Fatty acids, C18-22

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study tested with the source substance CAS 112-05-2. In accordance to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nonanoic acid

EC Number:

203-931-2

EC Name:

Nonanoic acid

Cas Number:

112-05-0

Molecular formula:

C9H18O2

IUPAC Name:

nonanoic acid

Details on test material:

- Name of test material (as cited in study report): Pelargonsäure
- Substance type: organic acid
- Physical state: liquid
- Analytical purity: 93% C9 fatty acid
- Lot/batch No.: 799800

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: mean males: 217 g; females: 176
- Housing: in groups of 5. Singly during activity monitoring overnight.
- Diet: ad libitum starting at 4 hours after dosing
- Water: tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-3
- Humidity (%): 30-70
- Air changes/hour: 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Formulations in vehicle were prepared daily within 4 hours prior to dosing.
Homogeneity and stability were checked.


VEHICLE
- Justification for use and choice of vehicle: based on results of a pre-test
- Concentration in vehicle: approx. 90-99.95%
- Amount of vehicle (if gavage): 5mL/kg bw/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A GC/MS method was developed and evaluated

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily, 7 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 150, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on results of a pre-test using dose levels of 150 and 1000 mg/kg bw/day

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily


BODY WEIGHT: Yes
- Time schedule for examinations: on days 1, 8, 15, 22, and 28


FOOD CONSUMPTION AND COMPOUND INTAKE (no feeding study): yes
- Time schedule: weekly


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


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Anaesthetic used for blood collection: Yes (iso-flurane)
- Animals fasted: Yes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: sensory activity; grip strength; motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Dunnett-test and exact Fisher-test

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

breathing difficulties in 1000 mg/kg bw/d group (non-adverse)

Mortality:

mortality observed, treatment-related

Description (incidence):

breathing difficulties in 1000 mg/kg bw/d group (non-adverse)

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):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

hyperplasia of squamous epithelium of forestomach in 1000 mg/kg bw/d group (non-adverse)

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No substance-related mortality occurred.
Slight to moderate breathing difficulties (rales and/or gasping) were seen in several high dose animals on some days during week 3. These signs subsided and were absent during week 4.
No signs were noted in the low and intermediate dose groups.


BODY WEIGHT AND WEIGHT GAIN
Body weight and body weight gain of treated animals remained in the same range as controls over the 4-week study period.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There was no effect on food consumption except from a slight transient reduction in high dose females during week 3.


HAEMATOLOGY
There was no effect on hematological parameters.


CLINICAL CHEMISTRY
There were no treatment-related differences between control and treated animals.


NEUROBEHAVIOUR
No changes were noted in hearing ability, pupillary reflex, static righting reflex and grip strength, or in motor activity.


ORGAN WEIGHTS
Absolute and relative organ weights were similar between control and treated animals.


GROSS PATHOLOGY
Finding No. 1: an irregular surface of the forestomach was noted in all high dose animals.
Finding No. 2: a thickened (glandular mucosa of the ) stomach was observed among the treated animals. Since none of these cases could be confirmed microscopically, they were considered to be of no toxicological relevance.


HISTOPATHOLOGY: NON-NEOPLASTIC
No other findings than slight to marked hyperplasia of the squamous epithelium of the forestomach in all high dose animals, and at a minimal degree in 3 intermediate dose group animals.

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOAEL

Remarks:

local

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Taking into account that there is no correlate for the rat’s forestomach in humans the NOAEL for systemic toxicity is considered to be 1000 mg/kg bw/day.