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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

For the assessment of toxicity to reproduction/fertility of Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe), the read-across approach was applied using data from a reproduction toxicity study conducted with the test item Acetic acid, oxo-, sodium salt, reaction products with cresol and ethylenediamine, iron sodium salts (FeNa-EDDHMA, CAS 84539-53-7, EC 283-041-9). The substances are structural analogues and have similar physicochemical properties and are therefore assumed to have similar (eco)toxicity profiles. Further justification is included as attachment in section 13 of IUCLID.

In a key one-generation reproduction toxicity study (NOTOX B.V., 1997) performed with the test item FeNa-EDDHMA in rats, the NOAEL for reproductive performance/fertility was established at 200 mg/kg bw/day based on a slight decrease in the conception indices and a minimal delay in precoital time noted at the high dose level of 750 mg/kg bw/day. In agreement with the read-across approach, this NOAEL is considered to represent a reliable key value for chemical safety assessment of MEAHA-Fe.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
In the 750 mg/kg bw/day group, 1/28 males and 4/28 females died during the study. At this dose level, hunched posture, piloerection and emaciated and/or pale appearance were noted. A few males of the 200 mg/kg bw/day group showed hunched posture.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight gain and food consumption were decreased in animals of both sexes at 750 mg/kg bw/day and in males at 200 mg/kg bw/day. This decrease was dose-related. During the lactation period, body weight gain of females at 750 mg/kg bw/day showed a marked increase. Body weight ratios were decreased during the first 5 weeks of treatment for males and during the first 3 weeks for females at 750 mg/kg bw/day.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
In the absence of concomitant histopathological findings, a slight decrease of the fertility and conception indices was noted at 750 mg/kg bw/day.

GROSS PATHOLOGY (PARENTAL ANIMALS)
There were no test item-related macroscopic findings at necropsy.

HISTOPATHOLOGY (PARENTAL ANIMALS)
There was no histopathological evidence of toxicity or infertility.
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity: based on clinical signs, incidences of mortality, and changes in body weight and food consumption at higher dose levels
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reproductive toxicity, fertility: based on a slight decrease in the conception indices and a minimal delay in precoital time at 750 mg/kg bw/day.
VIABILITY (OFFSPRING)
An increased mortality rate during post natal days 0-4 was seen at 200 and 750 mg/kg bw/day. A slight increase was noted at 50 mg/kg bw/day as well. The majority of the post natal loss was attributable to a few litters of each group, including 1, 3 and 3 litters in the low, mid and high dose groups, respectively. For further details, please refer to the table in the section "Any other information on results incl. tables".

CLINICAL SIGNS (OFFSPRING)
There were no unexpected clinical signs seen among pups of any dose group.

BODY WEIGHT (OFFSPRING)
Reduced body weights were noted during days 4 to 21 of lactation in pups of the high dose group (750 mg/kg bw/day).

GROSS PATHOLOGY (OFFSPRING)
There were no test item related macroscopic findings.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'remarks'
Reproductive effects observed:
not specified

POSTNATAL LOSS AND VIABILITY

 

Endpoint

Dose Group [mg/kg bw/day]

 

0

50

200

750

 

Dams with total litter loss at FLC [n]

1

0

0

0

(Pups lost [n])

(13)

 

 

 

Dead pups at FLC [n]

19

3

5

3

(Litters [n])

(5)

(3)

(3)

(1)

Postnatal loss PND 0-4 [n]

2

21

39

39

(Litters [n])

(1)

(7)*

(7)

(6)

Viability index (%)

99.4

94.9

90.4

85.4

 

 

 

 

 

FLC: first litter check

*: including 1 female with total pup loss (15/15)

 

CHEMICAL ANALYSIS

For the nominal concentrations of 0, 10, 40 and 150 mg/g, the concentrations analysed were in agreement with the concentrations prepared in this study. The test item was found to be mixed homogeneously through the vehicle and to be stable for 4 hours at ambient temperature.

Executive summary:

In a one-generation reproduction toxicity study (NOTOX B.V., 1997), the structural analogue FeNa-EDDHMANa in distilled water was administered to 28 Wistar rats/sex/dose level by single oral gavage (5 mL/kg bw) at dose levels of 50, 200 or 750 mg/kg bw/day. A concurrent control group was treated with the vehicle only. Treatment commenced 10 weeks prior to mating for males and 2 weeks prior to mating for females and continued for both sexes until at least the end of the lactation period. Pregnant females were allowed to litter normally. On day 4 of lactation, each litter was adjusted to 4 males and 4 females or as near as possible. The surviving offspring was euthanised as soon as possible after weaning.

The primary effect of treatment with the test item on parental animals was poor physical condition, resulting in premature mortality, growth reduction and reduced food consumption in male and female animals at 750 mg/kg bw/day. These signs of test item-related toxicity were seen with reduced severity at 200 mg/kg bw/day in males only. Thus, the NOAEL for systemic toxcity in parental animals was 50 mg/kg bw/day under the conditions of this study.

In the offspring, increased post natal loss and reduced viability were noted during PND 0 -4 at 200 and 750 mg/kg bw/day, and with lower incidence at 50 mg/kg bw/day. With special regard to the low incidence and unusual distribution pattern of findings noted at 50 mg/kg bw/day, the NOAEL for developmental toxicity was 50 mg/kg bw/day under the conditions of this study.

Based on a slight decrease in the conception indices and a minimal delay in precoital time at 750 mg/kg bw/day, the NOAEL for reproductive performance/fertility was 200 mg/kg bw/day.

This study is acceptable and satisfies the guideline requirement for a one-generation reproduction toxicity study (OECD 415).

Based on the structural similarity, the similar physico-chemical properties, similar predicted toxicokinetic behavior and the similar acute oral and local toxicity profiles between FeNa-EDDHMA and MEAHA-Fe, identical conclusions are drawn for the read-across target MEAHA-Fe.

Effect on fertility: via oral route
Dose descriptor:
NOAEL
200 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a one-generation reproduction toxicity study (NOTOX B.V., 1997), FeNa-EDDHMA was administered to 28 Wistar rats/sex/dose level by single oral gavage at dose levels of 50, 200 or 750 mg/kg bw/day. A concurrent control group was treated with the vehicle only. Treatment commenced 10 weeks prior to mating for males and 2 weeks prior to mating for females and continued for both sexes until at least the end of the lactation period. Pregnant females were allowed to litter normally. On day 4 of lactation, each litter was adjusted to 4 males and 4 females or as near as possible. The surviving offspring was euthanised after weaning.

The primary effect on parental animals was poor physical condition, resulting in premature mortality, growth reduction and reduced food consumption in both sexes at 750 mg/kg bw/day. These signs were seen with reduced severity at 200 mg/kg bw/day in males only. Thus, the NOAEL for systemic toxicity in parental animals was 50 mg/kg bw/day under the conditions of this study.

In the offspring, increased post-natal loss and reduced viability were noted during PND 0 -4 at 200 and 750 mg/kg bw/day, and with lower incidence at 50 mg/kg bw/day. With special regard to the low incidence and unusual distribution pattern of findings noted at 50 mg/kg bw/day, the NOAEL for developmental toxicity was 50 mg/kg bw/day under the conditions of this study.

Based on a slight decrease in the conception indices and a minimal delay in precoital time at 750 mg/kg bw/day, the NOAEL for reproductive performance/fertility was 200 mg/kg bw/day

Data Waiving for 2 -generation study:

The performance of a two-generation reproductive toxicity study is scientifically unjustified.

No evidence of reproduction toxicology is seen in any tests available. A one-generation study with a read across substance (FeEDDHMANa) and a developmental toxicity study with FeNaEDDHA administered via oral application are available. No signs of reproduction and developmental toxicity were found in both studies at concentration with maternal toxicity. In the developmental toxicity study no adverse effects on development were observed at all up to an exposure level of 500 mg/kg bw/day.

In two repeated dose toxicity studies with oral administration (28-day and 90 day exposure) and in one 28-day repeated dose dermal toxicity study, no adverse effects on the reproduction organs were seen (no organ weight changes and no adverse histopathological findings).

In summary, it is very unlikely that FeNaEDDHA will cause adverse reproductive and/or developmental toxicity effects in concentrations without maternal systemic toxicity in a two-generation reproductive toxicity study and conducting such a study is thus scientifically not justified. The available one-generation study (read across) and developmental toxicity study are sufficient for hazard assessment and risk characterisation.

Effects on developmental toxicity

Description of key information

For the assessment of developmental toxicity of Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe), the read-across approach was applied using data from a reproduction toxicity study conducted with the test item Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts (FeNa-EDDHA, CAS 84539-55-9, EC 283-044-5). The substances are structural analogues and have similar physicochemical properties and are therefore assumed to have similar (eco)toxicity profiles.

Further justification is included as attachment in section 13 of IUCLID.

In a key developmental oral toxicity study (CIBA-GEIGY Limited, 1995) with FeNa-EDDHA in rats, the NOEL for developmental effects was established at the high dose level of 500 mg/kg bw/day based on the absence of embryo-/foetotoxic or teratogenic effects.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There was a reduction in mean food consumption and body weight gain during the second half of the dosing period at 500 mg/kg bw/day.
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no indication for test item related embryotoxicity or teratogenic effects under the conditions of this study.
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Executive summary:

In a developmental toxicity study (CIBA-GEIGY, 1995), FeNa-EDDHA was administered once daily to groups of 24 mated female Sprague-Dawley derived rats by oral gavage at dose levels of 5, 100 or 500 mg/kg bw/day (10 mL/kg bw) from day 6 through day 15 of gestation. Control group females received the vehicle, 0.5 % (w/w) CMC in distilled water, only. The nominal concentrations, homogeneity and stability of the test item in the vehicle were confirmed by chemical analysis of dose formulations. All dams were sacrificed on day 21 of the gestation period and foetuses removed for examination. In dams, there were no treatment-related clinical signs or incidences of mortality. The body weight gain was reduced at 500 mg/kg bw/day for the period from days 6 -16 of gestation, and reduced food consumption was also noted at this dose level. No adverse effects on pregnancy and no embryo-/foetotoxic effects were observed. There was no indication of teratogenic potential. On the basis of these results, the NOEL was 100 mg/kg bw/day for maternal toxicity and 500 mg/kg bw/day for develomental toxicity and teratogenicity.

The developmental toxicity study in the rat is classified as acceptabel and satisfies the requirements of test guideline OECD 414.

Based on the structural similarity, the similar physico-chemical properties, similar predicted toxicokinetic behavior and the similar acute oral and local toxicity profiles between FeNa-EDDHA and MEAHA-Fe, identical conclusions are drawn for the read-across target MEAHA-Fe.

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
500 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a developmental toxicity study FeNa-EDDHA, CGA 65047 SG 100 (A-5787 A) was administered once daily to groups of 24 mated female Sprague-Dawley derived rats by oral gavage at 5, 100 or 500 mg/kg bw/day from day 6 through day 15 of gestation. Control group females received the vehicle only. All dams were sacrificed on day 21 of the gestation period and foetuses removed for examination. In dams, there were no treatment-related clinical signs or incidences of mortality. The body weight gain was reduced at 500 mg/kg bw/day for the period from days 6 -16 of gestation, and reduced food consumption was also noted at this dose level. No adverse effects on pregnancy and no embryo-/foetotoxic effects were observed. There was no indication of teratogenic potential. On the basis of these results, the NOEL was 100 mg/kg bw/day for maternal toxicity and 500 mg/kg bw/day for developmental toxicity and teratogenicity.

Justification for classification or non-classification

In the assessment of Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe), a read-across approach is followed based on the information available for Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts (FeNa-EDDHA, CAS 84539-55-9, EC 283-044-5) and Acetic acid, oxo-, sodium salt, reaction products with cresol and ethylenediamine, iron sodium salts (FeNa-EDDHMA, CAS 84539-53-7, EC 283-041-9). The substances are structural analogues and have similar physiochemical properties and are therefore assumed to have similar (eco)toxicity profiles.

The test item FeNa-EDDHA caused no developmental toxicity and no teratogenicity in the rat in a key developmental toxicity study according to test guideline OECD 414.

Effects on reproductive performance/fertility were assessed by means of a read-across approach using a one generation toxicity study according to test guideline OECD 415 conducted with the structural analogue FeNa-EDDHMA. Only a slight change in reproductive performance was noted in this study at 1000 mg/kg bw/day. In the absence of concomitant histopathological findings, this slight change in reproductive performance was considered to be secondary to the poor clinical condition of the animals at this dose level. Similarly, developmental effects were seen in this study at dose levels at pronounced maternal toxicity only.

Accordingly, MEAHA-Fe is not subject to classification for toxicity to reproduction according to Directive 67/548/EEC and Regulation 1272/2008/EC.