[No public or meaningful name is available]

Endpoint summary

Description of key information

28d-repeated dose, oral: NOAEL, oral = 150 mg/kg bw/day
90d-repeated dose, oral: waived
28d- and 90d-repeated dose, dermal: waived
28d- and 90d-repeated dose, inhalation: waived

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:

from 2008-01-07 till 2008-02-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline-conform study under GLP without deviations.

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

96/54/EG, B.7

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

rat, Hsd:Wistar rats (HsdRccHan : WIST)
Age at start of study 7-8 weeks

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Method of administration:
Gavage of a suspension, using a stomach tube

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Mean Recovery Rate of the Test Item Concentration in the Test Samples:
50 mg/5 mL: 105 % of nominal (n = 4; SD = 1 %)
150 mg/5 mL: 103 % of nominal (n = 4; SD = 3 %)
1000 mg/5 mL: 110 % of nominal (n = 4; SD = 17 %)

Duration of treatment / exposure:

Test duration: 28 days
In total 28 applications per animal were administered.

Frequency of treatment:

Once daily,
Dosing regime: 7 days/week

Remarks:

Doses / Concentrations:
0, 50, 150, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Male: 5 animals at 50 mg/kg bw/day Male: 5 animals at 150 mg/kg bw/day Male: 5 animals at 1000 mg/kg bw/day Female: 5 animals at 50 mg/kg bw/day Female: 5 animals at 150 mg/kg bw/day Female: 5 animals at 1000 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Details on study design:

The highest dose level was chosen with the aim of inducing toxic effects but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dosage related response and no-observed-adverse effects at the lowest dose level (NOAEL).

Positive control:

not applicable

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:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
No mortality occurred during the study period.

There were no test substance-related clinical signs in any
dose group. Daily food consumption and body weight
development of the test animals were unaffected during
treatment period.

No test substance-related effects were detected during
functional and behavioral assessments, responses to reflex
testing, and sensory reactivity assessments.

Laboratory findings:
No test substance-related differences of toxicological
significance were noted in haematology, clinical
biochemistry and urinalysis parameters when compared with
the control values.

Effects in organs:
The assessment of organ weight revealed increased absolute
and relative kidney weights (not statistically significant)
in males treated at 1000 mg/kg bw/d. Significant deviations
were observed in the liver, adrenals and brain. These
changes were either noted within the ranges of historical
control data, were only observed in one sex, or resulted
from a divergent control value. In absence of a dose
response relationship or corroborative findings in
microscopy, clinical biochemistry or other evidence of
severe organ dysfunction, these findings were considered to
be of no toxicological significance. The mean relative
testes weight was significantly increased in males at 1000
mg/kg bw/d in comparison to controls, which was found
without further corroborating findings.

No relevant changes occurred upon necropsy.

Histopathology revealed test substance-related findings in
the kidneys in males and females at 1000 mg/kg bw/d. There
was a cortical and modularly tubulopathy with casts, being
more prominent in males. The lesion was characterized by
mulitfocal areas of basophilic/regenerating tubules, dilated
tubules with minor tubuloepithelial single cell necrosis and
presence of intraluminal granular casts. In addition in
males, there was a tendency towards the occurrence of more
mononuclear cell infiltrates.

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Conclusions:

Considering the reported data of this toxicity study it can be stated, that the Medium Dose of 150 mg/kg BW is the no observed adverse effect dose level (NOAEL) of the test substance after a total of 28 applications by gavage in Corn oil over a period of 28 days.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP compliant and of high quality (Klimisch score=1)

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

During the whole life cycle of the substance and especially during its use in technical plastic articles, the oral, dermal or inhalation exposure of workers can be excluded, and there is no relevant exposure to consumers, as the substance is embedded into a polymer matrix. The information that would be obtained from a 90-day oral, or 28-day, or 90-day dermal or inhalation study is considered not to be needed, as oral, dermal, and respiratory exposure is avoided by safety measures which are already in place in case of potential dusty work places, and consumer exposure can be excluded. In view of animal welfare and to avoid unnecessary animal testing it was decided to waive such studies.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest duration (28d) and the lowest NOAEL was chosen (key study)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Testing waived based on limited inhalation exposure (acc. annex XI.3)

Binding occupational exposure limit values for fine dust are limiting exposure by the inhalation route so that no systemic effect in kidneys can be expected. Hazard assessment beyond binding occupational exposure limit values for fine dust is scientifically not justified.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Testing waived based on limited inhalation exposure (acc. annex XI.3)

Binding occupational exposure limit values for fine dust are limiting exposure by the inhalation route so that no local effect in kidneys can be expected. Substance not irritant to skin (500 mg) nor to eye (100 mg).


Binding occupational exposure limit values for fine dust are limiting systemic exposure by the inhalation route so that no systemic effect in kidneys can be expected. Hazard assessment beyond binding occupational exposure limit values for fine dust is scientifically not justified.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Testing waived based on limited inhalation exposure (acc. annex XI.3)

Binding occupational exposure limit values for fine dust are limiting dermal exposure. Systemic effect by the dermal route are very unlikely due to limeted absoprtion. The substance is not irritant to skin (500 mg) nor to eye (100 mg).

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Testing waived based on limited inhalation exposure (acc. annex XI.3)

Binding occupational exposure limit values for fine dust are limiting dermal exposure. Local dermal effects are very unlikely because the substance is not irritant to skin (500 mg) nor to eye (100 mg).

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

Justification for classification or non-classification

Based on the available toxicological data the substance is not hazardous. The only noticeable adverse effects are histopathological changes (cortical tubulopathy and medullary tubulopathy with casts) found at very high dose of 1000 mg/kg bw/day of the oral 28-day gavage study in rats. Nephrotoxicity is probably a consequence of overload and renal tubular epithelial cast formation (evidence: OECD-SIDS_CAS 108 -78 -1), and not due to intrinsic toxicological properties of the substance. The dose level at which this oral nephrotoxic effect occurs (LOAEL=1000 mg/kg bw/day) has a very large safety margin with regard to potential (worst case) human exposure (this CSR (calculated occupational exposure) -inhalation: 0.25 mg/m3 or dermal: 0.034 mg/kg bw/day). The internal exposure via the dermal route is further limited by low dermal absorption of the solid substance.

According to the criteria listed in Annex I to CLP, the substance does not have to be classified as a dangerous substance regarding chronic toxicity/specific organ toxicity.