Silver docosanoate

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

other: dose level selection purposes

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Principles of method if other than guideline:

No testing guidelines are applicable as this study was intended for dose level selection purposes only

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Silver docosanoate

EC Number:

219-641-4

EC Name:

Silver docosanoate

Cas Number:

2489-05-6

Molecular formula:

C22H44O2.Ag

IUPAC Name:

silver(1+) docosanoate

Constituent 2

Reference substance name:

CH03220

IUPAC Name:

CH03220

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): CH03220
- Molecular formula (if other than submission substance): C22H4402.Ag
- Molecular weight (if other than submission substance):447.44
- Physical state: white powder
- Analytical purity: 100 wt % silver docosanoate
- Lot/batch No.: CH03220/AJ
- Storage condition of test material: at room temperature, protected from light
- Stability under storage conditions: stable
- Expiry date: 25 nov 2012 (1 year after receipt of the test substance)

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

- Charles River Deutschland, Sulzfeld, Germany.
- 6 females (females were nulliparous and non-pregnant).
- Age: Approximately 11 weeks
- RAndomization: Animals were allocated at random at discretion of the biotechnician according to body weight, with all animals within ± 20% of the sex mean.
- Acclimatization: At least 5 days before the start of treatment under laboratory conditions.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

specific gravity 0.92

Duration of treatment / exposure:

15 days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Two groups were tested, each consisting of 3 females.

Examinations

Observations and examinations performed and frequency:

- Mortality: at least twice daily
- Clinical signs: Detailed clinical observations were made in all animals at 0-15 minutes, 1 hour (±15 minutes) and 3 hours (± 30 minutes) after dosing. The time of onset, grade and duration of any observed signs were recorded. Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored. In the data tables, the scored grades are reported, as well as the percentage of animals affected in summary tables.
- Body weight and food consumtpion: days 1, 5, 10 and 15

Sacrifice and pathology:

Animals were deeply anaesthetized using isoflurane (Abbott B.V., Hoofddorp, The Netherlands) and subsequently exsanguinated and subjected to a full post mortem examination. Descriptions of all macroscopic abnormalities were recorded. No organs were fixed.
Terminal body weight, kidney and liver weight were determined at scheduled necropsy.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg:
Hunched posture (all animals on Day 12 and/or 13), salivation (one animal on Day 15).
1000 mg/kg:
Hunched posture (all animals on Day 9, 12 and/or 13), salivation (all animals on Day 9, 11, 12 and/or 15), piloerection (all animals, on Day 9, 12, 13 and/or 15), lean appearance (one animal (sacrificed) on Day 10).

Mortality:

mortality observed, treatment-related

Description (incidence):

500 mg/kg:
No mortality.
1000 mg/kg:
One animal sacrificed in extremis on Day 10.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg:
Reduced weight gain/slight weight loss (all animals; up to 3%).
1000 mg/kg:
Significant weight loss for one animal (22%), reduced weight gain/slight weight loss (both surviving animals; up to 6%).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg:
Slightly reduced food consumption.
1000 mg/kg:
Reduced food consumption.

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

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg:
Greenish discolouration of the pancreas (two animals), reduced size of the thymus (one animal).
1000 mg/kg:
Greenish discolouration of the pancreas (two animals), reduced size of the thymus and emaciated appearance (sacrificed animal).

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

CH03220 was administered by daily oral gavage to female Wistar Han rats at dose levels of 500 or 1000 mg/kg.
Clear evidence of toxicity was found at a dose of 1000 mg/kg, and to a lesser extent at 500 mg/kg. At 1000 mg/kg, one female was sacrificed in extremis. Weight loss and/or reduced weight gain along with lower food intake was noted at 500 and 1000 mg/kg. Necropsy showed greenish discolouration of the pancreas in most animals at 500 and 1000 mg/kg. Liver and kidney weights were considered to have been unaffected by treatment at 500 and 1000 mg/kg.

Effect levels

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

mortality

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

CH03220 was administered by daily oral gavage to female Wistar Han rats at dose levels of 500 or 1000 mg/kg.
Clear evidence of toxicity was found at a dose of 1000 mg/kg, and to a lesser extent at 500 mg/kg. At 1000 mg/kg, one female was sacrificed in extremis. Weight loss and/or reduced weight gain along with lower food intake was noted at 500 and 1000 mg/kg. Necropsy showed greenish discolouration of the pancreas in most animals at 500 and 1000 mg/kg. Liver and kidney weights were considered to have been unaffected by treatment at 500 and 1000 mg/kg.

Executive summary:

SUMMARY

Title
15-Day repeated dose toxicity study with CH03220 by daily gavage in the rat

Aim of the study
The nature and purpose of this study was to assess the toxic potential of the test substance in order to select dose levels for a main study (combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test, which was later cancelled at request of the sponsor), and to determine the peak effect of occurrence of clinical signs after dosing.

Guidelines
No testing guidelines are applicable as this study was intended for dose level selection purposes only.

Rationale for dose levels
The dose levels for this 15-day toxicity study were selected to be 500 and 1000 mg/kg.

Study outline
The test substance, formulated in corn oil, was administered daily for 15 days by oral gavage to SPF- bred Wistar rats. Two groups were tested, each consisting of 3 females.

Evaluated parameters
The following parameters were evaluated: clinical signs daily at 0, 1 and 3 hours after dosing; body weight on Days 1, 5, 10 and 15; food consumption over Days 1-5, 5-10 and 10-15; macroscopy, and liver and kidney weight at termination.

Results

Clear evidence of toxicity was found at a dose of 1000 mg/kg, and to a lesser extent at 500 mg/kg. At 1000 mg/kg, one female was sacrificedin extremis. Weight loss and/or reduced weight gain along with lower food intake was noted at 500 and 1000 mg/kg. Necropsy showed greenish discolouration of the pancreas in most animals at 500 and 1000 mg/kg. Liver and kidney weights were considered to have been unaffected by treatment at 500 and 1000 mg/kg.