Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: repeated dose toxicity study in rats (atttention to reproductive organs)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline repeated dose toxicity study, according to GLP.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD guideline 452 (chronic toxicity studies)
Principles of method if other than guideline:
6 month repeated dose toxicity study with examination of reproductive organs
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
see 7.5.1: oral Minnema 1995

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Oral gavage of dose formulations prepared weekly. Amounts administered were adjusted weekly according to body weights.
Details on mating procedure:
No mating
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
RP-HPLC verification of dose concentrations and stability of formulations.
Duration of treatment / exposure:
6 months
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5, 15, 40 and 75 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
Includes ophthalmalogic examinatioon, and hematology, clinical chemistry and urinalysis.
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Twice daily clinical observations; weekly physical examination and weighing. At necropsy, ophthalmologic examination, and full histological examination of all organ systems.
Oestrous cyclicity (parental animals):
not specifically examined
Sperm parameters (parental animals):
not specifically examined
Litter observations:
not applicable
Postmortem examinations (parental animals):
yes, see 7.5.1: oral. Minnema 1995.

Organs were weighed after trimming of fat and other continguous tissue: adrenals, brain, heart, kidneys, liver, ovaries, pituitary, spleen, stomach, testes with epididymides, thymus, thyroid/parathyroids.

GROSS PATHOLOGY: Yes; all animals
HISTOPATHOLOGY: Yes, on groups 1 and 4 (control and 75 mg/kg/d) and any gross lesions from animals in any group. Tissues preserved in 10% netural buffered formalin were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically.

Tissues preserved were: adrenals, aorta, brain, colon with cecum and rectum, duodenum, jejunum and ileum, esophagus, exorbital lacrimal glands, eyes, femur, heart, kidneys, liver, lung, mammary gland, mesenteric lymph node, ovaries, pancreas, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicles, skin, spleen, sternum with bone marrow, stomach, spinal cord, testes with epididymides, thigh musculature, thyroid/parathyroids, thymus, trachea, urinary bladder, uterus with vagina and cervix.
Postmortem examinations (offspring):
not applicable
Statistics:
yes, see 7.5.1: oral. Minnema 1995
Reproductive indices:
not applicable
Offspring viability indices:
not applicable

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1 unexplained death at 75 mg/kg/d
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
significant decreases in body weight or body wight gain at 40 and 75 mg/kg
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
significant decreases in body weight or body wight gain at 40 and 75 mg/kg
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increases in absolute weight of the stomach
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
acanthosis and irritation/erosion/necrosis in the non-glandular stomach, distention of the cecum
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
inflammation and necrosis of the stomach
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: by gavage

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Details on results (P0)

Localized gastrointestinal irritation was observed in rats receiving CPC at dose levels of 15 mg/kg/d and higher. Symptoms included salivation at dosing, soft feces, decreased food consumption, decreased body weight, thickened appearance of the non-glandular stomach, increased stomach weight, hyperplasia/necrosis/erosion/edema of the stomach. There was no histologic evidence of toxicity in any other organ examined, including reproductive organs. The material was not systemically toxic. The NOAEL for CPC based on the finding of stomach irritation is 5 mg/kg bw/d.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Local irritation (with necrosis and hyperplasia) of the stomach occurred at higher doses. No systemic toxicity observed.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The effects of oral gavage dosing of CPC were studied in a repeated dose protocol for 6 months in rats at doses of 5 to 75 mg/kg bw/d. Reproductive organs were excised, weighed and examined histologically for adverse effects. The major finding was localized gastrointestinal irritation observed at dose levels of 15 mg/kg/d and higher. Symptoms included salivation at dosing, soft feces, decreased food consumption, decreased body weight, thickened appearance of the non-glandular stomach, increased stomach weight, hyperplasia/necrosis/erosion/edema of the stomach. There was no histologic evidence of toxicity in any other organ examined, including reproductive organs. The material was not systemically toxic. The NOAEL for CPC based on the finding of stomach irritation is 5 mg/kg bw/d.