Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study but some basic information regarding the study is not available.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crj:CD(SD)IGS
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Pre-mating period (14 days), during mating and post-mating up to 43 days for males; pre-mating (14 days) and mating period, during pregnancy and lactation, until day 4 post-partum for females
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
62.5, 250, and 1000 mg/kg bw/day in vehicle (corn oil)
Basis:
other: nominal concentration
No. of animals per sex per dose:
male (6/dose group) and female (12/dose group)
Control animals:
yes, concurrent vehicle
Details on study design:
Male (6/dose group) and female (12/dose group) Crj:CD(SD)IGS rats were dosed by oral gavage once a day at 0 (corn oil), 62.5, 250, and 1000 mg/kg bw/day, throughout the pre-mating period (14 days), during the mating and post-mating periods until final sacrifice for the males (at 43 days) and throughout pre-mating (14 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive for the females (Hashima, year not available).

Post-exposure period: Yes, for a sub group of males and females for 14 days

Examinations

Observations and examinations performed and frequency:
Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Detailed clinical observations and neurobehavioral tests were conducted at designated intervals. Blood and urine samples were collected from all males and females at the end of the treatment period.
Sacrifice and pathology:
At final sacrifice, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Two males and 1 female from the 1000 mg/kg group died (study day not available). Soiled hair, a decrease in locomotor activity, reddish urine, hypothermia, perioral smudges, perianal soiling, diarrhea, bradypnea, and/or piloerection were noted in the dying animals. Soiled hair and reddish urine were noted in the surviving males and females of the 1000 and 250 mg/kg groups. Low body weights and food consumption were also noted in males and females of the 1000 mg/kg group.

Urinalysis: Occult blood, epithelial cells, erythrocytes, and leucocytes were noted in both sexes receiving 1000 mg/kg.

Hematological examination: Low red blood cell counts, hemoglobin concentrations, hematocrit, MCV, and MCH and high fibrinogen concentrations were noted in males of the 1000 mg/kg group. Low hematocrit in females of the 1000 and 250 mg/kg groups, and low hemoglobin concentrations and high APTT in females of the 1000 mg/kg group were also noted.

Blood chemical analysis: Low total protein, albumin, A/G ratios, and potassium, and high g-GTP, urea nitrogen, and creatinine were noted in males of the 1000 mg/kg group. Low total protein and triglycerides in females of the 1000 mg/kg group were noted, and a tendency for high g-GTP in females of the 1000 and 250 mg/kg groups was observed.

At necropsy, swollen kidneys were noted in males of the 1000 mg/kg group. Organ weight measurement, decreased absolute thymus weights, increased absolute kidney weights, and increased relative weights of the spleen, kidneys, and adrenals were noted in males of the 1000 mg/kg group. Decreased relative thymus weights in females of the 1000, 250 and 62.5 mg/kg groups, and decreased absolute thymus weights and increased relative liver weights in females of the 1000 mg/kg group were noted. On histopathological examination, hyperplasia of transitional epithelium in the urinary bladder was noted in males of the 1000, 250 and 62.5 mg/kg groups. Vacuolization of the lamina propria in the duodenum, jejunum, and/or ileum in males of the 1000 and 250 mg/kg groups was noted, and sinus vacuolization in the mesenteric lymph nodes, hyperplasia of transitional epithelium and pyelonephritis in the kidneys, and hyperplasia of transitional epithelium of the urethra in males of the 1000 mg/kg group were noted. Vacuolization of the lamina propria in the duodenum and/or jejunum and hyperplasia of transitional epithelium in the urinary bladder were noted in females of the 1000 and 250 mg/kg groups, and atrophy of the cortex and medulla in the thymus, sinus vacuolization in the mesenteric lymph nodes, hyperplasia of transitional epithelium, regeneration of urinary tubules, and pyelitis in the kidneys, and hyperplasia of transitional epithelium, metaplasia of keratinized stratified squamous epithelium, cellular infiltration, and necrosis of epithelium in the urethra in females of the 1000 mg/kg group.

No information was available regarding the recovery group males and females.

Effect levels

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Dose descriptor:
NOAEL
Effect level:
< 62.5 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Effects were noted at all dose levels in this study, including the lowest dose level of 62.5 mg/kg bw/day.
Dose descriptor:
LOAEL
Effect level:
62.5 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Based on decreased relative thymus weight in females and histopathological changes in the urinary bladder of males

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The LOAEL was 62.5 mg/kg bw/day (based on decreased relative thymus weight in females and histopathological changes in the urinary bladder of males) and the NOAEL was < 62.5 mg/kg bw/day for both sexes.