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EC number: 416-530-4 | CAS number: 178949-82-1
- 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
- Flammability
- 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
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 17 February to 12 March 1994
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- treated to gestation day 15, not up to 1 day before birth
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 416-530-4
- EC Name:
- -
- Cas Number:
- 178949-82-1
- Molecular formula:
- C10H13N2Na3O8
- IUPAC Name:
- trisodium 2-({2-[(1-carboxy-2-carboxylatoethyl)amino]ethyl}amino)butanedioate
- Details on test material:
- - Name of test material (as cited in study report): trisodium EDDS (under code)
- Substance type: technical product
- Physical state: clear yellow liquid
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable for greater than study period
- Storage condition of test material: room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Sprague-Dawley derived Crl:CD VAF/Plus
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan, USA
- Age at study initiation: 12.5 weeks
- Weight at study initiation: 229-302 g
- Fasting period before study: no data
- Housing: individually (except when mating) in stainless steel, wire-mesh cages
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 10 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-25
- Humidity (%): 40-45
- Air changes (per hr): "environmentally controlled"
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 17 February To: 12 March 1994
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): powdered diet (mixed with an aliquot of diet which was then added to the bulk of diet and mixed)
- Storage temperature of food: no data
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- No data in report, samples sent to sponsor for analysis
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: no data
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no - Duration of treatment / exposure:
- gestation day 6-15
- Frequency of treatment:
- ad libitum (in diet)
- Duration of test:
- gestation day 0-20
- No. of animals per sex per dose:
- 34 females per group (4 animals/group were killed on gestation day 16 and blood sampled for levels of copper, zinc and iron)
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: based on a previous range-finding study
- Rationale for animal assignment (if not random): the order in which the animals were assigned corresponded to the day the copulatory plug was observed and the order of appearance on the breeding record. First mated female was assigned to the first group, the second mated female to the second group, and all the remaining animals were assigned in this manner until the required number of mated females had been placed into each group.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily throughout study; daily on gestational days 6 to 20.
- Cage side observations: mortality and signs of overt toxicity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 9, 10, 12, 16 and 20
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus in detail (see below); thoracic and abdominal cavities and organs subjected to gross examination for morphological changes
OTHER: four rats in each group were killed on gestation day 16 and blood samples were analysed for zinc, copper and iron. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: foetal weights - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No - Statistics:
- Analysis of variance, Bartlett's test for homogeneity of variance and t-tests to determine the significance of differences in body weights, food consumption, mean numbers of corpora lutea, total implantations, live foetuses, gravid uterine weight and mean foetal body weights. Male to female sex ratios and proportions of litters with malformations and developmental variations were compared using the Chi-square or Fisher's test for homogeneity of R x C contingency tables to determine the significance of differences. The proportions of resorbed and dead foetuses and postimplantational losses were compared using the Kruskal-Wallis test.
- Indices:
- - Pregnancy index = No. females pregnant/ No. females mating
- Preimplantation loss = (No. corpora lutea ¿ No. implantations)/No. corpora lutea
- Postimplantation loss = (No. implantations ¿ No. viable foetuses)/ No. implantations - Historical control data:
- Historical control data is tabulated as an appendix to the report
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- No maternal deaths occurred and no treatment related gross changes were observed. A statistically significant reduction in food consumption and body weight gain was noted for the high-dose group, as compared with the control group, during the entire dosing period, gestation days 6-15. A dose-dependent reduction in blood zinc levels was seen (which reached statistical significance at 551 mg/kg bw/day and above). Iron and copper levels were decreased in the high-dose groups, but this did not reach statistical significance. Mean gravid uterine weight for the high-dose group was significantly reduced.
There was a statistically significant increase in postimplantational losses in the high-dose group, which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio. The number of early resorptions was statistically significantly higher in the high-dose group.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 551 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- pre and post implantation loss
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Foetal body weights were significantly reduced in the high-dose group compared to the control group.
Gross malformations
A statistically significant increase in the following malformations was observed in the high dose group when compared with the incidence in the control group, (foetal incidence % control: foetal incidence % high-dose group): cleft palate (0:63), adactyly (0:33), microphthalmia (0.2:22), short lower jaw (0:21), microcephaly (0:3), anal atresia (0.2:8), malformed anal opening (0:4), omphalocele (0:3), gastroschisis (0:2.5), malformed genital tubercle (0:1.5), ectrodactyly (0:33), syndactyly (0:19), micromelia (0:11), short tail (0:5.3), bent tail (0:43), and short, bent tail (0:30). Some additional malformations were observed in the high-dose group at an incidence level above that in the control group but were not statistically significant. The numbers and type of malformations observed in the low- and mid-dose groups were similar to control levels.
In addition, subcutaneous white discolouration in the dorsal cervical and thoracic regions was observed only in the high-dose group (3.5% incidence, compared to none in the controls).
Soft tissue malformations:
Visceral examination revealed a statistically significant increase in the incidence of the following malformations in the high dose group as compared with the control group (foetal incidence % control: foetal incidence % high-dose group): short lower jaw (0:16), cleft palate (0:10), confirmed cleft palate (0:66), anophthalmia (0.4:5.2), confirmed microphthalmia (0:14), folded retina (0:14), malformed lens (0:7), internal hydrocephaly (0.4:21), malformed brain (0:3), syringomyelia (0:4), pulmonary hypoplasia and aplasia (both 0:82), malformed stomach (0:54), renal hypoplasia, malformed kidney (0:4), omphalocele (0:4), malformed intestine (0:5), malformed testes (0:7), malformed epididymis (0:5), malformed vas deferens (0:5), malpositioned testis (0:11), malformed ovary (0:17) and cavitation of the urinary and reproductive tract (0:4). Some additional visceral malformations were observed in the high-dose group at a frequency greater than the control group but were not statistically significant.
Skeletal malformations:
The incidence of several skeletal malformations occurred at a statistically significantly increased level for the high-dose group as compared with the control group, and consisted of the following (foetal incidence % control: foetal incidence % high-dose group): subcutaneous calcification (0:5), malformed skull bones (0:24), cleft palate (0:63), mandibular micrognathia (0:17), fused nasal bones (0:13), tail malformation (0.4:87), vertebral and associated rib malformation (0.4:34), bent scapula (0:66), bent clavicles (0:15), fused sternebrae (0:57), shortened rib (0:31), malformed ribs (0:5), and increased incidence of bent/malformed/absent limb bones and digits.
Additional skeletal malformations were observed in the high-dose group, but were not statistically significant.
There were instances of malformed bones observed in foetuses from the control, low-and mid-dose groups, however, the incidence level for each occurrence was one to two foetuses and no dose related increase was noted and hence these were of doubtful toxicological significance.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 551 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- external malformations
- skeletal malformations
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- In a GLP study, conducted according to EPA Guidelines (OPPTS 870.3700), 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.
- Executive summary:
In a GLP study, conducted according to EPA Guidelines (OPPTS 870.3700), trisodium EDDS was assessed for its potential to cause maternal and developmental toxicity in Charles River rats.
Groups of 34 pregnant female rats were given trisodium EDDS in the diet at 0, 2000, 8000 or 16000 ppm (about 0, 132, 551 or 944 mg/kg bw/day based on food consumption) from gestation days 6 to 15. Four rats in each group were killed on gestation day 16 and blood samples were analysed for zinc, copper and iron. The remaining animals were killed on gestation day 20 and the dams examined for gross abnormalities and the uterus was examined for viable foetuses, early and late resorptions, number of implantations and corpora lutea. Foetuses were weighed and examined for external malformations and variations. About one-half of the foetuses were examined for soft-tissue effects and the remaining foetuses were examined for skeletal alterations.
Evidence of maternal toxicity in the high-dose group was seen as reduced body weight gain and food consumption. A dose-dependent reduction in blood zinc levels was seen (which reached statistical significance at 551 mg/kg bw/day and above). Iron and copper levels were decreased in the high-dose groups, but this did not reach statistical significance. Mean gravid uterine weight for the high-dose group was significantly reduced. There was a statistically significant increase in postimplantational losses in the high-dose group, which selectively reduced the numbers of live male foetuses, thus affecting the sex ratio. The number of early resorptions was statistically significantly increased in the high-dose group. 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. The whole developmental period was therefore affected by the test substance.
In conclusion, 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.
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