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Administrative data

Description of key information

90-day feed study in rats, NOAEL 3000 ppm (approximately 209 mg/kg bw/day in male rats and approximately 244 mg/kg bw/day in female rats) 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
209 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

Due to a lack of experiments with the test substance and the existence of a structural analog (read-across substance) part of or the complete data was derived from the read-across substance. For details on the read-across reliability please refer to IUCLID Section 13. 

 

90-days oral toxicity study

In a 90 days study, Wistar rats (each 10 animals/sex/dose) were treated with dietary concentrations of 0, 1000, 3000 and 12000 (males) or 15000 ppm (females) read-across substance (Bis(2-propylheptyl) hexanedioate). Food consumption and body weight were determined weekly. The animals were examined for signs of toxicity or mortality at least once a day. Detailed clinical examinations in an open field were conducted prior to the start of the administration period and weekly thereafter. Beside this, a functional observational battery (FOB) as well as measurement of motor activity (MA) were carried out at the end of the administration period. Clinicochemical and hematological examinations as well as urinalyses were performed towards the end of the administration period. After the administration period, all rats were sacrificed and assessed by gross pathology. Organ weights were determined followed by histopathological examinations. Mid and high dose animals did not show any treatment-related adverse effects. High dose animals showed increased alkaline phosphatase (ALP) activities, urea and potassium levels (males), increased γ-glutamyltransferase (GGT) activities (females), decreased total protein and albumin levels (females) and increased incidences of granulated and epithelial casts were observed (males). Pathology findings were increased mean absolute and relative liver weights observed in males and females (in combination with clinical pathology) and minimal diffuse hepatocellular hypertrophy observed in 6 (out of 10) male and in 7 (out of 10) female animals(in combination with clinical pathology parameters).

The slightly increased ALP activities and slightly increased (GGT) activities indicated a liver cell swelling because of liver enzyme induction. Higher urea levels and decreased total protein and albumin levels were due to an increased protein metabolism in the liver. Regarding pathology, target organs were the liver and the thyroid glands. The absolute (+16 %/+26 %) and relative (+25 %/+28 %) liver weights were significantly increased and correlated with a minimal diffuse hepatocellular hypertrophy. These findings were considered to be a correlate for a microsomal enzyme induction in the liver. They were regarded to be treatment-related and adverse taking the changes in clinical pathology parameters into account. The minimally increased incidence of follicular hypertrophy/hyperplasia and of altered colloid in the thyroid glands of high dose male animals were regarded to be secondary to an induced UDP-glucuronyl transferase activityinhepatocellular hypertrophy. The well-known phenomenon is characteristic for rodents (Curran et al., 1991) and leads to an accelerated degradation of T4 with a compensatory increase of TSH causing thyroid gland hypertrophy/hyperplasia of follicular cells. These findings were regarded to be treatment-related but not relevant for humans.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The 90-day oral toxicity study with the read-across substance is a reliable study and the administration period of 90-day is commonly used to determine the toxicity after repeated treatment.

Justification for classification or non-classification

Based on the results obtained from repeated dose testing the read-across substance is not considered to be subject to classification and labelling for repeated dose toxicity according to Regulation (EC) No 1272/2008 (CLP/GHS) as amended for the seventh time in Regulation (EC) No 2015/1221.