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Description of key information

In a subchronical 3 month-feeding study male and female rats received the test substance via food in following doses: 0 (control-group); 750; 3000; 12000 ppm (male rats: 57; 91.2; 228 mg/kg bw/d; female rats: 70.5; 112.8; 282 mg/kg bw/d). No mortalities and no effects on behaviour were observed. Food and water intake were not modified up to 3000 ppm. In the highest dose group of 12000 ppm the female rats consumed more food and the male rats had an increased water intake. The body weight gain was decreased in male and female rats in the highest dose group. Absolute and relative liver weight was slightly increased at some dose levels, but these slight differences (<10%, no histopathologic observations in any group) were not considered as treatment related. Kidney weight only increased at the highest dose level. No substance related histopathological effects were observed. Ophtalmological, hematological and clinical parameters were within the normal range. Only a slightly increased tromboplastin-time was observed in male rats at 12000 ppm. The NOAEL for male and female rats therefore is 3000 ppm (228 mg/kg in male rats and 282 mg/kg in female rats) (Ramm W. /Eiben R., Bayer AG, 1987).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Method: other: 10 rats/group and sex
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Bor: WISW
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: test substance administered with food
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
750; 3000; 12000 ppm (dosage males:   55.4; 228.0;  985.2 mg/kg b.w./day (calculated)  dosage females: 68.7; 282.6; 1488.5 mg/kg b.w./day (calculated))
Basis:

No. of animals per sex per dose:
10/sex/dose
Control animals:
yes
Details on study design:
Post-exposure period: no
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
3 000 ppm
Sex:
male/female
Basis for effect level:
other: In the highest dose group of 12000 ppm the female rats consumed more food and the male rats had an increased water consume and a slightly increased tromboplastin-time was observed in male rats at 12000 ppm.
Critical effects observed:
not specified

RM-Freetext:
dosage males:   55.4; 228.0;  985.2 mg/kg b.w./day
(calculated) 
dosage females: 68.7; 282.6; 1488.5 mg/kg b.w./day
(calculated)

no death, no effect on behaviour, reduced body weight gain, increased  feed 

(females) and water consumption (males) at the high dose level,  absolute and

relative liver weight is significantly dose-related  increased at all dose 

levels, kidney weight only increased at the high  dose level, no 

substance-related histopathological effects (47 organs and  tissue), 

opthalmological, hematological and clinical- chemical parameters  within the 

normal range, slightly increased tromboplastin/time at the  high dose.

Executive summary:

In a subchronical 3 month-feeding study male and female rats received the test substance via food in following doses: 0 (control-group); 750; 3000; 12000 ppm.

No mortalities and no effects on behaviour were observed.

Food and water intake were not modified up to 3000 ppm. In the highest dose group of 12000 ppm the female rats consumed more food and the male rats had an increased water consume.

The growth was delayed in male and femal rats in the highest dose group.

The absolute and relative liver weight was significantly dose-related increased at all dose levels, but the kidney weight only increased at the high dose level. No substance related histopatological effects (aorta, eyes with lids, cecum, duodenum, femur, brain, bladder, testicles, skin, heart, pituitary gland, larynx, head, ileum, jejunum, liver, lung, mesenterial lymph node, mandibular lymph node, stomach, lactiferous gland, spleen, femoral musculature, epididymis, nervus ischiadicus, nervus opticus, kidneys, esophagus, ovaries, oviduct, pancreas, prostata, rectum, cervical, thoracal and lumbal spinal cord, seminal vesicle, thyroid gland, salivary gland, sternum, thymus (if present), trachea, extraorbitary lacrimal gland, uterus, vagina, tongue) were observed.

Ophtalmological, hematological and clinical parameters were within the normal range.

Only a slightly increased tromboplastin-time was observed in male rats at 12000 ppm.

The NOAEL for male and female rats therefore is 3000 ppm.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
228 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Conclusion: In a subchronical 3 month-feeding study the NOAEL for male and female rats was 3000 ppm. At 12000 ppm bodyweight gain was decreased and tromboplastin-time was slightly increased (Ramm W. /Eiben R., Bayer AG, 1987). There are no valid data available to characterize the repeated dosing using the dermal application and inhalation route.

Justification for classification or non-classification

Classification is not required.