Molybdenum, bis(N,N-dibutylcarbamodithioato-κS,κS')dioxodi-μ-thioxodi-, stereoisomer

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

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: 10-12 weeks (males), 11-14 weeks (females)
- Weight at study initiation: 265-372 g (males), 194-238 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 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 (%): 43-67
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Route of administration:

oral: gavage

Vehicle:

propylene glycol

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: 20, 60, 200 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/UV 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 50-62 days. Additional animals in the recovery groups (high dose) were treated similarly (males for 29 days, females for 54 days) and were terminated after a treatment-free period of 29 days.

Frequency of treatment:

once daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 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 weekly

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 for F0 males (both main and recovery) and recovery females; F0 main females were not fasted overnight
- 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

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 300 and 1000 mg/kg showed pale faeces starting at Treatment Day 27. In 1000 mg/kg males, the faeces appeared normal from Day 26 of the recovery period onwards. In 1000 mg/kg females, faeces were normal from Day 5 of recovery.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

see Tables on body weight attached as background material

Food consumption and compound intake (if feeding study):

no effects observed

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, non-treatment-related

Description (incidence and severity):

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:

no effects observed

Description (incidence and severity):

see Tables on organ weights attached as background material

Gross pathological findings:

no effects observed

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Any findings were within normal background values.

Histopathological findings: neoplastic:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no effects at highest dose tested

Key result

Critical effects observed:

no

Conclusions:

No adverse effects were observed in both sexes up to the highest dose level of 1000 mg/kg body weight/day which represents the NOAEL.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

In this combined repeated dose oral and reproduction toxicity screening study with subacute exposure no adverse effects up to the highest dose level of 1000 mg/kg body weight/day were observed. Therefore, classification according to Regulation 1272/2008 is not needed.