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Description of key information

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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Information from migrated NONS file, as per inquiry, permission to refer granted by ECHA
Reference:
Composition 0
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
other: deionized water
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days/week
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 150 mg/kg bw/day
Male: 10 animals at 500 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 150 mg/kg bw/day
Female: 10 animals at 500 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day
Critical effects observed:
not specified

Clinical observations: No animals died during the study.

Some test article-induced clinical changes were seen during the treatment period at the dose of 500 mg/kg/day; they included salivation after gavage (seen in most animals), fur loss (seen in one male and in most females), lacrimation and/or eyelid swelling (seen in a few males and in half of the females), chromodacryorrhea (observed in two females), abdomen dilation and poor conditions (seen in a few females).

At 150 mg/kg/day the only clinical finding was one episode of salivation after gavage seen in one male at the end of the administration period.

No clinical signs were observed at 50 mg/kg/day in either sex.

Reversibility of the above-mentioned clinical changes was acertained in the recovered animals previously treated at the highest dose of the test article.

Laboratory findings:

HEMATOLOGY: After 4 weeks of treatment with the test substance hematology profiles were found to have been unaffected in treated females. In males, the only finding worthmentioning was a dose-related but negligible increase in the hematocrit value, observed in all treated groups.

BLOOD CHEMISTRY: At the end of the treatment period, slight modifications in the serum protein pattern consisting of an increase in albumin percentage and A/G ratio with concomitant decrease in the globulin percentage (beta and gamma globulins appeared mainly involved) were found in all treated groups of both sexes. These changes showed dose-relationship in males only. Males treated at 150 and 500 mg/kg/day had a dose-related increase in total cholesterol serum levels (44-90% vs controls) while females of the same dose groups showed an increase in triglycerides (levels about twice as much as the controls). In females of the high dose group there was also an increase in alkaline phosphatase and in GPT serum activities, with some individual values out of the range of normality; moreover serum protein concentration appeared slightly reduced. Minor electrolyte changes, i.e. increase in calcium (two higher doses) and decrease in chloride (all doses) in both sexes, decrease in sodium (all doses) and increase in inorganic phosphorus (high dose) in females only, where observed. Such modifications, always slight in degree, were regarded as possible trends. On discontinuation of treatment the following slight biochemistry changes were still observed in the recoverd animals: increase in albumin percentage (concomitant with a decrease in globulin percentage) and in total cholesterol for males, decrease in total protein and increase in organic phosphours for females.

URINALYSIS: A slight decrease in the pH of urine was found at the end of the treatment period in the 500 mg/kg dosed animals of both sexes. No changes in urine parameters were observed after recovery in either sex.

Effects in organs:

ORGAN WEIGHT: At the end of the treatment period, a few changes were seen that were considered related to the tet article administration. These were on the whole slight increases in mean weights of liver and kidneys in males and females of the intermediate and high dose groups, (usually being statistically significant), a slight decrease in absolute values of testes in males and in spleen in females of the high dose group. At the end of recovery, the only change seen was an evident decrease in weights of tests in the group previously treated with 500 mg/kg/day, while other organs affected at the end of the treatment period showed complete recovery. GROSS PATHOLOGY: At the end of treatment, compound-related changes were noted. Some males of the intermediate dose group and all males of the high dose group had slight congestion of the cortico-medullary junction of the kidney. One male each of the two high dose groups had pale kidneys, and one male of the high dose group had pale liver. All males of the high dose group had a slight decrease in size of the prostate and seminal vesicles, while only one rat showed a slight decrease in size of testes. All females of the high dose group sacrificed at this time had moderate alopecia; two of this group had a decrease in size of spleen. One female of this group was thin, and decreased size of genital organs and paleness of Harder's lacrimal gland were noted. Slight eye opacity was also seen in one female. At the end of the recovery period, the only change still seen was an evident decrease in size of testes in most males previously treated at 500 mg/kg/day; one male of this group also had a slight decrease in size of epididymides.

HISTOLOGY: The following changes were seen at the end of the treatment period and considered related to administration of the test article:

- dose-related in frequency and degree of hepatic centrilobular hypertrophy in males and females of the intermediate and high dose groups. Liver hypertrophy may be regarded as a functional metabolic response rather than a toxic effect.

- presence of hyaline droplets in tubules of the renal cortex or the papilla seen in all treated male groups and in females of the intermediate and high dose group. One male treated at 500 mg/kg/day and two males treated at 150 mg/kg/day had slight tubule dilation, and one male of the high dose group also showed slight congestion of the cortico-medullary junction.

- atrophy of lymphatic tissue (mesenteric lymph nodes and/or spleen) in a few rats of the high dose group.

- presence of vacuolated histiocytes in lungs in a few rats of the high dose group; one female had a moderate presence of histiocytes and two rats had slight presene of fibrin.

- testicular changes in all males of the high dose group, consisting in a slight increase in vacuolation and/or degeneration of the tubular epithelium. Epididymides of all rats showed decreased number and degeneration of spermatic elements, with vacuolation of tubular epithelium. A decrease in secretory material was seen in seminal vesicles and in a few cases in prostate of these males.

- moderate to severe acute inflammation of the cornea, associated with conjunctivitis or degeneration of the corneal epithelium, in two females of the high dose group. One female of this group also had decreased secretory material in the Harder's lacrimal gland, with an increase in apoptotic figures.

- decrease in number of hair follicles of the skin in a few females of the high dose group.

Most of these changes showed complete recovery. The only change still noted was in testes and epididymides in males previously treated with 500 mg/kg/day. These rgans no longer showed vacuolation of tubule epithelium, but other changes seen at the end of treatment were now seen to a more severe degree. Most of these tests also had severe decrease in spermatogenesis; a few cases of multinucleated spermatids and tubule mineralization were seen. As a consequence an evident decrease in number of spermatic elements with varying decrees of degeneration was seen in epididymides.

Conclusions:
NOAEL: 150 mg/kg/bw
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Reliability according to Klimish score: 2- reliable with restrictions.

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

Mode of Action Analysis / Human Relevance Framework

Additional information

In the 28-day oral repeated-dose toxicity study in rats, a NOAEL of 150 mg/kg bw/day has been identified (mid-dose tested). At the higher dose tested (500 mg/kg bw/day), some effects like salivation after gavage, fur loss, lacrimation and/or eyelid swelling, chromodacryorrhea, abdomen dilation and poor conditions were observed. Reversibility of the above-mentioned clinical changes was ascertained.

At the end of the treatment period, a few changes were seen that were considered related to the test article administration. These were on the whole slight increases in mean weights of liver and kidneys in males and females of the intermediate and high dose groups, (usually being statistically significant), a slight decrease in absolute values of testes in males and in spleen in females of the high dose group. At the end of recovery, the only change seen was an evident decrease in weights of tests in the group previously treated with 500 mg/kg/day, while other organs affected at the end of the treatment period showed complete recovery.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys; urogenital: testes

Justification for classification or non-classification

According to available data and according to Regulation (EC) n. 1272/2008, no classification is deemed necessary for the specific target organ toxicity endpoint.