Cetylpyridinium chloride

Toxicity to reproduction

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 for cross-reference:

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

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

Test material information

Constituent 1

Reference substance name:

Cetylpyridinium chloride

EC Number:

204-593-9

EC Name:

Cetylpyridinium chloride

Cas Number:

123-03-5

Molecular formula:

C21H38N.Cl

IUPAC Name:

cetylpyridinium chloride

Constituent 2

Reference substance name:

CPC

IUPAC Name:

CPC

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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 generation)

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

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.