Registration Dossier

Administrative data

Description of key information

Fatty acids, C16-18 (even numbered), iron(III) salts at 100 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. 

 

Fatty acids, C16-18 (even numbered), iron(III) salts at 300 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.

Fatty acids, C16-18 (even numbered), iron(III) 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.

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:
26 October 2018 to 08 March 2019
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:
no
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. / Bx IRST7H780L
- 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: Inoriginal container in dry cool place.
- Stability under test conditions: Stable
- 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:
other: RCCHan:WIST
Details on species / strain selection:
The preferred species is the rat. It has been historically shown to be a suitable model for repeated dose toxicity studies and is recommended by the regulatory authorities. The results may be of value in predicting the toxicity of the test item to humans.
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 to 9 weeks
- Weight at study initiation: 278.62 to 284.42 g
- Fasting period before study: no data
- Housing: Rats were housed in groups of 2 or 3 rats/cage/sex during the study period in sterile solid floor polypropylene rat cages (size: 41 × 28.2 × 18 cm). Each cage was fitted with a stainless steel (grille) top having provision for keeping rodent pellet feed and a polypropylene water bottle with a stainless steel drinking nozzle. Cages were placed in multi-tier racks (5 x 5) to ensure similar environmental conditions for all groups.
- Diet: Teklad Certified Global 16% protein rodent maintenance diet, Envigo USA, ad libitum
- Water: Reverse Osmosis (RO) water ad libitum (RO water filtration system) in polypropylene bottles.
- Acclimation period: 7 days

DETAILS OF FOOD AND WATER QUALITY: Every feed consignment received is accompanied by a certificate of analysis of nutrient content from the feed supplier. The quality of feed and water is monitored in compliance with JRF/TOX/SOP-2077.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24°C
- Humidity (%): 64 to 66%
- Air changes (per hr): 21
- Photoperiod (hrs dark / hrs light): The photoperiod was 12 hours light and 12 hours darkness, fluorescence light hours being 06.00 - 18.00 hours.

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
other: 0.5% carboxy-methyl-cellulose (CMC) with 1% tween 80
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): at least twice a week.
- Mixing appropriate amounts with (Type of food): Teklad Certified Global 16% protein rodent maintenance diet
- Storage temperature of food: no data

VEHICLE
- Justification for use and choice of vehicle (if other than water): after consultation with the Sponsor,
- Concentration in vehicle: The test item was mixed with 1% tween 80 (i.e., 1% of total volume to be prepared) followed by mixing with 0.5% CMC. The final volume was made up with 0.5% CMC.
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Element : Iron (Fe)
Wavelength : 238.204 nm
RF power : 1300 Watts
Pump (Flow rate): 1.5 mL/minute

Gas Flow Rate
Plasma : 15.0 L/minute
Auxillary : 0.2 L/minute
Nebulizer : 0.8 L/minute
Duration of treatment / exposure:
14 days
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
G1 - control (vehicle)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
G2 - Low dose
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
G3 - mid dose
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
G4 - High dose
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of the present study, the dose levels were chosen for the definitive reproduction/developmental toxicity screening study:
- Rationale for animal assignment (if not random):
- Fasting period before blood sampling for clinical biochemistry: no blood sample taken.
- Rationale for selecting satellite groups:
- 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 included; mortality, morbidity and clinical

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight was recorded for individual rats on days 1 (before commencement of treatment), and on days 4, 8, 11 and 14. Rats were also weighed on the day of necropsy (fasted body weight).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
A weighed amount of feed was offered to rats in each cage on days 1, 4, 8 and 11 and the leftover feed was measured on days 4, 8, 11 and 14.

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): No
- 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
The thoracic and abdominal cavities were opened and a thorough examination of the organs was carried out to detect any abnormalities.
Organs were weighed from all rats. Adherent adipose tissue from organs was trimmed off and the wet weight of organs recorded for the liver, kidneys, adrenals, testes, epididymis, prostate, cowper’s gland, levator ani plus bulbocavernosus muscles (LABC), seminal vesicles with coagulating glands, thyroid with parathyroid, thymus, heart, brain, spleen, uterus with cervix, and ovaries. The thyroid with parathyroid were weighed after overnight fixation. Paired organs were weighed together and a combined weight presented. The organ weight ratio as percentage of body weight was calculated. The tissues (or any organs showing gross lesions, none present in this study) were weighed and fixed in 10% neutral buffered formalin.

HISTOPATHOLOGY: No
Histopathology was not performed, hence, preserved organs/tissues will be discarded during report finalisation.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
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
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
Key result
Critical effects observed:
no
Conclusions:
Fatty acids, C16-18 (even numbered), iron(III) salts at 100 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.

Fatty acids, C16-18 (even numbered), iron(III) salts at 300 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.

Fatty acids, C16-18 (even numbered), iron(III) 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.
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

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

Additional information

Justification for classification or non-classification

This substance will not be classified for repeat doase toxicity. A 14 dya study returned a NOAEL of > 1000 mg/kg bw/day.