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Administrative data

Description of key information

The NOEL and NOAEL of FP-100 in rats under the present study conditions were estimated to be 1,000 mg/kg/day

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
Study period:
27 Oct 2005 to 28 Feb 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: - Study generated according to generally valid and/or internationally accepted testing guidelines - Performed according to GLP - Test parameters based on specific testing guideline
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
Annex V
Deviations:
no
Principles of method if other than guideline:
N/A
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Full details are in the attached report
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
Method of administration:
Oral Gavage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC was used to determine and verify the doses of the FP-100
Duration of treatment / exposure:
Test duration: 28 days with a 14 day recovery period
Frequency of treatment:
Dosing regime: 7 days/week
Remarks:
Doses / Concentrations:
See report
Basis:
actual ingested
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 250 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 250 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent no treatment
Details on study design:
See The attached report
Observations and examinations performed and frequency:
Observations and examinations are detailed in the attahced report
Sacrifice and pathology:
Deatiled in the attached report
Statistics:
Data regarding body weights, food intakes, hematological examinations, blood chemistry examinations, urine volume and specific gravity, organ weights, grip strenght and locomotor activity count were analyzed using the Bartlett's test for homogeneity of variance.

Defecation and urination were analyzed using the Kruskal-Wallis's test.
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):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
LUC was decreased in the females who had received 1000 mg/kg in the recovery period
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Male Ca was increased
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Female brain increased in weight while heart and spleen decreased
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See report
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see report
Details on results:
Clinical observations:
Males: Salivation was noted in the control group.

Salivation and a reddish tear was noted in the 50

mg/kg group.

Salivation, scab formation and exudates on the neck

were noted in the 250 mg/kg group.



Females: Loss of hair was noted in the 250 mg/kg group.

Salivation and loss of hair was noted in the 1000

mg/kg group.

Laboratory findings:
Haematological examinations:

Males: No abnormalities were observed.

Females: Large unstained cells were decreased in the 1000

mg/kg group.


Blood chemical examination:

At termination of dosing period:


Males: Calcium was increased in the 50 and 1000 mg/kg

groups.

Females: No abnormailites were observed.

At termination of recovery period:

Males: Albumin:T-protein-Albumin ratio was increased in the

1000 mg/kg group.

Females: No abnormailites were observed.

Effects in organs:
Organ weights:

At termination of dosing period:

Males: No abnormalities were observed.

Females: Relative brain weight was increased in the 50

mg/kg group.

At termination of recovery period:

Males: No abnormalities were observed.

Females: Absolute heart and spleen weights were decreased

in the 1000 mg/kg group.


Necropsy:

At termination of dosing period:

Males: Whitish region in the heart was observed in the

vehicle group.

Females: Erosion on the skin was observed in the 250 mg/kg

group.

At termination of recovery period:

No abnormalities were observed in either males or females.


Histopathological examiniation:

At termination of dosing periods:

Males: Microgranuloma in the liver, focal myocarditis in

the heart, increased hyaline droplets, solitary cyst

in cortex and medulla in the kidney and aberran

craniopharyngael tissue in the pituitary gland were

noted in the vehicle control group.

Ulcer on skin was noted in the 250 mg/kg group.

Mineralisation in the glangular stomach was noted in

the 1000 mg/kg group.

Females: Mineralisation in corticomedullary junction of the

kidney and cyst formation in pars distalis gland

were noted in the vehicle control group.

Mineralisation in corticomedullary junction of the

kidney was noted in the 1000 mg/kg group.

At termination of recovery period:

No abnormalities were noted in either males or females.
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day.
Critical effects observed:
not specified
Conclusions:
Classified as: Not classified

A 28 day repeated oral dose toxicity study of FP-100 followed by a 14 day recovery study was performed in groups of five males and five females Crj:CD(SD) rats at 5weeks of age. the high dose was set a 1,000mg/kg/day and altogether 3 doses including 250 and 50 mg/kg/day were employed. Recovery gropus were also set for 1,000 mg/kg and vehicle control; groups.

No death occurred and no abnomalities were ntoed in the examinations.

No abnormalities were noted in the recovery test.
Based on these results. the NOEL and NOAEL of FP-100 in rats under the present study conditions were estimated to be 1,000 mg/kg/day
Executive summary:

FP-100 was orally administered by gavage to Crj:CD(SD) rats at doses of 50, 250 and 1,000mg/kg/day to perform a 28 day toxicity study followed by a 14 day recovery study.

The animals showed neither deaths nor any adverse effects of the treatment with the test substance in the detailed clinical observations, sensorimotor function and body weights during the dosing period, and hematology, urinalyses, organ weights and necropsy at the end of the dosing period.

Concerning the general conditions, salivation in males and females in all groups was transiently observed immediately after dosing, but it was considered to be of little toxicological significance

Concerning the food intakes, increased food intakes were noticed in males of the 1,000 mg/kg group on day 28, but it was considered to be accidental change since no abnormalities were noted in the general conditions and body weights.

Concerning the blood chemistry, Ca was increased in males of the 50 and 1,000 mg/kg group but it was not considered to be treatment related since showed no dose dependency

Concerning the histopathological examinations, mineralisation in the glandular stomach in males and mineralisation in the corticomedullary junction in the kidney of the females were noted in the 1,000 mg/kg group, but these were considered to be accidental changes since commonly observed in rat of this age and strain.

Other changes observed at the compeltion of the dosing period above mentioned ones were sporadic and showed no dose dependency, and these were considered to be accidental changes.

In the recovery test. inceased food intakes were continuously noted in males of the 1,000 mg/kg group on day 4, but it was considered to be accidental change since no abnormalities were noted in the general conditions and body weights.

Although other changes were observed only in the recovery test, these were considered to be accidental or of little toxicological significance.

The above mentioned results showed that FP-100 had no adverse affects. The NOEL and NOAEL of it in rats under the present study conditions were estimated to be 1,000 mg/kg/day

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

A 28 day repeated oral dose toxicity study of FP-100 followed by a 14 day recovery study was performed in groups of five males and five females Crj:CD(SD) rats at 5weeks of age. the high dose was set a 1,000mg/kg/day and altogether 3 doses including 250 and 50 mg/kg/day were employed. Recovery gropus were also set for 1,000 mg/kg and vehicle control; groups.

No death occurred and no abnomalities were ntoed in the examinations.

No abnormalities were noted in the recovery test.

Based on these results. the NOEL and NOAEL of FP-100 in rats under the present study conditions were estimated to be 1,000 mg/kg/day


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key Study

Justification for classification or non-classification

NOEL and NOAEL of 1,000mg/kg/day