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- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
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- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
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- Nanomaterial pour density
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- Endpoint summary
- Stability
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- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1997
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Deviations:
- not specified
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.34 (One-Generation Reproduction Toxicity Test)
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- solid
- Details on test material:
- - Name of test material (as cited in study report): FeEDDHMANa (trade name: Boliken Fe)
- CAS nr: 84539-53-7
- EC nr: 283-041-9
- Chemical name: N,N'-Bis(2-hydroxy-4-methylphenyl)ethylendiamine diacetic acid, ferric-sodium complex.
- Physical state: Red brown powder
- Analytical purity: 100 % (UVCB)
- Lot/batch No.: 954243
- Storage condition of test material: At room temperature, dry in the dark
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: (P) Males: 4 weeks, Females 12 weeks
- Weight at study initiation (pre-mating period): (P) Males: 165-218 g, Females: 265-330 g
- Housing: individually, in polycarbonate cages containing purified sawdust bedding (Woody SPF, Type BK10/20 or during lactation Type 3-4 was supplied by B.M.I., Helmond, The Netherlands). During mating, 1 female was caged together with 1 male in suspended stainless steel cages with wire mesh floors.
- Diet: standard pelleted laboratory animal diet (Carfil Quality BVBA, Type R-03-18-K, Oud Turnhout, Belgium), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature: 21 °C
- Humidity: 55 %
- Air changes: 15 air changes/hour
- Photoperiod: 12 hours dark/12 hours light
IN-LIFE DATES: From: 13-Mar-1996 (males), 08-May-1996 (females) To: 09-Aug-1996 (males), 08-Aug-1996 (females)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations of the test item in water (w/w) were prepared daily immediately prior to dosing. Formulations were stirred prior to and during dosing procedures. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: overnight for a maximum of 7 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged individually in a cage with sawdust bedding material. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of dose formulations were collected during the beginning of treatment, at an intermediate time and during the end of the dosing period. Samples of the highest and lowest concentrations were analysed to check stability (first analysis only) and homogeneity. Accuracy of preparation was determined for all concentrations.
- Duration of treatment / exposure:
- Parental males were treated until days 122 to 138 of the treatment period.
Parental females were treated until days 48 to 65 post coitum. - Frequency of treatment:
- 1x/day
- Details on study schedule:
- - Age at mating of the mated animals in the study: 16 weeks
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 200 and 750 mg/kg bw/day
Basis:
nominal conc.
- No. of animals per sex per dose:
- 28 rats
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The dose level selection was based upon the information obtained from previous oral toxicity studies using rats, i.e. a 28-day oral toxicity study (LSR 87/AKB005/802) and a teratogenicity study (NOTOX 158759). - Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: once daily for clinical signs, twice daily for incidences of mortality
BODY WEIGHT:
- Time schedule: weekly for males and females
Mated females were weighed on days 0, 7, 14 and 20 of pregnancy and days 1, 7, 14 and 21 of the lactation period.
Live pups of one litter were weighed individually according to sex on the morning after birth (day 1) and on days 4, 7, 14 and 21 of the lactation period.
FOOD CONSUMPTION
- Time schedule: weekly for males and females
During the mating period analysis of food consumption was suspended.
Food consumption of mated females was measured during days 0-7, 7-14 and 14-20 of pregnancy and weekly thereafter starting on day 1 of the lactation period. - Oestrous cyclicity (parental animals):
- No data on estrous cyclicity are given in the report.
- Sperm parameters (parental animals):
- No data on sperm parameters are given in the report.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum
- Litters were adjusted to 4 pups/sex or as near as possible; excess pups were killed and discarded. Litters of less than 8 pups remained intact.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
For external and internal abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: all surviving animals
- Maternal animals: all surviving animals
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY
The following tissues were prepared and examined microscopically: cervix, coagulation gland, epididymides, ovaries, pituitary, prostate, seminal vesicles, testes, uterus and vagina. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed when weaned on day 21 of the lactation period.
- These animals were subjected to postmortem examinations as follows:
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. All animals were sexed. - Statistics:
- For assumed normally distributed variables, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control group.
The Steel-test (many-to-one rank test) was applied instead of the Dunnett-test if the data were assumed not to be normally distributed.
The exact Fisher-test was applied if the variables could be dichotomised without loss of information.
All tests were two-tailed. - Reproductive indices:
- Fertility index, conception index, gestation index, sex ratio (F1)
- Offspring viability indices:
- Live birth index, viability index, weaning index and overall survival index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- 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
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
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.
Effect levels (P0)
open allclose all
- 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
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day
- 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.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
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.
Effect levels (F1)
- 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 'Remark'
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
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.
Applicant's summary and conclusion
- Executive summary:
In a one-generation reproduction toxicity study (NOTOX B.V., 1997), FeNa-EDDHMA 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).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

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