[No public or meaningful name is available]

Endpoint summary

Description of key information

A 14-day repeated-dose toxicity via the oral route (gavage) was conducted on rats. The NOAEL was established at 1000 mg/kg/day.

In accordance with Annex IX of REACH, a Testing Proposal is submitted in order to conduct a subchronic repeated-dose toxicity study via the oral route on the registered substance.

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

Remarks:

14 day repeated dose oral (gavage) range-finding toxicity study in the rat conducted as part of OECD 414 study.

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

5 January 2018 to 15 October 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Range find study conducted as part of OECD 414 study.

Qualifier:

according to guideline

Guideline:

other: Range-Finding Toxicity Study in the Rat, to inform dose selection in an OECD 414 study.

Deviations:

no

Principles of method if other than guideline:

This non-GLP study was conducted in accordance with Good Laboratory Practice principles.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

Appearance: Light yellow to tan solid.
Purity: 100% (nominal): This substance has unknown or variable compostion, is a Complex reaction product, or a biological material (UVCB)

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Limited.
- Age at study initiation: 62 to 68 days.
- Weight at study initiation: Males: 225 to 262 g Females 162 to 183 g
- Housing: The cages were polycarbonate body with a stainless steel mesh lid. Males and females were blocked by sex and the cages constituting each group were dispersed in the battery so that possible environmental influences arising from their spatial distribution were equilibrated, as far as was practicable. There were three of the same same sex rats per cage. Bedding was wood based which was changed at appropriate intervals each week. Plastic shelter was provided to each cage throughout the study and replaced when necessary.
- Diet (e.g. ad libitum): SDS VRF1 Certified, pelleted diet
- Water (e.g. ad libitum): Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark.

Route of administration:

oral: gavage

Details on route of administration:

Administration by using a suitably gradulated syringe and a rubber catheter inserted via the mouth.

Vehicle:

other: 0.5% w/v methylcellulose and 0.1% Tween 80

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

The required amount of test material was ground in a mortar using a pestle to a fine powder and mixed with a small amount of the vehicle to form a paste. Any agglomerates were broken down. Further amounts of vehicle were gradually added and mixed to produce a smooth, pourable suspension. The suspension was transferred to a measuring cylinder which had been wetted with vehicle, the mortar was rinsed with vehicle and this was added to the measuring cylinder. Vehicle was added to achieve the final volume and the suspension was transferred to a beaker and mixed using a high shear homogenizer. The
suspension was transferred to the final containers, via syringe whilst magnetically stirring.

A series of suspensions at the required concentrations were prepared by dilution of individual weighings of the test material.


Frequency of preparation: Weekly

Storage of formulation: Refrigerated (2 to 8°C)

VEHICLE
Vehicle: 05.% w/v methylcellulose and 0.1% Tween 80
Amount of vehicle (if gavage): 10 mL/kg

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 Days

Frequency of treatment:

Once daily at approximately the same time each day.

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

3 Male; 3 Female

Control animals:

yes

Details on study design:

- Dose selection rationale: Dosage levels were selected following consultation between the Study Director and the Study Monitor for the Sponsor. Information from the ECHA website on this compound indicates that, following an acute study with this compound, the LD50 was considered to be >2000 mg/kg/day.

Observations and examinations performed and frequency:

Detailed observations were recorded daily at the following times in relation to dose administration:
- Pre-dose
- As each animal was returned to its home cage
- At the end of the dosing all groups
- One to two hours after completion of dosing
- As late as possible in the working day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- The weight of food supplied to each cage, that remaining and and estimate of any spilled was recorded for the three days before treatment and twice weekly during the treatment period.

WATER CONSUMPTION: Yes
- Time schedule for examinations: Daily by visual observation.

Sacrifice and pathology:

TERMINATION
- Carbon dioxide asphyxiation with subsequent exsanguination.

NECROPSY
All animals were subject to a detailed necropsy. After a review of the history of each animal,
the thoracic and abdominal cavities were opened and examined visually. Any abnormality in
the appearance or size of any organ and tissue (external and cut surface) was recorded and the
required tissue samples preserved in appropriate fixative.

Statistics:

No statistical analysis of the data was performed on this study.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no clinical signs seen and no signs associated with treatment of the test item seen over the 2 week treatment period.

Mortality:

no mortality observed

Description (incidence):

All animals survived to scheduled sacrifice.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

When compared to Control, overall bodyweight gains for animals treated at 500 or 1000 mg/kg/day were slightly low and, at these levels, indicated a relationship to dose.
Females receiving 1000 mg/kg/day from Day 4 to 8 were observed with body weight loss.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

When compared to Control, overall food consumption was slightly low for males at 1000 mg/kg/day and low for females at 500 or 1000 mg/kg/day.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

A visual assessment of water intake did not reveal any effect of treatment.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Behavior of the animals were unaffected by treatment.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Group mean spleen weights at 500 or 1000 mg/kg/day in both sexes were increased slightly,
compared to controls, at the end of the two week treatment period but there was no dose response.
Kidney and liver weight were unaffected by treatment.

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

There were no treatement-related effects in clinical observations and no macroscopic changes at necropsy. The decrease in overall body weight gain and food consumption in males at 1000 mg/kg/day and females at 500 or 1000 mg/kg/day was minimal. It was concluded that oral doses up to 1000 mg/kg/day would be a suitable high dose level for the subsequent prenatal developmental toxicity study, and/or general toxicity studies of longer duration.

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:

body weight and weight gain

clinical signs

organ weights and organ / body weight ratios

Critical effects observed:

not specified

Conclusions:

Based on the results of this study, the test material was well tolerated in Han Wistar rats at oral doses up to 1000 mg/kg/day.

Executive summary:

The test material was well tolerated in Han Wistar rats at oral doses up to 1000 mg/kg/day. All animals survived to scheduled sacrifice. There were no treatment-related effects in clinical observations and no macroscopic changes at necropsy.

The decrease in overall body weight gain and food consumption in males at 1000 mg/kg/day and females at 500 or 1000 mg/kg/day was minimal. It was concluded that oral doses up to 1000 mg/kg/day would be a suitable high dose level for the subsequent prenatal developmental toxicity study, and/or general toxicity studies of longer duration.

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:

2

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

14-day repeated-dose toxicity study: oral (registered substance)

The test material was well tolerated in Han Wistar rats at oral doses up to 1000 mg/kg/day. All animals survived to scheduled sacrifice. There were no treatment-related effects in clinical observations and no macroscopic changes at necropsy.

The decrease in overall body weight gain and food consumption in males at 1000 mg/kg/day and females at 500 or 1000 mg/kg/day was minimal. It was concluded that oral doses up to 1000 mg/kg/day would be a suitable high dose level for the subsequent prenatal developmental toxicity study, and/or general toxicity studies of longer duration.

Justification for classification or non-classification

Based on the currently available experimental data, repeated exposure to the registered substance for 14 days does not result in noticeable adverse effects.

According to Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP), the registered substance does not meet the criteria for classification.