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EC number: 205-187-4 | CAS number: 135-37-5
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive 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 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- not specified
- Principles of method if other than guideline:
- 2-generation 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 2,2',2''-nitrilotriacetate
- 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)
- Sex:
- male/female
- 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:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): ground Purina Chow - Details on mating procedure:
- 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 (see chapter 7.8.2 Developmental toxicity / teratogenicity).
The F1b generation were bred twice to bear the generations F2a and F2b.
The F2a generation was discarded at weaning.
The F2b generation was used for teratological studies (see chapter 7.8.2 Developmental toxicity / teratogenicity).
No further specification of the mating procedure.
Day of conception (day 0) was determined by vaginal smears. - 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
For each generation, records of individual weekly feed consumption and body-weight gain were kept during the first 8 wk from weaning. Afterwards, the parent rats were weighed at the beginning of each mating phase and no records of feed consumption were kept. - Duration of treatment / exposure:
- Continuously throughout two generations.
- Frequency of treatment:
- Continously feeding
- Details on study schedule:
- 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 (see chapter 7.8.2 Developmental toxicity / teratogenicity).
The F1b generation were bred twice to bear the generations F2a and F2b.
The F2a generation was discarded at weaning.
The F2b generation was used for teratological studies (see chapter 7.8.2 Developmental toxicity / teratogenicity).
No detailed description of mating and age of rats.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 0.1 and 0.5 %
Basis:
nominal conc.
approximately 90 and 450 mg/kg bw/day for adult female rats
- No. of animals per sex per dose:
- 20
- 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).
- Positive control:
- no
Examinations
- Parental animals: Observations and 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):
- 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 - Oestrous cyclicity (parental animals):
- not determined
- Sperm parameters (parental animals):
- not determined
- Litter observations:
- STANDARDISATION OF LITTERS
- All live-born litters were counted at birth and again 4 days later, when the pups were weighed and their sex determined.
- Maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded on day 4.
PARAMETERS EXAMINED
The following parameters were examined in [F1a / F1b / F2a] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, weight gain, lactation index, average weaning weight of pups per sex
GROSS EXAMINATION OF DEAD PUPS:
no; possible cause of death was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- No post mortem examinations of parental animals
GROSS NECROPSY
- No gross necropsy of parental animals
HISTOPATHOLOGY / ORGAN WEIGTHS
No microscopic examination of parental animals - Postmortem examinations (offspring):
- SACRIFICE
- No post mortem examinations of animals (exept for teratogenicity study, see 7.8.2)
GROSS NECROPSY
- No gross necropsy
HISTOPATHOLOGY / ORGAN WEIGTHS
No microscopic examination (exept for teratogenicity study, see 7.8.2) - Statistics:
- Significance test, analysis of variance, not further specified
- Reproductive indices:
- Conception in %
- Offspring viability indices:
- 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
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- But no significant differences in food efficiency (body weight gain per food intake)
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- But no significant differences in food efficiency (body weight gain per food intake)
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- no significant differences in the conception rate during the specific phases of the study and no significant differences in the measures of fertility
Details on results (P0)
Mean total food consumption (determined by week 8) at the high dietary level (0.5% Na3NTA) was somewhat less than in the control and in the low dietary level (0.1% Na3NTA) group in both sexes in the F0 generation and in the F1 males, statistically significantly different, however only for the F0 males.
Mean body weight gain in male and female rats of both generations was slightly reduced for the high dietary level (0.5 %) in comparison to either controls or to the 0.1% group, statistically significantly different, however only for F0 females and for F1 males.
No significant differences in food efficiency (body weight gain per food intake)
For detailed data see table 1.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No significant differences in the conception rate during the specific phases of the study and no significant differences in the measures of fertility.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction
- Effect level:
- >= 450 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no effects on reproduction
- Remarks on result:
- other: Generation: F0, F1
- Dose descriptor:
- NOEL
- Remarks:
- systemic
- Effect level:
- 90 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: Generation: all
- Remarks:
- slight effect on BW most probably due to palatability issues
Results: P1 (second parental generation)
Effect levels (P1)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction
- Effect level:
- >= 450 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no effects on reproduction
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 90 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: slight effects on BW most probably due to palatability issues
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- body weights of new born not reported, offspring weaning weights were reduced at 0,5% in both sexes.
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
Details on results (F1)
No significant differences in the following measures: average number of live-borns per litter, live pups on day 4, average number of weaned pups per culled litter, lactation index.
For details see table 2.
BODY WEIGHT (OFFSPRING)
not reported for new born.
Offspring weaning weights were reduced at the 0.5% level in both sexes, an effect observed in litters of the first breeding trials and statistically significant for the F1 generation only, but not consistent across successive breedings and/or across generations.
For some detailed data see table 1.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 90 mg/kg bw/day
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: slight changes in BW gain of weanlings most probably due to palatibility issues
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 90 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: slight changes in BW in weanlings most probably due to palatibility issues
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
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 2. Effect of 0.1 and 0.5 % dietary NTA on the reproductive performance and lactation of first- and second-generation rats (Continuous feeding of dietary levels)
Control | 0.1% | 0.5% | |||||
Parameter | Generation and litters | F1a+ F1b | F2a | F1a+ F1b | F2a | F1a+ F1b | F2a |
Conception (%) | 95.0 | 92.0 | 95.0 | 92.0 | 97.0 | 86.0 | |
No. of stillborn | 15.0 | 13.0 | 9.0 | 10.0 | 27.0 | 5.0 | |
Average no. born alive/litter | 11.3 | 12.3 | 11.9 | 12.3 | 11.9 | 12.2 | |
Average no. alive 4 days post partum | 11.1 | 11.1 | 11.3 | 10.9 | 11.0 | 11.3 | |
Average no. weaned/litter+ + | 7.2 | 7.0 | 7.1 | 6.5 | 7.3 | 7.6 | |
Lactation index§ | 96.3 | 96.3 | 94.4 | 96.6 | 96.0 | 96.3 | |
Average weaning weight of pups: | |||||||
Male | 54.3 55.4 | 49.9 | 51.9 53.2 | 49.1 | 48.3* 51.9 | 48.7 t | |
Female | 52.4 55.3 | 47.5 | 49.9 50.3 | 47.3 | 46.1* 50.4 | 46.6 |
++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).
Applicant's summary and conclusion
- Conclusions:
- No significant effects on reproduction at 450 mg/kg/d.
- Executive summary:
In a two-generation reproduction study Na3NTA was administered to 20 Sprague Dawley rats/sex/dose in dietary concentrations of 0, 0.1% and 0.5% (resp. daily intake for adult female rats approximately 90 and 450 mg/kg/d).
There were no significant differences in food efficiency. With respect to reproductive performance there were no significant differences in the conception rate during the specific phases of the study and no significant differences in the measures of fertility and lactation in terms of average numbers of live-borns per litter, live pups on p.n. day 4, average number of weaned pups per culled litter and in the lactation index. Body weights of the new-borns were not reported. Offspring weaning weights were reduced at the 0.5% level in both sexes, an effect observed in litters of the first breeding trials and statistically significant for the F1 generation only, but not consistent across successive breedings and/or across generations.
No examination of effects on reproductive parameters, testes weights or morphology, epididymal sperm counts, motility, or morphology, daily sperm production, efficiency of daily sperm production, or prostate or dorsal prostate weights or histopathology was performed.
The only effect of Na3NTA on rats in this study 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.
The study shows that Na3NTA, even at highly exaggerated levels, causes no deleterious effects on reproduction in rats.
This study meets generally acceptable scientific standards, is sufficiently documented and accepted for assessment.
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