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Toxicological information

Repeated dose toxicity: oral

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Administrative data

sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Some examinations like neurobehaviour are missing due to the year when the study was conducted.
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
68890-70-0 (purity 30.1%)
68890-70-0 (purity 30.1%)
Details on test material:
- Name of test material (as cited in study report): trade name- Physical state: paste- Analytical purity: 30.1% a.i.- Impurities (identity and concentrations): No data- Lot/batch No.: No data- Storage condition of test material: No data

Test animals

Details on test animals or test system and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: feed
other: plain diet
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Doses / concentrationsopen allclose all
Doses / Concentrations:0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Doses / Concentrations:58, 113, 228, 470, 961 and 1944 mg/kg bw/day (males)Basis:other: reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
No. of animals per sex per dose:
10 test group20 control group
Control animals:
yes, plain diet


Observations and examinations performed and frequency:
BODY WEIGHT: - Time schedule for examinations: WeeklyFOOD AND WATER CONSUMPTION:- Time schedule for examinations: Twice weeklyHAEMATOLOGY: - Time schedule for collection of blood: At the end of the experimental period (13 weeks)- Anaesthetic used for blood collection: Yes (halothane)CLINICAL CHEMISTRY: - Time schedule for collection of blood: At the end of the experimental period (13 weeks)
Sacrifice and pathology:

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYTwo male rats were killed due to ill health during this study.BODY WEIGHT AND WEIGHT GAINThe two highest dose groups gained less weight.FOOD AND WATER CONSUMPTION The high dose groups ate less. High dose females drank less water.HAEMATOLOGYSerum protein decreased at the highest dose (males). CLINICAL CHEMISTRYSerum Mg, protein, cholesterol, decreased at the highest dose (males). Serum GOT was elevated in high dose males. Serum GPT, was elevated in males of the two highest dose groups (1.13% and 2.25%) and females of the second highest dose group (1.13%). Serum AP was increased in the 1.13% and 2.25% dose groups (females) and 1.13% group (males).ORGAN WEIGHTSRelative liver weights (both sexes) increased in the three highest dose groups (0.56%-2.25%). Absolute spleen weights increased in males at the two highest doses and females at the highest dose. Absolute kidney weights decreased in high dose males. Relative kidney weights increased in females at the two highest doses. Relative weights of the testes increased at the two highest doses.GROSS PATHOLOGYHigh dose males had virtually no abdominal fat and changes in color and consistency of intestinal contents. These findings were less frequently noted in high dose females.HISTOPATHOLOGY: NON-NEOPLASTICDiffuse (6 females, 3 males) and periportal (11/20) hypertrophy, reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat and hemodiderin content prominent at high dose. Periportal hypertrophy also observed at nest two highest doses (1.13% and 0.56%). Periportal parenchymal hypertrophy was observed in 4 females at the 0.28% level. reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat and hemodiderin conten were observed at the 0.56%-2.25% dose levels.Nephrocalcinosis is freqently observed in untreated females of the Wistar strain: the incidence and severity was reduced in the highest dose group.Lymphatic dilation of the small intestine was more prominent at the high dose.

Effect levels

open allclose all
Dose descriptor:
Effect level:
488 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No toxic effects.
Dose descriptor:
Effect level:
1 016 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: Systemic effects that could not be regarded solely as adaptive processess, e.g. increased testes weight.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Since the liver as the target organ showed only adaptive responses, the NOAEL was set at 0.56% (488 mg/kg bw/day). The adaptive changes included elevated relative liver weight due to a lower body weight and reduced food consumption, hepatic periportal hypertrophy as well as increased serum alkaline phosphatase (AP) activity. An increased serum AP activity is considered to represent a physiological adaptation resulting from changes in hepatic metabolism required for the breakdown and detoxification of the test material. Since AP is mainly localized in the hepatic parenchyma, enlargement of the hepatic parenchymal cells accompanied by an increased organ weight are an obvious consequence.