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EC number: 225-768-6 | CAS number: 5064-31-3
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: meets generally acceptable scientific standards, well documented and accepted for assessment
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 971
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- not specified
- Principles of method if other than guideline:
- Developmental toxicity study in rats as part of a combined Reproduction and Teratology Studies
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Trisodium nitrilotriacetate
- EC Number:
- 225-768-6
- EC Name:
- Trisodium nitrilotriacetate
- Cas Number:
- 5064-31-3
- Molecular formula:
- C6H9NO6.3Na
- IUPAC Name:
- trisodium 2-[bis(carboxylatomethyl)amino]acetate
- Details on test material:
- - Name of test material (as cited in study report): Trisodium nitrilotriacetate
- Substance type: pure substance
- purity: not further specified
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
Rat study
- Charles River CD rats
- Housing: caged individually
- Diet (e.g. ad libitum): ground Purina Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 weeks (after weaning)
ENVIRONMENTAL CONDITIONS
carefully controlled environment
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): ground Purina Chow - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- NTA had been mixed to ground Purina Chow to yield the target concentrations
- Details on mating procedure:
- The original parent rats (F0) were bred three times to bear the generations F1a, F1b and F1c.
The F1a generation was discarded at weaning.
The F1c generation was used for teratological studies
The F1b generation were bred twice to bear the generations F2a and F2b (see chaptr 7.8.1 Toxicity to reproduction).
The F2a generation was discarded at weaning.
The F2b generation was used for teratological studies
No further specification of the mating procedure.
Day of conception (day 0) was determined by vaginal smears. - Duration of treatment / exposure:
- Groups of 20 female rats each were fed two dose levels continuously during each period of organogenesis (days 6-15 of pregnancy).
- Frequency of treatment:
- Continously feeding
- Duration of test:
- 10 dams sacrificed on day 13
10 dams sacrificed on day 21
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 0.1% and 0,5%
Basis:
nominal conc.
(corresponds approximately to: 90 and 450 mg/kg bw/day for the adult female rats)
- No. of animals per sex per dose:
- Groups of 20 pregnant rats were exposed to diet containing 0.1 respectively 0.5% Trisodium nitrilotriacetate
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Dose levels had been chosen from previous subacute and long-term studies, from which the lower level had been reported to be without any effect, whereas the 0.5% level had been reported to produce some mild toxicity (not further specified).
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: weekly feed consumption and body weight gain during the first 8 weeks from weaning
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes / No / No data
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food and feed efficiency (%): Yes
Feed efficiency = body-weight gain/feed consumed × 10
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
POST-MORTEM EXAMINATIONS: No data - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: No data
- Number of early resorptions: No data
- Number of late resorptions: No data - Fetal examinations:
- Ten dams of each group were sacrificed on day 13 of gestation, respectively on day 21 of gestation:
1) In dams sacrificed on day 13 of gestation the numbers of corpora lutea, implantations and resorptions were recorded.
2) Fetuses removed from dams sacrificed on gestation day 21 were inspected for gross abnormalities, weighed and their sex determined and further investigated for skeletal and visceral defects. - Statistics:
- Significance test, analysis of variance, not further specified
- Indices:
- Conception in %
Average no. born alive / litter
Average no. alive 4 days post partum
Average no. weaned / litter
lactation index = no. of pups weaned/no. alive at 4 days after litters reduced × 100
average weaning weight of pups per sex - Historical control data:
- no data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no data
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 90 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 450 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects. Remark: oft tissue defects predominantly in the urinary system (hydroureter and /or hydronephrosis) were detected in all groups including control group and were attributed to some unknown agent, possibly a virus
Details on embryotoxic / teratogenic effects:
No differences were observed in the dams of either of the two treatment groups in comparison to controls with respect to food consumption and body weight gain. Dams sacrificed on day 13 of gestation did not differ significantly from those sacrificed at day 21 of gestation in the number of corpora lutea, implantations or resorptions. Overall, the treatment groups did not differ significantly from control groups with respect to average number of corpora lutea, resorptions, live or dead fetuses or in the average weight of male and female fetuses.
Fetal evaluation for abnormalities did not reveal any skeletal defects.
Soft tissue defects predominantly in the urinary system (hydroureter and /or hydronephrosis) were detected, however, the control groups of both generations were affected as much as any of the experimental groups. The authors therefore suggested that these effects were attributable to some unknown agent, possibly a virus.
For some detailed data see table 5.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 450 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects on fetuses
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1: Effect of feeding 0.1 and 0.5% dietary Na3NTA on the growth, feed consumption and feed efficiency of first- and second-generation rats
Gain in body weight (g) by wk 8 | Total feed consumed (g) by wk 8 | Feed efficiency (%) | ||||||||||
Generation | ||||||||||||
male | female | male | female | male | female | |||||||
Treatment | F0 | F1b | F0 | F1b | F0 | F1b | F0 | F1b | F0 | F1b | F0 | F1b |
Control | 359 | 322 | 205 | 137 | 1261 | 1463 | 943 | 956 | 28,5 | 22,3 | 21,7 | 14,5 |
0.1 % NTA | 356 | 311 | 200 | 141 | 1285 | 1405 | 926 | 1003 | 27,7 | 22,3 | 21,5 | 14,2 |
0.5 % NTA | 335 | 284* | 188* | 133 | 1191 t | 1398 | 891 | 1018 | 28,2 | 20,7 | 21,2 | 13,4 |
Values are means of groups of 20 rats. Those marked with an asterisk differ significantly (Analysis of Variance) from those of controls: *P >= 0,05. That marked with a dagger differs significantly from the group fed 0,1% NTA: t P <= 0,05 |
Table 3. Effect of 0.1 and 0.5 % dietary NTA on the reproductive performance and lactation of first- and second-generation rats (Feeding on days 6-15 of each pregnancy)
Control | 0,1% | 0,5% | |||||
Parameter | Generation and litters | F1a+ F1b | F2a | F1a+ F1b | F2a | F1a+ F1b | F2a |
Conception (%) | 95,0 | 92,0 | 82,0 | 100,0 | 93,0 | 92,0 | |
No. of stillborn | 15,0 | 13,0 | 15,0 | 5,0 | 17,0 | 5,0 | |
Average no. born alive/litter | 11,3 | 12,3 | 11,9 | 12,2 | 11,7 | 13,4 | |
Average no. alive 4 days post partum | 11,1 | 11,1 | 11,4 | 11,4 | 10,9 | 10,8 | |
Average no. weaned/litter+ + | 7,2 | 7,0 | 7,5 | 7,5 | 7,6 | 7,9 | |
Lactation index§ | 96,3 | 96,3 | 96,2 | 98,3 | 97,9 | 99,3 | |
Average weaning weight of pups: | |||||||
Male | 54,3 55,4 | 49,9 | 52,9 53,0 | 53,2 | 51,4 51,3 | 52,2 | |
Female | 52,4 55,3 | 47,5 | 50,8 51,0 | 5,3 | 49,6 48,2 | 49,5 |
++Litters containing more than eight pups were reduced to that number on day 4. §No. of pups weaned/no, alive at 4 days after litters reduced × 100. Values marked with an asterisk are significantly less (Analysis of Variance) than those of controls (*P <= 0,05) and that marked with a dagger is significantly less than that for the group fed 0.1 % NTA on days 6-15 of gestation (t P <= 0,05). |
Table 5: Incidence and distribution or foetal abnormalities observed in rats fed 0.1 and 0.5% Trisodium nitrilotriacetate in dietry on
days 6 -15 of each pregnancy
Control | 0.1 % | 0.5 % | ||||
Parameter | F1c | F2b | F1c | F2b | F1c | F2b |
No. of foetuses examined for skeletal defects* | 17 | 45 | 22 | 27 | 34 | 35 |
No. of foetuses examined for soft-tissue defects | 36 | 98 | 42 | 64 | 74 | 79 |
No. of abnormal foetuses | 9 | 16 | 8 | 8 | 10 | 7 |
Incidence of soft-tissue defects t: | ||||||
Total | 25 | 16 | 19 | 13 | 12 | 9 |
Hydroureter | 17 | 16 | 17 | 13 | 10 | 9 |
Hydronephrosis | 3 | – | – | – | – | – |
Distended bladder | 6 | – | 2 | – | 3 | – |
Folded retina | – | – | – | – | – | – |
Umbilical hernia | – | – | – | – | 1,0 | – |
Cleft lip | – | – | 2 | – | – | – |
Cleft palate | – | – | – | – | – | – |
* No skeletal defects found.
t A foetus may have had more than one defect, thus the percentages of the individual anomalies may not equal the total incidence.
Applicant's summary and conclusion
- Conclusions:
- No significant effects on embryonic development at dose levels up to 450 mg/kg/d.
- Executive summary:
In a developmental toxicity study Na3NTA was administered to female Charles River CD rats in dietary concentrations of 0, 0.1% and 0.5% (resp. daily intake for the adult female rats approximately 90 and 450 mg/kg bw / day) from days 6 through 15 of gestation.
No differences were observed in the dams of either of the two treatment groups in comparison to controls with respect to food consumption and body weight gain. Dams sacrificed on day 13 of gestation did not differ significantly from those sacrificed at day 21 of gestation in the number of corpora lutea, implantations or resorptions. Overall, the treatment groups did not differ significantly from control groups with respect to average number of corpora lutea, resorptions, live or dead fetuses or in the average weight of male and female fetuses. Fetal evaluation for abnormalities did not reveal any skeletal defects. Soft tissue defects predominantly in the urinary system (hydroureter and /or hydronephrosis) were detected, however, the control groups of both generations were affected as much as any of the experimental groups. The effects must be attributable to some unknown agent, possibly a virus.
The only effect of Na3NTA on rats was some growth depression in both adult and weanling animals fed the 0-5% level continuously. This effect was probably due mostly to a reduced palatability of the feed, since no such depression was seen in the weights of foetuses removed by Caesarean-section or in the weights of 4-day-old liveborn animals.
Thus the study shows that Na3NTA, even at highly exaggerated levels, causes no deleterious effects on embryonic development in rats.
The developmental toxicity study in the rat is classified acceptable, sufficienty documented and satisfies main guideline requirements for a developmental toxicity studies in rats.
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