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Description of key information

Repeated dose toxicity
Non-human information
Repeated dose toxicity: oral
In a subacute toxicity study the test substance Vulcuren (purity: 99.7%) was administered orally via gavage to male and female Wistar rats at target concentrations of 0, 40, 200 and 1000 mg/kg body weight for about 4 weeks (Bayer AG 2000d). In parallel male and female rats (5 per sex and group) were treated with 0 and 1000 mg/kg body weight. These rats were observed for reversibility, continuance or delay occurrence of toxic effects during a recovery period of about 2 weeks. No differences regarding the survival rat or general behaviour were noted compared to the untreated animals. In addition, no relevant differences were observed in mean feed intake and weight gain in any of the treatment groups evaluated compared to the negative control. No neuronal behaviour effects were noted in any of the treatment groups. There were no toxicologically relevant changes in haematology and clinical chemistry in animals treated with the test compound. No biologically relevant effects on the organ weights were found in any of the rats treated with the test substance compared to the control animals. In addition, there was no evidence of any gross pathological and histopathological findings associated to dosing with the test compound up to the highest dose group (1000 mg/kg body weight) in males and females.
The author concluded that the administration of Vulcuren (purity: 99.7%) to male and female Wistar rats for about 4 weeks was tolerated without adverse effects up to and including 1000 mg/kg. No delayed occurrence of toxic effects was observed during a recovery period of about 2 weeks (Bayer AG 2000d).


Repeated dose toxicity: inhalation
There are no data available.


Repeated dose toxicity: dermal
There are no data available.


Repeated dose toxicity: other routes
There are no data available.


Human information
There are no data available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and OECD Guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: 96/54/EG, B.7 (1996); OECD 407 (1995)
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH
- Age at study initiation: 5 to 6 weeks
- Fasting period before study:
- Housing:animals were housedindividually in type II A-cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 5%
- Air changes (per hr): 15 to 20 changes per hour
- Photoperiod: 12hrs dark / 12hrs light)


Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Method of administration:
Schlundsonde
the test substance was administered by gavage from the start of the study until day 27 for the recovery groups and until the day before scheduled sacrifice for the main group.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
during the study period, the test substance content in the vehicle was checked two times, determination of the test substance solved in corn oil was done by HPLC, homogeneity tested prior study and during study
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Remarks:
Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw
Basis:

No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 40 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 40 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
Main group: 0, 40, 200, 1000 mg/kg, 5 animals/dose/sex
Recovery group (14 d recovery period): 0, 1000 mg/kg 5 animals/dose group
Positive control:
none
Observations and examinations performed and frequency:
Inspection for morbidity, mortality and general clinical examinations: once a day; body surfaces and orifices, posture, general behavior, breathing and excretory products were assessed
Body weight determination: before the beginning of the study and weekly during the study, feed intake: once per week;
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Hematological investigations, clinical chemistry, neurotoxicity tests (functional observation battery, motor activity)
Statistics:
Dunnett test, p value adjusted Welch test, Kruskal-Wallis test, Mann-Whitney.Wilcoxon test (U tests)
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
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Details on results:
HAEMATOLOGY: The examination of the red blood cells, thrombocyte counts and prothrombin time showed no toxicologically relevant changes. A statistically significant decrease in erythrocyte counts was seen in high-dose males of the main group treated with the test substance. Hematocrit was unaffected in that group leading to a corresponding increase in mean corpusular volume of single erythrocyte. These changes were only slight and ranged within the 2s limits of historical controls. Furthermore the mean of the concurrent control group was somewhat above the mean male historical controls. No effects were observed in the other sex. Therefore, these changes are considered to be incidental findings of no biologic significance and are unrelated to treatment.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Key result
Critical effects observed:
no

Clinical observations: No mortality occurred during the study period.

There were no changes in clinical appearance, functional observations, body weights, and food consumption

The functional observations showed no signs or symptoms indicating evidence for systemic toxic and neurotoxic potential. Grip strength and motor activity measurements exhibited no treatment-related changes in both sexes at doses of 1000 mg/kg bw/d and below.

Laboratory findings: There were no biological significant effects of treatment on hematological and biochemical parameters. For a small number of parameters the differences between control and test groups attained a degree of statistical significance. However, the differences were small, not dose-related and inconsistent between the sexes.

Effects in organs: There were no treatment-related findings in organ weights, gross or microscopic pathology in rats of both sexes given 1000 mg/kg bw/d and below. Histopathological changes seen were of a minor nature and at a similar level to those seen in the controls.

Conclusions:
The application of Vulcuren Trial Product KA 9188 to male and female Wistar rats for about 4 weeks was tolerated without adverse effects up to and including 1000 mg/kg (ther highest applied dose).
Executive summary:

In a subacute toxicity study the test substance Vulcuren Trial Product KA 9188 was administered orally via gavage to male and female Wistar rats at target concentrations of 0, 40, 200 and 1000 mg/kg body weight for about 4 weeks. In parallel male and female rats (5 per sex and group) were treated with 0 and 1000 mg/kg body weight. These rats were observed for reversibility, continuance or delay occurrence of toxic effects during a recovery period of about 2 weeks. No differences regarding the survival rat or general behaviour were noted compared to the untreated animals. In addition, no relevant differences were observed in mean feed intake and weight gain in any of the treatment groups evaluated compared to the negative control. No neuronal behavior effects were noted in any of the treatment groups. There were no toxicologically relevant changes in haematology and clinical chemistry in animals treated with the test compound. No biologically relevant effects on the organ weights were found in any of the rats treated with the test substance compared to the control animals. In addition, there was no evidence of any gross pathological and histopathological findings associated to dosing with the test compound up to the highest dose group (1000 mg/kg body weight) in both genders. The author concluded that the administration of Vulcuren Trial Product KA 9188 to male and female Wistar rats for about 4 weeks was tolerated without adverse effects up to and including 1000 mg/kg. No delayed occurrence of toxic effects was observed during a recovery period of about 2 weeks (Bayer AG 2000d).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and OECD Guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The findings of the subacute toxicity study revealed, that administration of Vulcuren (purity: 99.7%) to male and female Wistar rats was tolerated without effects up to and including 1000 mg/kg body weight. In addition, no delayed occurrence of toxic effects was observed during a recovery period of about 2 weeks. Therefore, 1000 mg/kg body weight and day is assumed to be the No Adverse Effect Level (NOAEL) and was used for the DNEL calculation.


Justification for classification or non-classification

The oral application of Vulcuren Trial Product KA 9188 to male and female Wistar rats for about 4 weeks was tolerated without adverse effects up to and including 1000 mg/kg (the highest applied dose).

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.