Isooctadecanoic acid, reaction products with tetraethylenepentamine

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3/01/2006-2/16-2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to an internationally approved protocol and followed Good Laboratory Practice standards.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

Animals in the 12 and 50 mg/kg dose group were underdosed. This did not affect the outcome of the study since the highest dose level was properly administered and no adverse effects were observed. Other deviations did not affect the outcome either.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of fatty acids, C14-C18 (branched and linear) and C18 (unsaturated) with tetraethylenepentamine (linear, branched, cyclic)

EC Number:

701-204-9

Cas Number:

68784-17-8

IUPAC Name:

Reaction products of fatty acids, C14-C18 (branched and linear) and C18 (unsaturated) with tetraethylenepentamine (linear, branched, cyclic)

Test material form:

liquid: viscous

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: 8 weeks
- Weight at study initiation: 204-270 g (male); 151-207 (female)
- Housing: individually in wire mesh suspension cages
- Diet (e.g. ad libitum): ad libitum except prior to blood collection
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Test article formulations were prepared weekly as single formulations for each dosage level through Apr 7. For the remainder of the study, the 12 adn 50 mg/mL formulations were prepared every other day and the 200 mg/mL formulation continued to be prepared weekly. Formulations were divided into aliquots for daily dispensation and stored at room temperature with continuous stirring.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples (1mL) for concentration analysis were collected from each test group during the first week and last week. By extrapolation from the available information, Group 2 animals were under-dosed by up to 80% during the first two weeks and by up to 22.2% during the last two weeks. Group 3 animals were under-dosed by up to 50% during the first two weeks. The 1000 mg/kg/day group was dosed within acceptable ranges for the entire 28 days of dosing.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 60, 250, 1000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

14/sex/dose in control and high dose; 7/sex/dose in the low and mid dose

Control animals:

yes, concurrent vehicle

Details on study design:

Following 4 weeks of dose administration, 7 rats/sex/group were euthanized; the remaining 7 rats/sex in the control and high dose groups were euthanized following a 14-day nondosing (recovery) period.

Examinations

Observations and examinations performed and frequency:

All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily, and detailed physical examinations were performed weekly. Individual body weights and food consumption were recorded weekly. Functional observational battery and locomotor activity data were recorded for 7 animals/sex/group prior to the initiation of dose administration and during study week 3. Clinical pathology evaluations (hematology, serum chemistry and urinalysis) were performed for all rats assigned to the primary (study week 4) and recovery (study week 6) necropsies.

Sacrifice and pathology:

Complete necropsies were conducted on all animals, and selected organs were weighed. Selected tissues were examined microscopically from all animals in the control and 1000 mg/kg/day groups. Gross lesions were examined from all animals in the 60 and 250 mg/kg/day groups.

Statistics:

All statistical tests were performed using appropriate computing devices or programs.

Results and discussion

Results of examinations

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

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

There was a low incidence of chronic and chronic active inflammation in the lungs that were considered due to accidental aspiration of dosing formulation and not a manifestation of systemic toxicity.

Effect levels

1

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:

other: No signs of toxicity were observed in any of the parameters evaluated at any dose level tested.

2

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No signs of toxicity were observed in any of the parameters evaluated at any dose level tested.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, EC 701-204-9 did not exhibit adverse toxic effects and the NOAEL >1000 mg/kg/day (the highest dose tested)

Executive summary:

The registered substance was administered orally (gavage) to Crl:CD(SD) rats for 28 consecutive days at dose levels of 0, 60, 250, and 1000 mg/kg/day. All animals survived until scheduled necropsy. There were no test article related clinical findings or effects on body weight, food consumption, functional observational battery evaluations, locomotor activity, clinical pathology parameters or organ weights at any dose level. There were no test article related macroscopic or microscopic changes observed either. The No Observed Adverse Effect Level is greater than 1000 mg/kg/day.