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EC number: 273-381-6 | CAS number: 68958-92-9
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline 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)
- Version / remarks:
- 2016
- Deviations:
- yes
- Remarks:
- , all were minor deviations not having an effect on the study outcome
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10-11 weeks (males), 13-14 weeks (females)
- Weight at study initiation: 253-307 g (males), 206-253 g (females)
- Fasting period before study: no
- Housing: group housing up to 5 animals of the same sex and dosing group ; mated females were housed individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6-7 days prior to start of dosing
DETAILS OF FOOD AND WATER QUALITY: pelleted rodent diet (SM R/M-Z from SNIFF Spezialdiäten GmbH, Germany), drinking water
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 44-67
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): suitable vehicle
- Concentration in vehicle: 5, 20, 80 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- the concentrations of the test substance analysed in the formulations by HPLC/MS were in agreement with target concentrations and were homogeneous.
- Duration of treatment / exposure:
- Males were dosed for 29 days. Females that delivered offspring were dosed for 51-62 days. Additional animals in the recovery groups (high dose) were treated similarly (males for 29 days, females for 55 days) and were terminated after a treatment-free period of 29 days.
- Frequency of treatment:
- once daily
- Dose / conc.:
- 25 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 400 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
based on results of a dose range finding study
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: yes (overnight)
- Rationale for selecting satellite groups: based on the results of the dose range finding study
- Post-exposure recovery period in satellite groups: 29 days
- Section schedule rationale (if not random):
- Other: - Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice daily
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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 / No / Not specified
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood of Main F0-animals was collected at the end of the treatment period on the day of scheduled necropsy. Blood of Recovery animals was collected at the end of the treatment period and on the day of scheduled necropsy at the end of the recovery period.
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5/sex/dose
- Parameters checked in table [No.?] were examined. see table on haematology attached
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: as for haematology
- Animals fasted: Yes
- How many animals: 5/sex/dose
- Parameters checked in table [No.?] were examined. see table on blood chemistry attached
URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / Not specified
- Animals fasted: Yes / No / Not specified
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: males: during week 4, females: during the last week of lactation
- Dose groups that were examined: all dose groups
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
IMMUNOLOGY: No
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% or 5% levels.
Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible.
Parametric: Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test).
Non-Parametric: Datasets with at least 3 groups was compared using a Steel-test (many-to-one rank test). The motor activity data set was compared using an overall Kruskal-Wallis.
Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using Fisher’s exact test whenever the overall test is significant. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- All males and females at 400 mg/kg showed pale and soft faeces starting at Treatment Day 4. In males, the faeces appeared normal from Day 7 of the recovery period onwards. In females, soft faeces persisted until about one week before the end of the treatment period, while faeces remained pale until the end of treatment. Faeces of females looked normal throughout the recovery period.
Hunched posture occurred in all 400 mg/kg males and females from Treatment Day 10. In males, the clinical sign persisted until Day 3 of the recovery period. In females, hunched posture persisted until about one week before the end of the treatment period in most animals. (4/9 lactating females showed hunched posture until the end of treatment).
Piloerection was noted in all 400 mg/kg males and females between Treatment Days 10-16 and in a single female (no. 90) at 400 mg/kg on Treatment Day 17. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- one animal of the mid-dose group died after 4 days due to a gavage dosing accidient
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- see Tables on body weight attached as background material
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- see Tables on food consumption attached as background material
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- see Tables on haematology summaries attached as background material
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The following statistically significant changes, mostly at 400 mg/kg, distinguished treated animals from control animals. Differences (fold-change) from the control group means are indicated between parentheses.
• Higher alanine aminotransferase (ALAT) in males (1.40x of control) and Recovery females (1.48x of control) at 400 mg/kg at the end of the treatment period. ALAT was no longer increased at the end of the recovery period.
• Lower alkaline phosphatase (ALP) in 400 mg/kg Recovery females (0.60x of control) at the end of the treatment period. Lower ALP values were also noted in males (0.72x of control) and Main females (0.56x of control) at 400 mg/kg at the end of treatment, but statistical significance was not achieved. ALP was no longer decreased at the end of the recovery period.
• Higher bile acids in males (1.68x of control) and Main females (2.32x of control) at 400 mg/kg at the end of the treatment period. Mean bile acids was also higher in 400 mg/kg Recovery females at the end of the treatment period (1.74x of control) but not statistically significantly. Bile acids were still increased (1.51x of control) in Recovery females at the end of the recovery period, although not statistically significant.
• Lower total bilirubin in males at 100 and 400 mg/kg (0.28 and 0.39x of control, respectively) and in 400 mg/kg Recovery females (0.11x of control) at the end of the treatment period. Total bilirubin was no longer reduced at the end of the recovery period.
• Lower cholesterol in 400 mg/kg Recovery females (0.69x of control) at the end of the treatment period. Cholesterol in these females was still lower (0.77x of control) at the end of the recovery period, but no longer statistically significantly.
• Higher urea in 400 mg/kg Recovery females (1.43x of control) at the end of the treatment period. Except in female no. 94, urea values had returned to normal at the end of the recovery period.
• Lower potassium in Main females at 400 mg/kg (0.86x of control). Potassium in 400 mg/kg Recovery females was similar to that in Recovery controls.
Mean ALAT and urea in 400 mg/kg animals slightly exceeded the P95-limit of the historical control ranges. Bilirubin values in all males at 100 and 400 mg/kg and all Recovery 400 mg/kg females were far below the historical ranges (below the detection limit in several animals). Mean values for ALP, bile acids, cholesterol and potassium remained within the historical control ranges.
Serum levels of T4 in F0 males were considered not to be affected by treatment. Although not reaching statistical significance serum levels of TSH in F0 males were increased at 400 mg/kg, (2.41x of control). In the absence of a clear dose-response relationship and as values remained within the historical control range, this finding was considered not toxicologically relevant.
Serum levels of T4 in F0 females were considered not to be affected by treatment. Similar to what was observed in F0 males, serum levels of TSH in F0 females were increased at 100 and 400 mg/kg, (1.94x and 1.74x of control, respectively). As all values remained well within the historical control range, this finding was considered not toxicologically relevant
see Tables on clinical biochemistry attached as background material - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- The variation in motor activity did not indicate a relation with treatment.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- At the end of the treatment period, test item-related higher weights of the liver and kidneys were noted in both sexes. Liver weights (absolute and relative to body weight) were increased in 400 mg/kg Main males and females. Kidney weights were increased in Main males at 100 and 400 mg/kg (absolute and relative to body weight) and in Main females at 400 mg/kg (absolute).
At the end of the recovery period, organ weights were back within normal limits. Organ weights of treated Recovery females showed no remarkable differences from those of recovery controls.
see Tables on organ weights attached as background material - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals.
Grip strength values of treated animals (fore and hind limbs) at 400 mg/kg/d were 13-20% lower than controls but remained within the historical control ranges. - Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Hepatocellular hypertrophy, mainly centrilobular, was present at 400 mg/kg in Main males at minimal degree and in Main females at minimal to slight degree. This correlated with the increased liver weight. After the 28-day treatment-free recovery period, there were no test item-related liver findings.
Follicular cell hypertrophy of the thyroid gland was present at increased incidence and severity in Main females at 400 mg/kg up to slight degree. After the 28-day treatment-free recovery period, this finding was within normal background values.
There were no other test item-related histologic changes. - Histopathological findings: neoplastic:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 400 mg/kg bw/day (actual dose received)
- System:
- other: discomfort/general toxicity
- Organ:
- other: discomfort, general toxicity
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Conclusions:
- Clinical signs of discomfort/toxicity (hunched posture, piloerection) were observed in both sexes at the highest dose level of 400 mg/kg body weight/day. In addition, several effects were observed at study termination (28 days for males and 51-62 days for females having offspring) that all were reversible after a 28 day recovery period without dosing.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 2016
- Deviations:
- yes
- Remarks:
- all were minor deviations not having an effect on study outcome
- GLP compliance:
- yes
Test material
- Reference substance name:
- Bis[O,O-bis(2-ethylhexyl) dithiophosphorato-S,S']dioxodi-μ-thioxodimolybdenum
- EC Number:
- 273-381-6
- EC Name:
- Bis[O,O-bis(2-ethylhexyl) dithiophosphorato-S,S']dioxodi-μ-thioxodimolybdenum
- Cas Number:
- 68958-92-9
- Molecular formula:
- C32H68Mo2O6P2S6
- IUPAC Name:
- Bis[O,O-bis(2-ethylhexyl) dithiophosphorato-S,S']dioxodi-μ-thioxodimolybdenum
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10-11 weeks (males), 13-14 weeks (females)
- Weight at study initiation: 253-307 g (males), 206-253 g (females)
- Fasting period before study: no
- Housing: group housing up to 5 animals of the same sex and dosing group
; mated females were housed individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6-7 days prior to start of dosing
DETAILS OF FOOD AND WATER QUALITY: pelleted rodent diet (SM R/M-Z from SNIFF Spezialdiäten GmbH, Germany), drinking water
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 44-67
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light):
12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): suitable vehicle
- Concentration in vehicle: 5, 20, 80 mg/ml
- Amount of vehicle (if gavage): 5 mg/kg body weight
- Lot/batch no. (if required):
- Purity: - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: max. 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. not applicable
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how): indivually
- Any other deviations from standard protocol: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- the concentrations of the test substance analysed in the formulations by HPLC/MS were in agreement with target concentrations and were homogeneous.
- Duration of treatment / exposure:
- Males were dosed for 29 days. Females that delivered offspring were dosed for 51-62 days.
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 25 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 400 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
based on results of a dose range finding study
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: yes (overnight)
- Other: animals of satelite groups for a post-exposure recovery period were not mated - Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice daily
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations:
Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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 / No / Not specified
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified
- Time schedule for examinations: - Oestrous cyclicity (parental animals):
- Estrous cycles were evaluated by examining the vaginal cytology of samples obtained by vaginal lavage.
Daily vaginal lavage was performed for all females (Main and Recovery) during 14 days prior to treatment (pretest period) and the first 14 days of treatment. For Main females, daily vaginal lavage was continued during mating until evidence of copulation was observed. - Sperm parameters (parental animals):
- For the testes of all selected Main males of Groups 1 and 4 and all Main males that failed to sire, a detailed qualitative examination was made, taking into account the tubular stages of the spermatogenic cycle.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were used for blood sampling, killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups,
GROSS EXAMINATION OF DEAD PUPS: no
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after 28 days of dosing
- Maternal animals: All surviving animals on PND 14-16
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring was sacrificed on PND 14-16
- These animals were subjected to postmortem examinations (macroscopic examination) as follows:
On PND 4, the surplus pups (> 8 pups per litter) were euthanized by decapitation. From two surplus pups per litter, blood was collected, if possible. All remaining pups were euthanized on PND 14-16. Sex was determined both externally and internally. Descriptions of all external abnormalities were recorded. Particular attention was paid to the external reproductive genitals to examine signs of altered development.
In addition, blood was collected from two pups per litter, and the thyroid from two pups per litter (one male and one female pup) was preserved in 10% buffered formalin. The pups selected for blood sampling were the same pups as selected for thyroid preservation.
GROSS NECROPSY
- Gross necropsy consisted of external examinations
HISTOPATHOLOGY / ORGAN WEIGTHS: not performed - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% or 5% levels.
Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible.
Parametric: Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test).
Non-Parametric: Datasets with at least 3 groups was compared using a Steel-test (many-to-one rank test). The motor activity data set was compared using an overall Kruskal-Wallis.
Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using Fisher’s exact test whenever the overall test is significant - Reproductive indices:
- see "reproduction and viability indices" attached as background material
- Offspring viability indices:
- see "reproduction and viability indices" attached as background material
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- All males and females at 400 mg/kg showed pale and soft faeces starting at Treatment Day 4. In males, the faeces appeared normal from Day 7 of the recovery period onwards. In females, soft faeces persisted until about one week before the end of the treatment period, while faeces remained pale until the end of treatment. Faeces of females looked normal throughout the recovery period.
Hunched posture occurred in all 400 mg/kg males and females from Treatment Day 10. In males, the clinical sign persisted until Day 3 of the recovery period. In females, hunched posture persisted until about one week before the end of the treatment period in most animals. (4/9 lactating females showed hunched posture until the end of treatment).
Piloerection was noted in all 400 mg/kg males and females between Treatment Days 10-16 and in a single female (no. 90) at 400 mg/kg on Treatment Day 17. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- one animal of the mid-dose group after 4 days due to a gavage dosing accident
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- see respective Table in endpoint study record of repeated dose toxicity study attached as background material
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- see respective Table in endpoint study record of repeated dose toxicity study attached as background material
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- see respective Table in endpoint study record of repeated dose toxicity study attached as background material
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see respective Table in endpoint study record of repeated dose toxicity study attached as background material
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Hepatocellular hypertrophy, mainly centrilobular, was present at 400 mg/kg in Main males at minimal degree and in Main females at minimal to slight degree. This correlated with the increased liver weight. After the 28-day treatment-free recovery period, there were no test item-related liver findings.
Follicular cell hypertrophy of the thyroid gland was present at increased incidence and severity in Main females at 400 mg/kg up to slight degree. After the 28-day treatment-free recovery period, this finding was within normal background values.
There were no other test item-related histologic changes. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- see Table on estrous cycles attached as background material
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- see Tables on reproduction data attached as background material
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- Remarks on result:
- other: discomfort/toxicity (hunched posture, piloerection)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- for reproductive function
- Effect level:
- > 400 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no effects at highest dose tested
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
- System:
- other: only general, clinical toxicity was observed, no specific organ toxicity
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Viability index (number of live offspring on PND 4 before culling as percentage of number of live offspring on PND 1) was considered not to be affected by treatment. Viability indices were 99, 100, 98 and 97% for the control, 25, 100 and 400 mg/kg groups, respectively. One pup of the control group, two pups at 100 mg/kg (from two litters) and four pups at 400 mg/kg (from four litters) went missing (presumed cannibalized) on PND 2, 3 or 4. This post-natal loss was regarded as unrelated to treatment due to the incidental occurrence (within the range considered normal for pups of this age).
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- see Table on body weights of pups attached as background material
- Food consumption and compound intake (if feeding study):
- not examined
- Description (incidence and severity):
- pups were killed on PND 14-16
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- In female PND 14-16 pups there was a trend towards an increase in total T4 with increasing dose levels. The relative differences from controls were 4, 10 and 18% at 25, 100 and 400 mg/kg, respectively (statistical significance was not achieved). Mean T4 values at 100 and 400 mg/kg approached the P95-limit of the historical control range (whereas the concurrent control mean was close to the historical mean) and about half of the individual values at 100 and 400 mg/kg exceeded the historical range. TSH levels in female PND 14-16 pups were decreased at 400 mg/kg (0.85x of control), although not reaching statistical significance. As all values remained within the range of the historical control data, this finding was considered not toxicologically relevant.
Serum T4 and TSH levels in male PND 14-16 pups were considered not to be affected by
treatment.
Serum levels of T4 in PND 4 pups were considered not to be affected by treatment.
see Table on T4 and TSH levels of PND 14-16 pups attached as background material - Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Anogenital distance (AGD):
- no effects observed
- Description (incidence and severity):
- see Table on anogenital distance and nipple retention of pups attached as background material
- Nipple retention in male pups:
- no effects observed
- Description (incidence and severity):
- see Table on anogenital distance and nipple retention of pups attached as background material
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
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:
- > 400 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks:
- dams were dosed
- Sex:
- male/female
- Remarks on result:
- other: no effects at highest dose tested
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Clinical signs of discomfort/toxicity (hunched posture, piloerection) were observed in parental animals of both sexes at the highest dose level of 400 mg/kg body weight/day. In addition, several effects were observed at study termination (28 days for males and 51-62 days for females having offspring) that all were reversible after a 28 day recovery period without dosing.
Despite parental toxicity observed at the highest dose level of 400 mg/kg/d no effects on reproductive function and on development of offspring until PND 14-16 was observed at the highest dose level.
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