Registration Dossier
Registration Dossier
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EC number: 916-918-8 | CAS number: -
- 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:
- 25 August 2017 - 12 April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 25 August 2017 - 12 April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females nulliparous and non-pregnant: [yes/no]
- Age at study initiation:
Male: approximately 11 weeks old
Female: approximately 14 weeks old
- Weight at study initiation:
Male: 281 to 343g
Female: 198 to 235g
- Fasting period before study: Not specified
- Housing: All animals were housed in groups of three in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 hours continuous light and 12 hours darkness
IN-LIFE DATES: From: 25 September 2017 (first day of treatment) To: 27 November 2017 (final day of necropsy). - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- - Concentration in vehicle (mg/mL): 5, 15, 35
- Dose Level (mg/kg bw/day): 0, 25, 75 and 175.
- Amount of vehicle (if gavage): 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples: Distilled water were accurately fortified with known amounts of test item equivalent to the lowest and highest anticipated dose concentrations. These samples were then prepared for analysis as the test samples. The concentration of test item in the final solution was quantified by HPLC using UV/Visible detection.
- Duration of treatment / exposure:
- Approximately six weeks (for males) and up to ten weeks (for females) (including a two week pre-pairing phase, pairing, gestation and early lactation for females).
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes
- Positive control:
- No
- Parental animals: Observations and examinations:
- Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 12 post partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group. Additionally, blood samples were taken at termination from all adult animals and from one male and one female offspring per litter (where possible) on Days 4 and 13 post partum, for thyroid hormone analysis; samples from adult males and Day 13 offspring were analyzed for Thyroxine (T4).
Vaginal smears were performed for all females from the day after arrival (enabling the exclusion of females not showing appropriate estrous cycling from dosing) and for all treated females including controls through pre-pairing, pairing and up to confirmation of mating.
Vaginal smears were also performed in the morning on the day of termination for all treated females. Adult males were terminated on Day 44 or 45, followed by the termination of all surviving offspring and adult females on Days 13 and 14 post partum, respectively. Any female which did not produce a pregnancy was terminated around the same time as littering females. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. All offspring were examined externally; where external observations were detected an internal necropsy was performed. - Litter observations:
- During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and ano-genital distance and visible nipple count (male offspring only).
- Postmortem examinations (parental animals):
- All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. All offspring were examined externally; where external observations were detected an internal necropsy was performed.
- Statistics:
- Where considered appropriate, quantitative data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows:
Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variances were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found but the data shows nonhomogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel
(non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).
Data not analyzed by the Provantis data capture system were assessed separately using the R Environment for Statistical Computing. Initially, the distribution of the data was assessed by the Shapiro-Wilk normality test, followed by assessment of the homogeneity of the data using Bartlett’s test. Where considered appropriate, parametric analysis of the data was applied incorporating analysis of variance (ANOVA), which if significant, was followed by pair-wise comparisons using Dunnett’s test. Where parametric analysis of the data was considered to be unsuitable, non-parametric analysis of the data was performed incorporating the Kruskal-Wallis test which if significant was followed by the Mann-Whitney "U" test. Dose response relationships were also investigated by linear regression. Where the data were unsuitable for
these analyses then pair-wise tests were performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric). - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Throughout the treatment period, noisy respiration, increased salivation, fur stained by the test item (pink/red) and pink stained bedding was evident in animals of either sex from all treatment groups. One male treated with 175 mg/kg bw/day also showed an isolated incidence of hunched posture.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female treated with 175 mg/kg bw/day was found dead on Day 10. This female had mild degenerate/inflammatory changes in the stomach and hyperkeratosis in the stomach, however, the cause of death was not identified. One male treated with 25 mg/kg bw/day was killed in extremis on Day 15 due to the severity of clinical signs noted, which included gasping/labored/noisy respiration, decreased respiratory rate, stained snout, fur stained by test item and a distended abdomen. Changes were apparent in the gastrointestinal tract at necropsy; however, no histopathological changes were evident in the tissues examined. One female treated with 25 mg/kg bw/day was killed in extremis on Day 38 due to difficulties during parturition. There were no further unscheduled deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males from all treatment groups showed a reduction in body weight gain during Weeks 1, 2 and 4, which resulted in a reduction in overall body weight gain. Females treated with 175 mg/kg bw/day showed a reduction in overall body weight gain during maturation. Reductions in body weight gain were also evident during the final two weeks of gestation and during lactation. No adverse effect in body weight development was evident in females treated with 75 or 25 mg/kg bw/day during maturation, gestation or lactation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Males treated with 175 mg/kg bw/day showed a reduction in overall food consumption and food conversion efficiency. No such effects were evident in males treated with 75 or 25 mg/kg bw/day. Females treated with 175 mg/kg bw/day showed a slight reduction in overall food consumption during maturation and a reduction in food consumption throughout lactation. Food conversion efficiency for these females during maturation was comparable to controls. No such effects on food consumption were evident in females treated with 75 or 25 mg/kg bw/day.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Stomach: Hyperplasia of the non-glandular mucosa was present in two males treated with 75 mg/kg bw/day and in one male and two females treated with 175 mg/kg bw/day. Hyperkeratosis was also evident in one male each from the 75 and 175 mg/kg bw/day dose group. No such effects were evident in females treated with 75 mg/kg bw/day or in animals of either sex treated with 25 mg/kg bw/day.
- Description (incidence and severity):
- Thyroid Hormone Analysis
An evaluation of Thyroxine (T4) in adult males and male/female offspring (Day 13 of age) did not identify any treatment-related findings. - Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 175 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no adverse effects seen
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- As a consequence of the slightly lower litter size at birth in females treated with 175 mg/kg bw/day, litter weights were reduced in these females throughout lactation. Offspring body weight gains in these litters were slightly lower than controls from Day 4 of lactation onwards. No such effects were detected in females treated with 75 or 25 mg/kg bw/day.
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 175 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no adverse effects seen
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- There were no effects on fertility, the ‘No Observed Effect Level’ (NOEL) for fertility is considered to be 175 mg/kg bw/day.
- Executive summary:
The oral administration of FAT 31016/T TE to rats by gavage, at dose levels of 25, 75 and 175 mg/kg bw/day in this study conducted according to OECD Guideline 422, resulted in treatment-related microscopic effects in animals of either sex treated with 175 mg/kg bw/day and in males treated with 75 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 75 mg/kg bw/day for females and 25 mg/kg bw/day for males.
The reduced body weight development and microscopic changes evident in the stomach were considered to be the result of an irritant effect of the test item rather than a true systemic effect and as such was considered adaptive and non-adverse. Therefore, a ‘No Observed Adverse Effect Level’ (NOAEL) can be established at 175 mg/kg bw/day for animals of either sex.
There were no effects on fertility, the ‘No Observed Effect Level’ (NOEL) for fertility is considered to be 175 mg/kg bw/day. A 'No Observed Adverse Effect Level' (NOAEL) for developmental toxicity may be established at 175 mg/kg bw/day due to the effects seen in litter size, litter weights and offspring body weight gain being minimal, group mean values being within historical control ranges and most likely a result of the impaired health of the dam from lower body weight gain and food consumption during lactation.
There was no effect of treatment with the test item at any dose level on the nature of estrous cycle with most females showing regular cycles over the pre-pairing phase of the study. There were also no intergroup differences in the stage of estrus on the day of necropsy.
Mating
There was no effect of treatment on mating performance. With the exception of five animals, all remaining animals mated within four days of pairing.
Fertility
There were no treatment-related effects in conception rates for test item-treated animals in relation to controls.
Gestation Lengths
There were no differences in gestation lengths in animals receiving the test item when compared with controls.
Offspring Litter Size, Sex Ratio and Viability
There was no detrimental effect of treatment with the test item on the mean number of implantations or post-implantation loss at 175, 75 or 25 mg/kg bw/day. Litter size at birth and subsequently during lactation was slightly reduced in females treated with 175 mg/kg bw/day, however, sex ratio and subsequent offspring survival to Day 13 of age was unaffected. No such effect on litter size was evident at 75 or 25 mg/kg bw/day. Sex ratio and subsequent offspring survival to Day 13 of age at 75 and 25 mg/kg bw/day was comparable to controls.
DEVIATIONS FROM STUDY PLAN
The following deviations from the study plan occurred:
Clinical Observations
The one hour post-dosing observations were performed approximately thirty minutes after they were due on Day 30 relative to the start of dosing. All other observations were performed correctly on that day and whilst this omission was regrettable it does not affect the purpose or integrity of the study.
Selection of Animals for Extended Observations
Due to the death of Male No. 29 during the study, Male No. 30 was selected as a replacement for the extended observations. Sensory Reactivity, Motor Activity, Grip Strength, Hematology and Blood Chemistry were all performed on this male, however, at necropsy the full tissue list was not retained in error. In view of the incomplete data for this male, another male (No. 31) had the full extended observations performed. All of the data recorded for both animals will be reported.
Mortalities
There were a small number of instances during the study where the early mortality checks were not performed at times considered acceptable by the Study Director. However, as all animals were monitored twice daily from arrival to termination, this deviation can be considered not to have affected the purpose or scientific integrity of the study.
Litter data
The sex for offspring No. 7 from Litter 94 was not recorded on Day 4 of lactation in error. The sex on Day 1 and Day 13 of lactation for this offspring was confirmed as male, therefore, for reporting purposes, this offspring will be reported as male for Day 4 of lactation.
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 25 August 2017 - 12 April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females nulliparous and non-pregnant: [yes/no]
- Age at study initiation:
Male: approximately 11 weeks old
Female: approximately 14 weeks old
- Weight at study initiation:
Male: 281 to 343g
Female: 198 to 235g
- Fasting period before study: Not specified
- Housing: All animals were housed in groups of three in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 hours continuous light and 12 hours darkness
IN-LIFE DATES: From: 25 September 2017 (first day of treatment) To: 27 November 2017 (final day of necropsy). - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- - Concentration in vehicle (mg/mL): 5, 15, 35
- Dose Level (mg/kg bw/day): 0, 25, 75 and 175.
- Amount of vehicle (if gavage): 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples: Distilled water were accurately fortified with known amounts of test item equivalent to the lowest and highest anticipated dose concentrations. These samples were then prepared for analysis as the test samples. The concentration of test item in the final solution was quantified by HPLC using UV/Visible detection.
- Duration of treatment / exposure:
- Approximately six weeks (for males) and up to ten weeks (for females) (including a two week pre-pairing phase, pairing, gestation and early lactation for females).
- Frequency of treatment:
- daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 12 post partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group. Additionally, blood samples were taken at termination from all adult animals and from one male and one female offspring per litter (where possible) on Days 4 and 13 post partum, for thyroid hormone analysis; samples from adult males and Day 13 offspring were analyzed for Thyroxine (T4).
Vaginal smears were performed for all females from the day after arrival (enabling the exclusion of females not showing appropriate estrous cycling from dosing) and for all treated females including controls through pre-pairing, pairing and up to confirmation of mating.
Vaginal smears were also performed in the morning on the day of termination for all treated females. - Sacrifice and pathology:
- Adult males were terminated on Day 44 or 45, followed by the termination of all surviving offspring and adult females on Days 13 and 14 post partum, respectively. Any female which did not produce a pregnancy was terminated around the same time as littering females. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. All offspring were examined externally; where external observations were detected an internal necropsy was performed.
- Other examinations:
- During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and ano-genital distance and visible nipple count (male offspring only).
- Statistics:
- Where considered appropriate, quantitative data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows:
Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variances were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found but the data shows nonhomogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel
(non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).
Data not analyzed by the Provantis data capture system were assessed separately using the R Environment for Statistical Computing. Initially, the distribution of the data was assessed by the Shapiro-Wilk normality test, followed by assessment of the homogeneity of the data using Bartlett’s test. Where considered appropriate, parametric analysis of the data was applied incorporating analysis of variance (ANOVA), which if significant, was followed by pair-wise comparisons using Dunnett’s test. Where parametric analysis of the data was considered to be unsuitable, non-parametric analysis of the data was performed incorporating the Kruskal-Wallis test which if significant was followed by the Mann-Whitney "U" test. Dose response relationships were also investigated by linear regression. Where the data were unsuitable for
these analyses then pair-wise tests were performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric). - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Throughout the treatment period, noisy respiration, increased salivation, fur stained by the test item (pink/red) and pink stained bedding was evident in animals of either sex from all treatment groups. One male treated with 175 mg/kg bw/day also showed an isolated incidence of hunched posture.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female treated with 175 mg/kg bw/day was found dead on Day 10. This female had mild degenerate/inflammatory changes in the stomach and hyperkeratosis in the stomach, however, the cause of death was not identified. One male treated with 25 mg/kg bw/day was killed in extremis on Day 15 due to the severity of clinical signs noted, which included gasping/labored/noisy respiration, decreased respiratory rate, stained snout, fur stained by test item and a distended abdomen. Changes were apparent in the gastrointestinal tract at necropsy; however, no histopathological changes were evident in the tissues examined. One female treated with 25 mg/kg bw/day was killed in extremis on Day 38 due to difficulties during parturition. There were no further unscheduled deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males from all treatment groups showed a reduction in body weight gain during Weeks 1, 2 and 4, which resulted in a reduction in overall body weight gain. Females treated with 175 mg/kg bw/day showed a reduction in overall body weight gain during maturation. Reductions in body weight gain were also evident during the final two weeks of gestation and during lactation. No adverse effect in body weight development was evident in females treated with 75 or 25 mg/kg bw/day during maturation, gestation or lactation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Males treated with 175 mg/kg bw/day showed a reduction in overall food consumption and food conversion efficiency. No such effects were evident in males treated with 75 or 25 mg/kg bw/day.
Females treated with 175 mg/kg bw/day showed a slight reduction in overall food consumption during maturation and a reduction in food consumption throughout lactation. Food conversion efficiency for these females during maturation was comparable to controls. No such effects on food consumption were evident in females treated with 75 or 25 mg/kg bw/day. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no toxicologically significant effects detected in the organ weights measured.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The female treated with 175 mg/kg bw/day that was found dead on Day 10 had a dark liver and red content in the stomach. The stomach was also stained by the test item. The male treated with 25 mg/kg bw/day that was killed in extremis on Day 15 had gaseous distension in the stomach and intestines, small seminal vesicles, a thin cecum, red contents in the stomach and sloughing/thinning of the non-glandular region of the stomach. The female treated with 25 mg/kg bw/day that was killed in extremis on Day 38 had a dead fetus which had rotated in the vagina.
One female treated with 175 mg/kg bw/day had gaseous distension in the cecum, colon and rectum and a further female from this treatment group had raised white areas on the nonglandular region of the stomach. No such effects were evident in males treated with 175 mg/kg bw/day or in animals of either sex treated with 75 or 25 mg/kg bw/day. - Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Stomach: Hyperplasia of the non-glandular mucosa was present in two males treated with 75 mg/kg bw/day and in one male and two females treated with 175 mg/kg bw/day. Hyperkeratosis was also evident in one male each from the 75 and 175 mg/kg bw/day dose group. No such effects were evident in females treated with 75 mg/kg bw/day or in animals of either sex treated with 25 mg/kg bw/day.
- Description (incidence and severity):
- Thyroid Hormone Analysis
An evaluation of Thyroxine (T4) in adult males and male/female offspring (Day 13 of age) did not identify any treatment-related findings. - Details on results:
- Other examinations:
Thyroid Hormone Analysis
An evaluation of Thyroxine (T4) in adult males and male/female offspring (Day 13 of age) did not identify any treatment-related findings.
Estrous Cycle
There was no effect of treatment with the test item at any dose level on the nature of estrous cycle with most females showing regular cycles over the pre-pairing phase of the study. There were also no intergroup differences in the stage of estrus on the day of necropsy.
Mating
There was no effect of treatment on mating performance. With the exception of five animals, all remaining animals mated within four days of pairing.
Fertility
There were no treatment-related effects in conception rates for test item-treated animals in relation to controls.
Gestation Lengths
There were no differences in gestation lengths in animals receiving the test item when compared with controls.
Offspring Litter Size, Sex Ratio and Viability
There was no detrimental effect of treatment with the test item on the mean number of implantations or post-implantation loss at 175, 75 or 25 mg/kg bw/day. Litter size at birth and subsequently during lactation was slightly reduced in females treated with 175 mg/kg bw/day, however, sex ratio and subsequent offspring survival to Day 13 of age was unaffected. No such effect on litter size was evident at 75 or 25 mg/kg bw/day. Sex ratio and subsequent offspring survival to Day 13 of age at 75 and 25 mg/kg bw/day was comparable to controls.
Offspring Growth and Development
As a consequence of the slightly lower litter size at birth in females treated with 175 mg/kg bw/day, litter weights were reduced in these females throughout lactation. Offspring body weight gains in these litters were slightly lower than controls from Day 4 of lactation onwards. No such effects were detected in females treated with 75 or 25 mg/kg bw/day.
Ano-genital distance on Day 1 post partum, visible nipple count in male offspring on Day 13 post partum and clinical signs up to Day 13 of age at 25, 75 and 175 mg/kg bw/day for all treated litters was comparable to controls. - Dose descriptor:
- NOEL
- Effect level:
- 25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: local irritant effects in non-glandular stomach resulting in a lower food consumption and lower body weight gain at 75 and 175 mg/kg bw/day
- Dose descriptor:
- NOEL
- Effect level:
- 75 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: local irritant effects in non-glandular stomach resulting in a lower food consumption and lower body weight gain at 175 mg/kg bw/day
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 175 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects were observed
- Critical effects observed:
- no
- Conclusions:
- ‘No Observed Effect Level’ (NOEL) for local toxicity was therefore considered to be 75 mg/kg bw/day for females and 25 mg/kg bw/day for males. The ‘No Observed Adverse Effect Level’ (NOAEL) can be established at 175 mg/kg bw/day for animals of either sex.
- Executive summary:
The oral administration of FAT 31016/T TE to rats by gavage, at dose levels of 25, 75 and 175 mg/kg bw/day was evaluated in this study conducted according to OECD Guideline 422. Clinical signs were detected in animals of either sex from all treatment groups. Episodes of increased salivation and noisy respiration were evident throughout the study. The physical condition of treated males was also affected with reductions in body weight development generally being observed throughout the study. Subsequently, a reduction in overall body weight gain was evident in treated males and reductions in food consumption and food conversion efficiency was also evident throughout the treatment period for males treated with 175 mg/kg bw/day. Females treated with 175 mg/kg bw/day also showed reductions in body weight gains during maturation, the final two weeks of gestation and during lactation and food consumption was reduced in these females during lactation. Observations of this nature are often reported when a test item formulation is unpalatable or irritant and can be associated with gastric irritancy rather than attributable to true systemic toxicity. This was supported microscopically in animals of either sex treated with 175 mg/kg bw/day and in males treated with 75 mg/kg bw/day, where hyperplasia and hyperkeratosis of the non-glandular region of the stomach was evident. Based on the above findings, the ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 75 mg/kg bw/day for females and 25 mg/kg bw/day for males.
The reduced body weight development and microscopic changes evident in the stomach were considered to be the result of an irritant effect of the test item rather than a true systemic effect and as such was considered adaptive and non-adverse. Further the microscopic changes observed were seen in the non-glandular region of the rodent stomach. The corresponding non-glandular area is not present in the man and hence the adverse effects were considered not significant to the man. Therefore, a ‘No Observed Adverse Effect Level’ (NOAEL) can be established at 175 mg/kg bw/day for animals of either sex.
DEVIATIONS FROM STUDY PLAN
The following deviations from the study plan occurred:
Clinical Observations
The one hour post-dosing observations were performed approximately thirty minutes after they were due on Day 30 relative to the start of dosing. All other observations were performed correctly on that day and whilst this omission was regrettable it does not affect the purpose or integrity of the study.
Selection of Animals for Extended Observations
Due to the death of Male No. 29 during the study, Male No. 30 was selected as a replacement for the extended observations. Sensory Reactivity, Motor Activity, Grip Strength, Hematology and Blood Chemistry were all performed on this male, however, at necropsy the full tissue list was not retained in error. In view of the incomplete data for this male, another male (No. 31) had the full extended observations performed. All of the data recorded for both animals will be reported.
Mortalities
There were a small number of instances during the study where the early mortality checks were not performed at times considered acceptable by the Study Director. However, as all animals were monitored twice daily from arrival to termination, this deviation can be considered not to have affected the purpose or scientific integrity of the study.
Litter data
The sex for offspring No. 7 from Litter 94 was not recorded on Day 4 of lactation in error. The sex on Day 1 and Day 13 of lactation for this offspring was confirmed as male, therefore, for reporting purposes, this offspring will be reported as male for Day 4 of lactation.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of 5-[{4-[Benzyl(methyl)amino]phenyl}diazenyl]-1,4-dimethyl-4H-1,2,4-triazol-1-ium methyl sulfate and 3-[{4-[Benzyl(methyl)amino]phenyl}diazenyl]-1,4-dimethyl-4H-1,2,4-triazol-1-ium methyl sulfate
- EC Number:
- 915-761-2
- Molecular formula:
- C19H24N6O4S
- IUPAC Name:
- Reaction mass of 5-[{4-[Benzyl(methyl)amino]phenyl}diazenyl]-1,4-dimethyl-4H-1,2,4-triazol-1-ium methyl sulfate and 3-[{4-[Benzyl(methyl)amino]phenyl}diazenyl]-1,4-dimethyl-4H-1,2,4-triazol-1-ium methyl sulfate
- Test material form:
- solid: crystalline
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Male: approximately 11 weeks old; Female: approximately 14 weeks old
- Weight at study initiation: Male: 281 to 343 g; Female: 198 to 235g
- Fasting period before study: Not specified
- Housing: All animals were housed in groups of three in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 hours continuous light and 12 hours darkness
IN-LIFE DATES: From: 25 September 2017 (first day of treatment) To: 27 November 2017 (final day of necropsy).
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- - Concentration in vehicle (mg/mL): 5, 15, 35
- Dose Level (mg/kg bw/day): 0, 25, 75 and 175.
- Amount of vehicle (if gavage): 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples: Distilled water were accurately fortified with known amounts of test item equivalent to the lowest and highest anticipated dose concentrations. These samples were then prepared for analysis
as the test samples. The concentration of test item in the final solution was quantified by HPLC using UV/Visible detection. - Details on mating procedure:
- Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 13 of lactation.
- Duration of treatment / exposure:
- Approximately six weeks (for males) and up to ten weeks (for females) (including a two week pre-pair ing phase, pairing, gestation and early lactation for females).
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 12 post partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group. Additionally, blood samples were taken at termination from all adult animals and from one male and one female offspring per litter (where possible) on Days 4 and 13 post partum, for thyroid hormone analysis; samples from adult males and Day 13 offspring were analyzed for Thyroxine (T4).
Vaginal smears were performed for all females from the day after arrival (enabling the exclusion of females not showing appropriate estrous cycling from dosing) and for all treated females including controls through pre-pairing, pairing and up to confirmation of mating.
Vaginal smears were also performed in the morning on the day of termination for all treated females. Adult males were terminated on Day 44 or 45, followed by the termination of all surviving offspring and adult females on Days 13 and 14 post partum, respectively. Any female which did not produce a pregnancy was terminated around the same time as littering females. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. All offspring were examined externally; where external observations were detected an internal necropsy was performed. - Fetal examinations:
- During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and ano-genital distance and visible nipple count (male offspring only).
- Statistics:
- Where considered appropriate, quantitative data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows:
Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variances were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found but the data shows nonhomogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel
(non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).
Data not analyzed by the Provantis data capture system were assessed separately using the R Environment for Statistical Computing. Initially, the distribution of the data was assessed by the Shapiro-Wilk normality test, followed by assessment of the homogeneity of the data using Bartlett’s test. Where considered appropriate, parametric analysis of the data was applied incorporating analysis of variance (ANOVA), which if significant, was followed by pair-wise comparisons using Dunnett’s test. Where parametric analysis of the data was considered to be unsuitable, non-parametric analysis of the data was performed incorporating the Kruskal-Wallis test which if significant was followed by the Mann-Whitney "U" test. Dose response relationships were also investigated by linear regression. Where the data were unsuitable for
these analyses then pair-wise tests were performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Throughout the treatment period, noisy respiration, increased salivation, fur stained by the test item (pink/red) and pink stained bedding was evident in animals of either sex from all treatment groups. One male treated with 175 mg/kg bw/day also showed an isolated incidence of hunched posture.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female treated with 175 mg/kg bw/day was found dead on Day 10. This female had mild degenerate/inflammatory changes in the stomach and hyperkeratosis in the stomach, however, the cause of death was not identified. One male treated with 25 mg/kg bw/day was killed in extremis on Day 15 due to the severity of clinical signs noted, which included gasping/labored/noisy respiration, decreased respiratory rate, stained snout, fur stained by test item and a distended abdomen. Changes were apparent in the gastrointestinal tract at necropsy; however, no histopathological changes were evident in the tissues examined. One female treated with 25 mg/kg bw/day was killed in extremis on Day 38 due to difficulties during parturition. There were no further unscheduled deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males from all treatment groups showed a reduction in body weight gain during Weeks 1, 2 and 4, which resulted in a reduction in overall body weight gain. Females treated with 175 mg/kg bw/day showed a reduction in overall body weight gain during maturation. Reductions in body weight gain were also evident during the final two weeks of gestation and during lactation. No adverse effect in body weight development was evident in females treated with 75 or 25 mg/kg bw/day during maturation, gestation or lactation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Males treated with 175 mg/kg bw/day showed a reduction in overall food consumption and food conversion efficiency. No such effects were evident in males treated with 75 or 25 mg/kg bw/day.
Females treated with 175 mg/kg bw/day showed a slight reduction in overall food consumption during maturation and a reduction in food consumption throughout lactation. Food conversion efficiency for these females during maturation was comparable to controls. No such effects on food consumption were evident in females treated with 75 or 25 mg/kg bw/day. - Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no toxicologically significant effects detected in the organ weights measured.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The female treated with 175 mg/kg bw/day that was found dead on Day 10 had a dark liver and red content in the stomach. The stomach was also stained by the test item. The male treated with 25 mg/kg bw/day that was killed in extremis on Day 15 had gaseous distension in the stomach and intestines, small seminal vesicles, a thin cecum, red contents in the stomach and sloughing/thinning of the non-glandular region of the stomach. The female treated with 25 mg/kg bw/day that was killed in extremis on Day 38 had a dead fetus which had rotated in the vagina.
One female treated with 175 mg/kg bw/day had gaseous distension in the cecum, colon and rectum and a further female from this treatment group had raised white areas on the nonglandular region of the stomach. No such effects were evident in males treated with 175 mg/kg bw/day or in animals of either sex treated with 75 or 25 mg/kg bw/day. - Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Stomach: Hyperplasia of the non-glandular mucosa was present in two males treated with 75 mg/kg bw/day and in one male and two females treated with 175 mg/kg bw/day. Hyperkeratosis was also evident in one male each from the 75 and 175 mg/kg bw/day dose group. No such effects were evident in females treated with 75 mg/kg bw/day or in animals of either sex treated with 25 mg/kg bw/day.
- Details on results:
- Thyroid Hormone Analysis
An evaluation of Thyroxine (T4) in adult males and male/female offspring (Day 13 of age) did not identify any treatment-related findings.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Description (incidence and severity):
- Estrous Cycle
There was no effect of treatment with the test item at any dose level on the nature of estrous cycle with most females showing regular cycles over the pre-pairing phase of the study. There were also no intergroup differences in the stage of estrus on the day of necropsy.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 175 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- histopathology: non-neoplastic
- Remarks on result:
- other: local toxicity observed in stomach, while no effects on reproductive system/functions were seen
- Remarks:
- The reduced body weight development and microscopic changes evident in the stomach were considered to be the result of an irritant effect of the test item rather than a true systemic effect and as such was considered adaptive and non-adverse. Therefore, a ‘No Observed Adverse Effect Level’ (NOAEL) can be established at 175 mg/kg bw/day for animals of either sex.
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- As a consequence of the slightly lower litter size at birth in females treated with 175 mg/kg bw/day, litter weights were reduced in these females throughout lactation. Offspring body weight gains in these litters were slightly lower than controls from Day 4 of lactation onwards. No such effects were detected in females treated with 75 or 25 mg/kg bw/day.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Litter size at birth and subsequently during lactation was slightly reduced in females treated with 175 mg/kg bw/day.
- Changes in postnatal survival:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- Ano-genital distance on Day 1 post partum, visible nipple count in male offspring on Day 13 post partum and clinical signs up to Day 13 of age at 25, 75 and 175 mg/kg bw/day for all treated litters was comparable to controls.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 175 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no adverse effects observed
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
DEVIATIONS FROM STUDY PLAN
The following deviations from the study plan occurred:
Clinical Observations
The one hour post-dosing observations were performed approximately thirty minutes after they were due on Day 30 relative to the start of dosing. All other observations were performed correctly on that day and whilst this omission was regrettable it does not affect the purpose or integrity of the study.
Selection of Animals for Extended Observations
Due to the death of Male No. 29 during the study, Male No. 30 was selected as a replacement for the extended observations. Sensory Reactivity, Motor Activity, Grip Strength, Hematology and Blood Chemistry were all performed on this male, however, at necropsy the full tissue list was not retained in error. In view of the incomplete data for this male, another male (No. 31) had the full extended observations performed. All of the data recorded for both animals will be reported.
Mortalities
There were a small number of instances during the study where the early mortality checks were not performed at times considered acceptable by the Study Director. However, as all animals were monitored twice daily from arrival to termination, this deviation can be considered not to have affected the purpose or scientific integrity of the study.
Litter data
The sex for offspring No. 7 from Litter 94 was not recorded on Day 4 of lactation in error. The sex on Day 1 and Day 13 of lactation for this offspring was confirmed as male, therefore, for reporting purposes, this offspring will be reported as male for Day 4 of lactation.
Applicant's summary and conclusion
- Conclusions:
- 'No Observed Adverse Effect Level' (NOAEL) for developmental toxicity was considered to be 175 mg/kg bw/day.
- Executive summary:
The oral administration of FAT 31016/T TE to rats by gavage, at dose levels of 25, 75 and 175 mg/kg bw/day in this study conducted according to OECD Guideline 422, resulted in treatment-related microscopic effects in animals of either sex treated with 175 mg/kg bw/day and in males treated with 75 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 75 mg/kg bw/day for females and 25 mg/kg bw/day for males.
The reduced body weight development and microscopic changes evident in the stomach were considered to be the result of an irritant effect of the test item rather than a true systemic effect and as such was considered adaptive and non-adverse. Therefore, a ‘No Observed Adverse Effect Level’ (NOAEL) can be established at 175 mg/kg bw/day for animals of either sex.
There were no effects on fertility, the ‘No Observed Effect Level’ (NOEL) for fertility is considered to be 175 mg/kg bw/day. A 'No Observed Adverse Effect Level' (NOAEL) for developmental toxicity may be established at 175 mg/kg bw/day due to the effects seen in litter size, litter weights and offspring body weight gain being minimal, group mean values being within historical control ranges and most likely a result of the impaired health of the dam from lower body weight gain and food consumption during lactation.
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