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EC number: 401-100-0 | CAS number: 109037-78-7 TILCOM CA35; TILCOM IA10; TYTAN AP 100; TYTAN CA 100; TYTAN CX 35; TYZOR IAM
- 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:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29.02.2016-07.11.2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- adopted: 28 July 2015
- Deviations:
- yes
- Remarks:
- All changes, were considered to have no impact on the toxicological results of this study. As no amendment or formal change control procedure was initiated, they were each filed as a deviation, but classified as non-critical.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Butyl (dialkyloxy(dibutoxyphosphoryloxy))titanium(trialkyloxy)titanium phosphate
- EC Number:
- 401-100-0
- EC Name:
- Butyl (dialkyloxy(dibutoxyphosphoryloxy))titanium(trialkyloxy)titanium phosphate
- Cas Number:
- 109037-78-7
- Molecular formula:
- not applicable
- IUPAC Name:
- dititanium(4+) triethanolate bis(propan-1-olate) dibutyl phosphate butyl phosphate
- Test material form:
- liquid
- Details on test material:
- The test material is a clear, yellow liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Wistar Han (IGS)
- Details on species / strain selection:
- Rattus norvegicus
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Clean conventional housing: airing with approx. 10 air changes per hour, room climate 22 ± 3°C, relative humidity at 30-70%, (actual relative humidity was not altered due to meteorological circumstances), artificial lighting 12 h light/12 h dark.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The test item Printcat 508 was administered daily by oral gavage to 12 male and 12 female rats per dose group throughout the in-life phase of this study (see table 2). The test item was administered at three graduated doses in an application volume of 5 ml per kg body weight. The individual dose volumes were calculated from the latest actual animal body weight data. 24 animals (12 males / 12 females) received pure corn oil as vehicle control via the same route.
- Details on mating procedure:
- During acclimatisation, pre-exposure and pre-mating, male rats were caged in groups of three animals per cage; females were housed individually. Throughout the mating period, animals were kept in pairs of one female and one male rat. The female was placed with the same male until pregnancy occured or two weeks had elapsed. In case a male died during the mating period or successful mating was not be detectable after 14 days, re-mating of females with proven males (sires) of the same group was considered. After the mating period, male rats were housed in groups of three originally formed during pre-mating phase; female rats were housed individually.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Since direct quantification of the intact chemical Printcat 508-complex was not feasible, Titanium (Ti), as a distinct component of the chemical Printcat 508-complex, was used as the analytical marker for a quantitative re-analysis of the test item dissolved in corn oil. A preparative
procedure had to be validated that causes a complete decomposition of Ti from the chemical Printcat 508-complex as well as from the corn oil matrix. The subsequent fraction-analysis of the released Ti should be carried out via Inductively Coupled Plasma- Optical Emission Spectrometry (ICP-OES). As part of the method validation, two different protocols for sample preparation (protocols for dry ashing and wet ashing preparations) were carried out in a preliminary study. For either protocol tested, the study results returned a recovery rate below 5% for the released Ti, given that the nominal Ti-concentration in the utilized test item-solution of 1,2 mg/L was applied as the basis for the calculations of the test item-recovery rates. A matrix effect of the dissolvent in combination with the low amount of bound Ti within the chemical Printcat 508-complex could be considered a cause for the low recovery rates. In due consideration of the matrix effect caused by the dissolvent, the determination of the test item in corn oil via measurement of released Titanium per ICP-OES is considered not feasible and for this reason a test item re-analysis was not performed for this study. - Duration of treatment / exposure:
- Males were dosed daily for 42 days to 46 days, including the day before the scheduled termination of the in-life phase. This included two weeks of dosing prior to mating and continued throughout the mating period until approximately two weeks post-mating.
Females were dosed two weeks prior to mating, covering at least two complete oestrous cycles, the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled termination of the in-life phase. Therefore the duration of the study following acclimatisation and pre-dosing estrus-cycle evaluation depended on the female performance (14 days pre-mating, up to 14 days until mating, an average of 22 days of gestation, and a minimum of 13 days of lactation) and was at least 63 days. - Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 160 mg/kg bw/day (nominal)
- Dose / conc.:
- 400 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Positive control:
- Not set
Examinations
- Parental animals: Observations and examinations:
- Cage-side observations to detect signs of illness or reactions to treatment, moribund animals or fatalities were conducted as scheduled in chapter 3.2. Data were recorded within the raw data. For the adult animals, individual body weight, individual/group food and individual/group
water consumption was monitored as scheduled in chapter 3.2. During pregnancy, females were weighed individually on days 0,7,14 and 20 and within 24 hours of parturition (at birth: day 0 or 1 post partum) and on day 4, 9 and on day of scheduled necropsy (at least on day
13 post-partum). - Oestrous cyclicity (parental animals):
- Yes
- Sperm parameters (parental animals):
- Not included
- Litter observations:
- Each litter was examined as soon as possible after delivery to establish parameters as follow: numbers, sex and presence of gross abnormalities were evaluated for pups, stillbirth, live birth and runts.
- Postmortem examinations (parental animals):
- All adult animals were sacrificed humanely by asphyxiation in a CO2 atmosphere and were examined macroscopically. All occurring lesions were recorded on checklists for each individual animal. Special attention was paid to the organs of the reproductive system. The number of implantation sides was recorded. The testes, epididymides and the LABC muscle, the cowper’s glands and the glans penis of all male adult animals were surgically extracted and weighed as soon as possible after dissection. Paired organs were weighed individually. The ovaries, testes, epididymides, accessory sex organs (cervix, prostate etc.) and all other organs showing macroscopic lesions of all adult animals were
preserved in the appropriate fixative. Adult animals: Terminal procedures, tissue preservation, organ weights and implantation sites. - Postmortem examinations (offspring):
- Dead pups and pups humanely killed on day 13 post partum, or shortly thereafter, were examined externally for gross abnormalities. External reproductive genitals were examined for signs of altered development. Immediately after death, the thyroid gland from one male and one female pup per litter were preserved.
- Statistics:
- Spread sheet calculations were performed using Microsoft® Excel® 2011 for Mac. Data on body weight were recorded for each individual animal. Food- and water consumption were documented sorted by experimental groups and sex. For each experimental group, means and standard deviations were calculated.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animal behavioral signs of wiping of nose and mouth through cage bedding, salivation before and after dose application were especially observed in all test item-treated male animal groups, but the findings were predominantly observed at the high dose. Although the observed behavioral signs were probably related to the test item, they were considered to be of minor toxicological importance. No adverse clinical signs were observed during the course of the study.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- On premating day 2, one female of the low dose group (E79/0) was found dead. Necropsy did not identify a plausible cause for the death. Based on the animal’s behavior immediately after the last dose administration [animal lay outstretched in cage, behaved lethargic), it is assumed that a gavage error was most likely the cause of death. While there were no necropsy findings to support this conclusion, and the lung volume was not checked for remnants of the test item at necropsy, this effect was not considered test item-related.
Additional animals were found dead on pre-mating day 3 [one female animal of the low dose group (E104/0)], pre-mating day 5 [one female animal of the high dose group (E108/0)], day 14 of the pre-mating phase [one male animal of the low dose group (E62/1)], and day 20 of gestation [one female animal of the medium dose group (E76/0)]. In all cases, test item was found inside the lungs at necropsy, so that aspiration caused by a failed administration was regarded as the most plausible cause for the death of the animals. Thus, these deaths were considered not test item-related. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Over the course of the study no statistical differences in the mean body weights of female test groups and the respective control group detected. Correspondingly, the mean body weight gain was comparable between all female groups either treated with the test item or the vehicle control item. All values were within normal range for female rats of this strain and age. Occasional differences especially towards the end of the gestation phase were assumed to be within the physiological variation caused by the pregnancy status of the animals.
For male animals, no statistical differences in mean body weights were observed between the test groups and the respective control group over the course of the study. Correspondingly, the mean body weight gain was comparable between all male animal groups either treated with the test item or the vehicle control item. All values were within normal range for rats of this strain and age. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- In summary, the monitored time intervals did not reveal any changes of toxicological relevance in regard to food consumption between the animal test groups and their respective vehicle control groups throughout male and female in-life phases. Some variances were observed for the female animal groups, which could be associated with the specific animal condition during phases of late pregnancy and subsequent lactation.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- In summary: the majority of monitored intervals revealed a test item-related slight increase in water consumption for the female high and medium dose groups, when compared to the respective vehicle control group. For the male dose groups no test item related-effect could be observed in this respect. The observed test item–related differences in water consumption in the majority of monitored time intervals could be regarded as within the normal range for female animals of this strain and age and were therefore not considered adverse. The differences in female water consumption observed between late pregnancy/lactation and the earlier in life-phases resulted from the specific physiological condition of the animals and therefore considered as not adverse or even toxicologically relevant.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- In comparison to the respective vehicle controls, no difference in total T4-hormone content in blood plasma was detected for the sires and the day 13 pp pups in a t-test analysis. In summary: no test item-related change of total T4-hormone content in blood plasma could be detected in the experimental animals.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- With the exception of one female animal (high dose), only males and sires showed particular animal behavior, predominately at the high dose. The role of the test item on these effects could not be fully excluded. These observed effects were considered not adverse as they were mild in severity and had a minor impact on the experimental animals during the course of the study.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- According to guideline OECD421, tissue samples from a selective panel of reproductive organs and macroscopic lesions as well as vaginal smears prepared at necropsy from dams and sires of the experimental high dose group and respective vehicle control group were correlated and conclusively analyzed by the histopathologist. The histopathological analysis (on macroscopic and microscopic level) revealed no evidence for a test item-related effect on the reproductive organs from experimental adult animals.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- The daily monitoring of the animal’s estrus cycles revealed a regular cycle for each experimental female at the start of the mating phase, hence each female was considered for participation in the subsequent mating.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- Germ cells in the testis were evaluated by identifying tubules with respect to their stage in the spermatogenic cycle. Neither germ cell depletion nor spermatid retention were found. The population of Sertoli cells was normal and interstitial Leydig cells did neither show atrophy or hyperplasia. Epididymides did not show desquamated germ cells, cell debris or reduced number of sperm.
Unilateral focal sperm granuloma in the epididymis was found in one animal treated with 1000 mg/kg (animal no. E60/0), but is not considered test item-related, because it is a common spontaneous finding in Wistar rats that may develop as a consequence of congenital ductal aplasia. - Reproductive performance:
- no effects observed
- Description (incidence and severity):
- In regard to evaluated parameters “numbers of pups, abnormal pups and loss of offspring” no statistical significant differences between the test groups and the respective vehicle control group were noted.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- water consumption and compound intake
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: neoplastic
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive function (oestrous cycle)
- reproductive function (sperm measures)
- reproductive performance
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Within the litter (11 pups in total) of the high dose group-animal E73/0 and within the litter (16 pups in total) of the medium dose group-animal E88/0 one stillborn pup each was found. Within the litter (8 pups in total) of the low dose group-animal E80/0 two stillborn pups were found and within the litter (13 pups in total) of the vehicle group-animal E93/0, one stillborn pub was identified.
The examination of each stillborn`s body did not reveal any signs of deformation or developmental delays. The distribution of identified stillborns within the experimental groups did not correlate in a dose-dependent manner. Therefore a test item-related effect could be excluded for each particular incident with high probability. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the high dose group, one animal (E84/0) gave birth to 13 pups, from which one was identified as physically smaller when compared to its siblings [body weights: 3,6g / 6,2 g (small pup / mean pup weight/litter)] and to pups of the vehicle group at necropsy. Besides considerably smaller body size, the runt showed no other signs of developmental delay or signs of deformation until end of the in-life phase.
In the medium dose group, one animal (E87/0) gave birth to 13 pups from which one was identified as physically smaller when compared to its siblings on day d0 pp. However, the particular pup went missing the next day. An apparent cause for the pup’s death was not identified.
Another animal of the medium dose group (E113/0) gave birth to 2 pups of which one pup was considerably smaller in size, when compared to its normal sized sibling at day of actual birth (d0 pp) or to normal sized pups of the vehicle group at necropsy. The smaller pup showed no other signs of developmental delay or signs of deformation until end of the in-life phase. The normal sized pup vanished at d1 pp.
One animal of the vehicle control group (E107/0) gave birth to 5 pups of which one pup was identified as a runt when compared to its siblings. The particular pup showed no other signs of developmental delay or signs of deformation until end of its in-life phase.
Individual pups from litters of all dose groups and the vehicle group did not have their eyes open on day 13 post partum and retroorbital blood sampling could not be performed. As the pups from litters of all experimental groups had at latest their eyes open at day 14 post partum, no difference in pup development could be identified between the pups of the dose groups and the pups of the vehicle group.
However, in some animal litters, individual pups with delayed body growth were identified along with other siblings, which were regarded as normal in size and appearance. The occurrence of these particular pups within litters of the different experimental groups did not reveal a dose-dependent correlation. Therefore a test item-related effect was considered as most unlikely. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- The careful examination of d13 pp pups did not return any signs of gross abnormalities either in terms of general toxicity or in terms of alterations or developmental delays of organs within the reproductive system. According to the macroscopic results a test item-related effect on the organs relevant within the reproduction system can be excluded with high probability.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- In regard to evaluated parameters “sex ratio, anogenital distance (AGD) and nipple retention” no statistical significant differences were detected between the test groups and the respective control group.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- ca. 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- gross pathology
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- A daily oral administration of the test item Printcat 508 to male and female Wistar rats up to 1000 mg/kg/day in current reproduction/developmental screening did not lead to adverse toxicity to P0 animals and neither an effect on the reproduction performanc as well as development of F1 pups. Therefore it is concluded the NOAEL for parental systemic and reproduction toxicity, as well as fetal development toxicity is 1000 mg/kg/day.
- Executive summary:
A daily oral administration of the test item Printcat 508 to male and female Wistar rats at dose levels of 1000 mg, 400 mg and 160 mg/kg body weight over a time period of 51 to 63 days for males and 42 to 46 days for females resulted in some minor animal behavioral changes in male animals and some minor changes in the water consumption of females. Neither were considered adverse nor toxic. As the findings could not be associated with a substantial impact on the animal’s health, the NOAEL regarding the subchronic toxicity was set to 1000 mg/kg body weight. Furthermore, no pathological evidence for toxic effects on the reproduction performance of female and male rats was found. Regarding the overall time period of gestation/lactation and after birth until end of in-life phase no evidence for a toxic effect on the pup development could be detected. The NOAEL regarding reproduction and development of Printcat 508 under these study conditions was estimated to be 1000 mg/kg body weight for the female and male animals.
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