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Administrative data

Description of key information

Under the conditions of the 14 day repeated dose study no effects were observed at the 1000 mg/kg bw/day. Therefore the NOAEL is > 1000 mg/kg bw/day

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

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
Study period:
2 November 2018 (Experimental Start) to 25 November 2019 (Experimental Completion)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Nitika Pharmaceutical Specialities Pvt. Ltd./ MNST9H796L
- Expiration date of the lot/batch: August 2023
- Purity test date: September 2018

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In original container at ambient.
- Stability under test conditions:
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: none
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid:

FORM AS APPLIED IN THE TEST (if different from that of starting material)

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)

OTHER SPECIFICS:
- measurement of pH, osmolality, and precipitate in the culture medium to which the test chemical is added:
- other information:
Species:
rat
Strain:
Wistar
Remarks:
RccHan:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Commercial laboratory animal supplier.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8-9 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: Rats were housed in groups of 2 or 3 rats per cage/sex during the study period in sterile solid floor polypepylene cages.
- Diet: Teklad certified global 16% protein rodent maitenance diet, ad libitum
- Water: ad libitum
- Acclimation period: a minimum of 8 days.

DETAILS OF FOOD AND WATER QUALITY: Every feed consignment is accompanied by a certificate of analysis of nutrient content and water is analaysed for purity.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23°C
- Humidity (%): 64 - 66%
- Air changes (per hr): 21
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): twice a week
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on solubilty of test substance and after consultaion with the sponsor.
- Concentration in vehicle:
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Each dose level was analysed for test substance stability.
Duration of treatment / exposure:
14 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
G1; vehicle control
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
G2; low dose
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
G3; mid-dose
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
G4; high dose
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Chosen as a range finding study for the OECD 422.
- Rationale for animal assignment (if not random): randomised by computer program.
- Fasting period before blood sampling for clinical biochemistry: no data
- Rationale for selecting satellite groups: n/a
- Post-exposure recovery period in satellite groups:
- 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: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Fasted rats on day 1 before treatment and days 4, 8, 11 and 14.

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 / No / Not specified
- 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: Yes / No / Not specified

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: No
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / Not specified
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No
- Time schedule for collection of blood:
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

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: No
- Time schedule for examinations:
- Dose groups that were examined:
- 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
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight changes in treated rats were the same as the control group
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption of treated rats was comparable to the control group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Relative organ weights of the treated groups were comparable to the control group.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Internal examinations of terminally sacrificed rats of both sexes and belonging to all groups revealed no abnormalities with the exception of one male rat in the high dose group which has reduced testes and epididymis size (bilateral).
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
Clinical and pathological observation showed no effects from the test substance in all concentration groups.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
other:
Key result
Critical effects observed:
no
Conclusions:
Fatty acids, C16-18 (even numbered), manganese (II) salts at 1000 mg/kg b. wt./day
- No mortality or clinical signs were observed.
- No treatment related effects on body weight, body weight gain, food consumption and organ weights (absolute and relative) were observed.
- External and internal examination of rats of either sex did not reveal any abnormality.

Based on results of the present study, the following dose levels are suggested for the definitive reproduction/developmental toxicity screening study:
Option Low Dose Mid Dose High Dose
I 100 300 1000
II 250 500 1000

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a sub-chronic toxicity study (90 days) does not need to be conducted because the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day 'limit test' and human exposure is limited
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a sub-chronic toxicity study (90 days) does not need to be conducted because the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day 'limit test' and human exposure is limited
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

Additional information

Justification for classification or non-classification

Under the conditions of the 14 day repeated dose study no effects were observed at the 1000 mg/kg bw/day. Therefore the NOAEL is > 1000 mg/kg bw/day.