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- Life Cycle description
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- Appearance / physical state / colour
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- Endpoint summary
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- Environmental data
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- 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
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- Sediment toxicity
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- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
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- Additional toxicological data

Toxicity to reproduction
Administrative data
- Endpoint:
- three-generation reproductive toxicity
- Remarks:
- based on generations indicated in Effect levels (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 29.10.1976 to 15.08.1978
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 979
- Report date:
- 1979
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Three generation reproduction toxicity study with the following restrictions: no assessment of estrus cycle, sperm parameters, sexual milestones, no analytical confirmation of exposure levels.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Details on test material:
- - Name of test material (as cited in study report): CP 42902 (Dequest 2001; nitrilotrimethylenetris(phosphonic acid))
- Substance type: Phosphonic acid
- Physical state: white crystalline solid
- Analytical purity: 100%
- Composition of test material, percentage of components: 90% aminotris(methylene phosphonic acid) and possibly 10% methyliminobis(methylene phosphonic acid)
- Purity test date: No data
- Lot/batch No.: 222638 and 1059624
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: Room temperature in locked storage cabinet.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Long-Evans
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York.
- Age at study initiation: (P) 6-7 wks
- Weight at study initiation: (P) males approx. 370 g, females approx. 240 g at mating
- Fasting period before study: No data
- Housing: Individually (except during mating and lactation) in elevated stainless steel wire mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 14 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
IN-LIFE DATES: From: 12.11.1976 To: 15.08.1978
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): Purina Laboratory Chow (standard laboratory diet)
- Storage temperature of food: No data - Details on mating procedure:
- - M/F ratio per cage: 1/2 (See table 1)
- Length of cohabitation: Overnight for up to 15 days.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- Remated (for F1b/F2b/F3b generation) following a 14 d rest period.
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): individually in elevated stainless steel wire mesh cages.
- Any other deviations from standard protocol: None apparent. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Diet samples were taken from control and treated groups weekly. Samples were stored frozen and sent to the sponsor at regular intervals throughout the study. No further details.
- Duration of treatment / exposure:
- From 60 days prior to first mating of P generation then continuous over 3 generations . Duration of test in total was approximately 21 months.
- Frequency of treatment:
- Daily
- Details on study schedule:
- - F1 and F2 parental animals not mated until after a growth period (unspecified duration) following selection from the F1b and F2b litters.
- Selection of parents from F1 and F2 generation when pups were 7 days post weaning.
- Age at mating of the mated animals in the study: Not clear, but there was a 14 day rest period between matings.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm (nominal)
- Dose / conc.:
- 300 ppm (nominal)
- Remarks:
- See table 3 for conversion to mg/kg bw/day
- Dose / conc.:
- 1 000 ppm (nominal)
- Remarks:
- See table 3 for conversion to mg/kg bw/day
- Dose / conc.:
- 3 000 ppm (nominal)
- Remarks:
- See table 3 for conversion to mg/kg bw/day
- No. of animals per sex per dose:
- 12 male and 24 females (see Table 1)
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: No data
- Rationale for animal assignment (if not random): Random - Positive control:
- None
Examinations
- Parental animals: Observations and examinations:
- Examination conducted on F0, F1, F2 AND F3 (all adult generations)
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Gross signs twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during growth and rest periods of all animals. As well as pregnant females (F0, F1b, F2b) on GD 0, 6, 15 and 20 and lactating females (F0, F1) on LD 0, 4, 14 and 21.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Weekly for males and non-pregnant females.
- 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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: F0 parents after weaning of F1b litter. - Oestrous cyclicity (parental animals):
- Not investigated.
- Sperm parameters (parental animals):
- Not investigated.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, to 10 pups/sex/litter as nearly as possible; excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, physical or behavioural abnormalities. See Tables 4, 5 and 6 for pup survival data.
GROSS EXAMINATION OF DEAD PUPS:
yes, sex determined and stomach checked for presence of milk. Cause of death was not determined. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after completion of pup selection for the F0 and F1 generations, and after weaning of last litters for the F2 generation.
- Maternal animals: All surviving animals after completion of pup selection for the F0 and F1 generations, and after weaning of last litters for the F2 generation. Also non-pregnant dams from first mating.
- Dead and moribund animals examined as death occurred.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- Dams uterine contents examined for the presence of implantation sites and/or scars.
HISTOPATHOLOGY / ORGAN WEIGHTS: None scheduled for adults.Only grossly abnormal tissues were examined. - Postmortem examinations (offspring):
- SACRIFICE
- The F1a/F2a/F3a offspring not selected as parental animals were sacrificed at 21 days of age.
- F1b and F2b progeny (non-parental): sacrificed after pup selection for next generation.
- F3b sacrificed at weaning.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table 2 were prepared for microscopic examination from 10 pups/sex/group of the F3b generation. In addition any grossly abnormal tissues were examined. - Statistics:
- Offspring body weights, off-spring numbers (LD 0 LD 4): F-test and Student's T-test.
Offspring survival, litter deaths, litters weaned, mortality, mating rates, pregnancy rates, fertility rates: Chi square.
Body weights, body weight change, food intake: Dunnett's test. - Reproductive indices:
- mating indices (%), pregnancy rates (%) and fertility (%). No details given.
- Offspring viability indices:
- No details given.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
Physical observations comparable between all groups.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): There was no effect in either sex on mean body weight or body weight gain during growth or rest periods. There were no effects on maternal body weight or body weight change during gestation or lactation periods.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): See Table 3
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Gestation length, mean number of live and dead pups at birth and percentage of live pups at birth were comparable between groups. A high number of dead pups within a single mid dose litter lead to a significant decrease in the survival index at birth in the mid dose group for F1b. The F2 generation high dose group had a significantly higher survival index at birth for the second litters. No adverse effect was concluded. There was no effect on mating indices (%), pregnancy rates (%) or fertility (%).
GROSS PATHOLOGY (PARENTAL ANIMALS): There were no adverse findings.
HISTOPATHOLOGY (PARENTAL ANIMALS): Not conducted.
OTHER FINDINGS (PARENTAL ANIMALS): The ophthalmoscopic examination revealed four rats (one control female, two mid dose males and one high dose male) with ocular abnormalities. However, these were not considered to be treatment related.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 000 ppm
- Based on:
- other: Nominal in diet
- Sex:
- male/female
- Basis for effect level:
- other: General and reproductive toxicity
Results: P1 (second parental generation)
Effect levels (P1)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 000 ppm
- Based on:
- other: Nominal in diet
- Sex:
- male/female
- Basis for effect level:
- other: General and reproductive toxicity
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
CLINICAL SIGNS (OFFSPRING): None reported.
BODY WEIGHT (OFFSPRING): Comparable between all groups.
GROSS PATHOLOGY (OFFSPRING): No adverse findings.
HISTOPATHOLOGY (OFFSPRING): scattered red foci present in lung from some F2b offspring from the mid and high dose groups (not present in controls and low dose group) considered unrelated to treatment by authors (since not present in other generations). All other necropsy observations similar for control and treated litters. Evaluation of selected tissues from 10 control weanlings and 10 high dose weanlings from the F3b generation revealed no abnormalities. Changes present in lung consistent with minimal to mild interstital pneumonia, microscopic appearance of the gonads unremarkable and consistent with sexually immature rats.
OTHER LITTER PARAMETERS: Sex ratio was not affected by treatment.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 3 000 ppm
- Based on:
- other: Nominal in diet
- Sex:
- male/female
- Basis for effect level:
- other: General and reproductive toxicity
Results: F2 generation
Effect levels (F2)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 3 000 ppm
- Based on:
- other: Nominal in diet
- Sex:
- male/female
- Basis for effect level:
- other: General and reproductive toxicity
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- other: F3
- Effect level:
- 3 000 ppm (nominal)
- Based on:
- other: Nominal in diet
- Sex:
- male/female
- Basis for effect level:
- other: General and reproductive toxicity
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 3 Test substance intake based on
food intake (weekly mean data) measurements .
Males (mg/kg bw/day) | Females (mg/kg bw/day) | |||||
Group (ppm) | II (300) | III (1000) | IV (3000) | II (300) | III (1000) | IV (3000) |
F0 growth | 33.4 | 111.6 | 342.3 | 37.3 | 117.1 | 362.5 |
F0 rest | 18.4 | 60.7 | 182.9 | 24.3 | 75.7 | 247.2 |
F1 growth | 26.3 | 89.6 | 270.2 | 28.1 | 98.4 | 290.2 |
F1 rest | 14.4 | 41.7 | 141.0 | 20.1 | 67.3 | 201.1 |
F2 growth | 29.6 | 95.4 | 296.6 | 34.3 | 112.6 | 337.8 |
F2 rest | 17.6 | 58.3 | 171.9 | 25.0 | 81.4 | 243.9 |
Table 4 Summary of offspring survival for the F1 generation.
Group (ppm) | Mean gestation length | % pups born alive | Mean no weaned/litter | Postnatal survival (%) | % litters with death (days 0 -21)c | % litters weanedc | Sex ratio (M/F) | ||
0 -4a | 4 -14b | 14 -21 | |||||||
F0 to F1a | |||||||||
I (0) | 22.5 | 98.8 | 9.1 | 92.0 | 94.3 | 100 | 57.1 | 95.2 | 0.87 |
II (300) | 22.4 | 98.2 | 8.6 | 97.3* | 90.5 | 100 | 65 | 100 | 0.87 |
III (1000) | 22.5 | 98.1 | 7.6* | 96.2 | 85.4** | 100 | 47.6 | 95.2 | 0.88 |
IV (3000) | 22.3 | 98.1 | 8.7 | 99.2** | 91.4 | 99 | 52.2 | 100 | 1.24 |
F0 to F1b | |||||||||
I (0) | 22.1 | 93.0 | 8.9 | 87.2 | 96.0 | 99.3 | 61.1 | 88.9 | 1.07 |
II (300) | 22.1 | 96.0 | 8.7 | 91.7 | 91.3 | 99.4 | 83.3 | 100 | 1.12 |
III (1000) | 22.1 | 97.2 | 9.3 | 94.8* | 93.7 | 100 | 56.3 | 100 | 0.84 |
IV (3000) | 22.1 | 95.8 | 9.2 | 97.6** | 96.5 | 99.5 | 28.6 | 100 | 0.96 |
Significantly different from control *p≤0.05; **p≤0.01
aComparison between days for postnatal offspring survival are calculated using Day 4 pre-cull data.
bComparison between days for postnatal offspring survival are calculated using Day 4 post-cull data.
cOnly those pups found alive at Day 0 of lactation are used in calculations.
Table 5 Summary of offspring survival for the F2 generation.
Group (ppm) | Mean gestation length | % pups born alive | Mean no weaned/litter | Postnatal survival (%) | % litters with death (days 0 -21)c | % litters weanedc | Sex ratio (M/F) | ||
0 -4a | 4 -14b | 14 -21 | |||||||
F1 to F2a | |||||||||
I (0) | 22.2 | 99.5 | 9.2 | 96.2 | 93.5 | 100 | 33.3 | 94.4 | 1.09 |
II (300) | 22.3 | 100 | 9.5 | 96.8 | 99.5** | 100 | 35.0 | 100 | 1.18 |
III (1000) | 22.1 | 99.6 | 9.4 | 95.4 | 99.5** | 98.6 | 40.9 | 100 | 1.06 |
IV (3000) | 22.3 | 97.4 | 9.1 | 97.3 | 100** | 100 | 30.4 | 100 | 0.92 |
F1 to F2b | |||||||||
I (0) | 22.4 | 99.3 | 8.8 | 78.5 | 100 | 100 | 35.7 | 85.7 | 0.89 |
II (300) | 22.1 | 96.1 | 8.8 | 93.6** | 92.5 | 98.1 | 61.1 | 100 | 1.11 |
III (1000) | 22.1 | 92.5** | 8.2 | 92.4** | 88.5** | 58.8 | 93.8 | 93.8 | 0.95 |
IV (3000) | 22.5 | 99.1 | 9.0 | 96.6** | 97.8 | 98.9 | 50.0 | 100 | 0.94 |
Significantly different from control *p≤0.05; **p≤0.01
aComparison between days for postnatal offspring survival are calculated using Day 4 pre-cull data.
bComparison between days for postnatal offspring survival are calculated using Day 4 post-cull data.
cOnly those pups found alive at Day 0 of lactation are used in calculations.
Table 6 Summary of offspring survival for the F3 generation.
Group (ppm) | Mean gestation length | % pups born alive | Mean no weaned/litter | Postnatal survival (%) | % litters with death (days 0 -21)c | % litters weanedc | Sex ratio (M/F) | ||
0 -4a | 4 -14b | 14 -21 | |||||||
F2 to F3a | |||||||||
I (0) | 22.3 | 97.9 | 7.8 | 89.5 | 94.3 | 99.4 | 54.5 | 95.5 | 0.91 |
II (300) | 22.4 | 91.3 | 6.4 | 87.2 | 89.5 | 100 | 75.0 | 100 | 1.13 |
III (1000) | 22.2 | 96.2 | 7.7 | 85.9 | 89 | 100 | 57.1 | 87.7 | 1.09 |
IV (3000) | 22.2 | 98.6 | 8.8 | 96.7** | 91.9 | 99.4 | 66.7 | 94.7 | 1.11 |
F2 to F3b | |||||||||
I (0) | 22.2 | 92.9 | 9.1 | 89.5 | 97.4 | 98.6 | 50.0 | 88.9 | 1.00 |
II (300) | 22.4 | 96.1 | 8.7 | 92.4 | 98.5 | 99.2 | 43.8 | 93.8 | 1.06 |
III (1000) | 22.1 | 92.7 | 8.3 | 93.5 | 97.3 | 100 | 38.5 | 100 | 0.83 |
IV (3000) | 22.2 | 98.5** | 9.2 | 89.9 | 98.7 | 100 | 52.9 | 94.1 | 1.45 |
Significantly different from control *p≤0.05; **p≤0.01
aComparison between days for postnatal offspring survival are calculated using Day 4 pre-cull data.
bComparison between days for postnatal offspring survival are calculated using Day 4 post-cull data.
cOnly those pups found alive at Day 0 of lactation are used in calculations.
Applicant's summary and conclusion
- Conclusions:
- In a reasonably well conducted three generation reproductive toxicity study conducted before the adoption of OECD test guidelines and GLP, the general and reproductive toxicity NOAEL for ATMP was greater than the highest dose tested, 3000 ppm in the diet, in rats (approximately equal to a dose of 275 mg/kg bw/day in males and 310 mg/kg bw/day for females).
- Executive summary:
Male and female Long-Evans rats were administered CP 42902 (nitrilotrimethylenetris(phosphonic acid)) continuously in the diet at fixed concentrations of 0, 300, 1000 and 3000 ppm for three consecutive generations. The litters from F0, F1 and F2 matings were raised to maturity and also mated. Offspring from the first litter of each generation (F1a, F2a, F3a) were taken for necropsy on lactation Day 21. The parents were remated following a 14 d rest period and the offspring randomly selected at seven days post-weaning to continue as the F1b and F2b generation parents. Remaining F1b and F2b animals, as well as the F3a and F3b generation, were taken for necropsy. A gross internal axamination was conducted on these animals. Randomly selected offspring from the F3a litters (10 pups/sex/group) were necropsied and selected tissues examined microscopically. Evaluations of adult mortality, mating, pregnancy, fertility, body weight data, food consumption data (growth and rest periods), litter survival, offspring viability at parturition, offspring weight and sex, and necropsy of adults and offspring, did not indicate any treatment-related adverse effects. The NOAEL for general toxicity and reproductive toxicity was greater than the highest dose tested, 3000 ppm. The concentration of the test substance and mean weekly food intake values were used to determine the approximate doses received by the animals. 3000 ppm was approximately equal to a dose of 275 mg/kg bw/day in males and 310 mg/kg bw/day in females.
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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