Registration Dossier

Diss Factsheets

Administrative data

Description of key information

The NOAEL was determined to be 160 mg/kg bw/day in a subacute repeated dose oral toxicity study in rats performed according to OECD guideline 422.


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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to chapter 13 for the read-across justification.
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOEL
Effect level:
43 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
food consumption and compound intake
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
food consumption and compound intake
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
600 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
160 mg/kg bw/day
Study duration:
subacute
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

Repeated dose toxicity: oral

Read-across justification for target substance (CAS 14960 -06 -6):

There are no valid subacute or subchronic studies available investigating the repeated dose toxicity of the test item. Therefore a read-across was performed using the structural analogue substance (CAS 3655-00-3) as the source substance. Both target and source substance strongly correlate as both are of same basic structure and only have a variance in the amount of sodium. As it is assumed that the toxicological effects are not primary triggered by the sodium content and the Anion is the same for both substances. It is assumed that the read-across is suitable and even possible. See for additional information the RA justification attached to section 13.

Source study record (CAS 3655 -00-3):

A study was conducted to generate information concerning the effects of CAS 3655-00-3 on the possible health hazards likely to arise from repeated exposure according to OECD guideline 422 (Harlan Laboratories Ltd., 2008). In addition the study was conducted to provides information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition. Therefore the substance was administered to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum at the following dosages 0 mg/kg bwt/day (control group), 43 mg/kg bw/day, 160 mg/kg bw/day and 600 mg/kg bw/day. Dose levels were adjusted for content of the active ingredient (30.89%) and its purity (87%), applying a correction factor of 3.72. A standard dosage volume of 10 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (highly purified water). The following results were obtained: No test item-related mortality occurred during the study. The death of one female at 43 mg/kg bw/day after blood sampling was considered to be incidental. Only signs of discomfort (i.e. pushing the head through the bedding material after administration, a single occasion of salivation) in animals treated at 600 mg/kg bw/day, but no test item-related clinical signs were observed. At 160 and 600 mg/kg bw/day, mean body temperature was statistically significantly reduced in males. Locomotor activity was not affected by treatment with the test item. For males at 600 mg/kg bw/day, mean food consumption was statistically significantly reduced on days 1-8 of the pre-pairing period. For females at 160 and 600 mg/kg bw/day mean food consumption was dose-dependently reduced during the first week of the pre-pairing period. At 160 and 600 mg/kg bw/day body weight gain was dose dependently decreased during the pre-pairing period in males and female. The decrease was statistically significant at 600 mg/kg bw/day for males and 160 and 600 mg/kg bw/day for females. Because body weight was only marginally affected for males at 160 mg/kg/day, the effect at this dosage level was not considered to be an adverse effect. At 600 mg/kg bw/day, urea and potassium concentrations were statistically significantly increased in males. These alterations were considered to be possibly test item-related as they correlated with a slightly increased incidence and severity of hyaline/droplets in the kidneys. At 600 mg/kg bw/day, relative kidney weight was increased in males. This finding was considered to be test item-related as it correlated with the histopathological findings in the kidney and the clinical biochemistry changes. Absolute and relative liver weights were statistically significantly increased in males and females. According to the histopathological evaluation that detected hepatocellular hypertrophy, the effect on liver weights was considered to be an adaptive response. The findings noted during the macroscopic examinations did not provide any indication of any test item-related effects. At 160 and 600 mg/kg bw/day, the liver cell hypertrophy was considered to represent an adaptive response to an increased need for metabolizing the test item. The minimally increased incidence and severity of diffuse follicular cell hypertrophy observed in the thyroid gland of males and females treated at 600 mg/kg bw/day was considered to be secondary to the enhanced liver cell metabolism. The stomach lesions, observed in both the forestomach (acanthosis associated with chronic inflammation) and the glandular stomach (focal/multifocal chronic inflammation) of several animals treated at 160 and 600 mg/kg bw/day were considered to be related to the local irritating effect of the test item. The minimal increase in incidence of hyaline droplets/granules at 160 mg/kg bw/day was considered to be within the biological range. Because this finding, reflecting an increased content of α-2μ-globulin within the cytoplasm (phagolysosomes) of proximal convoluted tubules of sexually mature male rats, was accompanied by a slight increase in severity in males at 600 mg/kg/day, it was considered to be an adverse effect at this dosage level. 

Based on the statistically significant reductions in food consumption and body weight gain observed in males and females at 600 mg/kg bw/day and the transient effects in females at 160 mg/kg bw/day, on the histopathological findings and clinical biochemistry changes in males at 600 mg/kg bw/day, and on reduced body temperature recorded in males at 160 and 600 mg/kg bw/day, the systemic NOEL (No Observed Effect Level) was established at 43 mg/kg bw/day and the NOAEL 160 mg/kg bw/day. The available information from read across substance points to a NOAEL of 160 mg/kg bw/day in rat after 28 day of repeated application. The major finding (histopathological finding in kidney) are in connection with a male rat specific behaviour of increase α-2μ-globulin. This effect does not happen in humans and is therefore not relevant for human risk assessment. Nevertheless there are additional effects on food consumption, body weight gain and body temperature observed. Therefore the NOAEL of 160 mg/kg bw/day is used as a value for human risk assessment even as there only slight effects observed, if rat specific effects are excluded, as a conservative approach adding an additional safety factor.

Repeated dose toxicity: dermal:

There is a 91-day percutaneous toxicity study with rabbits performed for cosmetic reasons available reported in a CIR, 1990. As this study is not reliable it is not integrated into the dossier.

Justification for classification or non-classification

Based on the available information classification for repeated dose toxicity via the oral route is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.

Categories Display