions:

A correction factor of 1.4 for differences in exposure conditions between animals and humans was applied in case of oral NOAEL that was used for derivation of inhalation DNEL. The animals were administered test substance 7 days a week, while workers are exposed 5 days a week (7/5=1.4).

A correction factor of 0.75 for differences in exposure conditions between animals and humans was applied in case of dermal NOAEL that was used for derivation of dermal DNEL. The animals were administered test substance 6 hours per day, while workers are exposed 8 hours per days (6/8 = 0.75). Animals and humans are exposed 5 days per week, thus an AF of 1 is appropriate (5/5 =1).

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the dermal NOAEL from 28 -day study, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the 90 -day study was used for the derivation of inhalation long-term DNEL;

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in both cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers.

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure in case of the 90-day study (sub-chronic to chronic) and an assessment factor of 6 was applied for duration of exposure (subacute-to-chronic) in case of the 28-day dermal study.

Quality of whole data base:

The assessment factors for uncertainties to the quality of the data base were used: 1 (GLP study is used).

Issues related to dose response:

A default assessment factor of 1 was applied when NOEL was used.

Calculation of DNELs:

Long-term exposure – systemic effects (dermal DNEL)

The dermal rat NOAEL of 100 mg/kg bw was converted into the corrected dermal NOAEL: Dermal NOAEL = dermal NOAEL x (ABSdermal-rat/ABSdermal-human) x (5/5 x 6/8) = 100 mg/kg bw x (10%/10%) x 0.75 = 75 mg/kg bw.

DNEL = 75 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 0.25 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 300.

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat NOAEL of 10 mg/kg bw was converted into the corrected inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinhal-human) x (6.7 m³/10 m³) = 10 mg/kg bw x (1/0.38 m³/kg/day) x (100%/100%) x (6.7/10) x 1.4 = 24.67 mg/m³

DNEL = 24.67 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 0.987 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.148 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):
50
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
7.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
29.8 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Value:
17.9 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
50 µg/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):
200
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption by oral route)

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account.

Standard respiratory volume of 1.15 m³ (24 hours) proposed in ECHA guidance is adjusted to 60-kg body weight for general population that results in 1.35 m³ according to SECO guidance (2016).

Exposure conditions

A correction factor of 1 is applied for differences between animal and human exposure conditions in case of oral rat NOAEL of 10 mg/kg bw that was used to derive inhalation and oral DNELs. The animals were exposed 7 days per week and exposure of general population is also considered to be 7 days per week (7/7).

A correction factor of 0.179 is applied for differences between animal and human exposure conditions in case of dermal NOAEL of 100 mg/kg bw that was used to derive dermal DNEL. Animals were exposed 6 hours per day and 5 days per week while general population can be exposed 24 hours per day and 7 days per week (6/24 x 5/7 = 0.179) (SECO guidance, 2016).

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNEL for general population

Long-term exposure – systemic effects (dermal DNEL)

The dermal rat NOAEL of 100 mg/kg bw was converted into the corrected dermal NOAEL: Dermal NOAEL = dermal NOAEL x (ABSdermal-rat/ABSdermal-human) = 100 mg/kg bw x (10 %/10%) x 0.179 = 17.9 mg/kg bw.

DNEL = 17.9 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 29.8 µg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 600.

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat NOAEL of 10 mg/kg bw was converted into the inhalation NOEC:

Inhalation NOEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinhal-human) = 10 mg/kg bw x (1/1.35 m³/kg/day) x (100 %/100 %) = 7.4 mg/m³

DNEL = 7.4 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 0.148 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 50.

Long-term exposure – systemic effects (oral DNEL)

The oral rat NOAEL of 10 mg/kg bw was not modified for differences in absorption by oral route since oral absorption is considered to be the same in rats and humans.

DNEL = 10 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 0.05 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 200.