Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 04 - June 25 2010
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to
Guideline:
other: Combined repeated dose Toxicity study with the Reproduction/ developmental Toxicity screening Test. EPA 712-C-00-368, July 2000.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: Fatty acids, tall-oil, reaction products with diethylenetriamine, maleic anhydride, tetraethylenepentamine and triethylenetetramine
CAS No.: 68990-47-6
Batch no.: TEE3316/22
Expiry Date: November 2011
Physical state at RT: solid
Colour: dark
Purity: Date of analysis 11 February 2010 97% (w/w)
Storage Conditions: at room temperature, protected from light
Solubility in Water: very low
Safety Precautions: Standard Safety procedures were sufficient to assure personnel health and safety.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
Name: Corn oil
Justification for use and choice of vehicle (if other than water):The vehicle was chosen as suggested by sponsor and the test item‟s solubility.
Batch No.: 11KBC6753
Storage conditions: at room temperature (RT),
Safety precautions: Routine hygienic procedures were sufficient to assure personnel health and safety
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
The animals will be dosed with the test item on 7 days per week for a period of approximately 54 days. The test substance will be administered daily during 14 days pre mating and 14 days mating in both male and in female, during gestation period and up to post natal day 3 in females. Males will be dosed after the mating period until the minimum total dosing period of 28 days has been completed.
Frequency of treatment:
daily; The animals were dosed with the test item on 7 days per week basis.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
300 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
600 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
80 animals (10 non pregnant nulliparous females and 10 adult males /group) were included in the study.
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Animals were examined for the daily clinical signs, mortality, weekly detailed clinical observations, pre treatment and at termination for functional observations. Body weight and food consumption was measured weekly except food consumption was not measured during the mating period (female) and mating/post mating period (male). Haematological and clinical biochemistry evaluations were performed on blood samples collected at terminal sacrifice from five males and five randomly selected females from each group. Urinalysis was performed on samples collected at terminal sacrifice from five randomly selected males from each group.


Sacrifice and pathology:
Males and females were sacrificed on treatment day 29-30, post natal day 4 respectively and subjected to necropsy. Non Pregnant females were sacrificed on their respective day 26 after the evidence of mating.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
due to gavaging error
Mortality:
mortality observed, treatment-related
Description (incidence):
due to gavaging error

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEL
Effect level:
<= 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Based on the limited histopathological evaluation of the two decedents treated at 600 mg/kg/day, no cause of death could be determined for female animal No. 23. Histopathological lung findings in male No. 61 (intraalveolar eosinophilic material, perivascular edema/hemorrhage and diffuse congestion) suggest gavaging error as its cause of death.

Reproductive organs:

In the female and male reproductive organs, no histopathological lesions considered to be test item-related were noted. Histologically, female reproductive organs showed physiological postpartum morphology in most surviving animals. The number of large corpora lutea in the ovaries was essentially similar in all study groups. Based on clinical observations, each one female treated at 0, 300 or 600 mg/kg/day was found not to be pregnant at terminal sacrifice, and reproductive organ histomorphology of these animals indicate normal sexual cycling activity.

In the male reproductive organs, a minimal number of unilateral atrophic tubules in the testis were seen in one male treated at 600 mg/kg/day without dose relationship and were considered to be incidental. In the epididymis, spermatic granuloma was observed in a small number of treated males and in one control, corroborating the macroscopic finding of spots on the epididymis, and was considered a spontaneous lesion. There were also incidental infiltrates with inflammatory cells in the prostate gland.

Other organs:

In the other organs evaluated in this study, test item-related histopathological changes were seen in the lung. Multifocal subacute bronchopneumonia, characterized by peribronchial foci of prominent fibrosis, with re-epithelialization, infiltration with mononuclear cells, histiocytes and occasional multinucleated cells, was observed in a small proportion of treated males and females of all dose groups, without dose relationship. In some animals the lesions contained also foci of necrosis, and in some animals the pulmonary changes were less well organized and contained larger numbers of mixed cells. The mechanism of this lesion is not clear.

A mild amount of intrahistiocytic black material was seen in the lung of each one male treated at 300 or 1000 mg/kg/day.

All other histopathological changes seen in this study were considered to be incidental in origin and/or within the range of expected changes for rats of this age and strain kept under laboratory conditions.

Applicant's summary and conclusion

Conclusions:
Test item-related histopathological changes were restricted to the lung. Multifocal subacute bronchopneumonia, characterized by peribronchial foci of prominent fibrosis, with re-epithelialization, infiltration with mononuclear cells, histiocytes and occasional multinucleated cells, was observed in a small proportion of treated males and females of all dose groups, without dose relationship. In addition, a mild amount of intrahistiocytic black material was seen in the lung of each one male treated at 300 or 1000 mg/kg/day.
As a conclusion, based on the pathological evaluation, a No-Observed-Effect-Level (NOEL) could not be determined in this study.
Executive summary:

Macroscopic observations recorded at necropsy and histological slides were evaluated from male and female Wistar rats of a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with daily oral administration by gavage of Fatty acids, tall-oil, reaction products with diethylenetriamine, maleic anhydride, tetraethylenepentamine and triethylenetetramine (test item) at dose levels of 0 (vehicle control), 300, 600 or 1000 mg/kg/day. The dosing period was daily during 14 days pre-mating, during the mating period, then during the gestation period and up to post-natal day 3 in females. Dosing of the males was continued after the mating period until completion of a minimum total dosing period of 28 days. Two rats treated at 600 mg/kg/day were found dead during the early treatment period. Based on the limited pathological evaluation of these decedents, no cause of death could be determined for the female, and gavaging error was considered to be the probable cause of death for the male. In the female and male reproductive organs, no histopathological lesions considered to be test item-related were noted. Based on clinical observations, three females had been recorded not to be pregnant during the study and showed normal sexual cycling activity in histopathology. Test item-related histopathological changes were restricted to the lung. Multifocal subacute bronchopneumonia, characterized by peribronchial foci of prominent fibrosis, with reepithelialization, infiltration with mononuclear cells, histiocytes and occasional multinucleated cells, was observed in a small proportion of treated males and females of all dose groups, without dose relationship. In addition, a mild amount of intrahistiocytic black material was seen in the lung of each one male treated at 300 or 1000 mg/kg/day. As a conclusion, based on the pathological evaluation, a No-Observed-Effect-Level (NOEL) could not be determined in this study.