Registration Dossier

Administrative data

Description of key information

Oral (OECD 408), 90 days, rat:

NOAEL (systemic) = 100 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
System:
other: hepatobiliary, urinary
Organ:
kidney
liver

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

Subacute oral toxicity

CAS 111937-03-2

Subacute information:

A 28-day oral repeated dose toxicity study was performed according to a protocol similar to OECD 407, using isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) (Pitterman, 1993). 10 Wistar rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day by gavage, 5 days/week, over a period of 28 days. In addition, satellite groups of 5 rats/sex/dose were administered 0 and 1000 mg/kg bw/day for 28 days, followed by an observation period of 35 days. There was no mortality and no treatment-related clinical signs were observed. No effects on body weight or food and water consumption were noted in main or satellite groups. A dose-related increase in white blood cell (WBC) levels was observed in males, although it was statistically significant only in the high-dose group (22% increase compared with the control group). As no change in the WBC levels in the females, nor other haematological effects or related histopathologic effects were observed, this was most likely a treatment-related, but not a toxicologically relevant effect. A statistically significant increase in relative liver weight in high-dose females was observed. This is probably due to an increase in non-degenerative fat deposits and is not considered to have toxicological relevance. No other treatment-related effects on organ weights were seen. During the gross pathology examination, swelling of the forestomach mucosa was noted in 2/10 male and 3/10 female animals in the high-dose main group. This is probably caused by the administration of the test substance by stomach tube and is not considered to be toxicologically relevant. A slight to moderate yellowish-brownish liver discolouration was noted in 5/10 males and 10/10 females in the high-dose main group. No gross pathological abnormalities were observed in the animals of the control and treatment satellite groups. In 1/10 male and 10/10 female animals in the high-dose main group, slight to moderate peripheral lobular located fat deposits were observed in liver (non-degenerative). 6/10 female animals in the mid-dose group showed slight peripheral lobular fat deposition in the liver (non-degenerative). The hepatic fat deposits were most likely related to the treatment with the fatty ester; however, this effect was considered to be non-adverse and found to be reversible, since none of these findings were observed in animals of the high dose satellite group after a recovery period of 35 days. In addition to the alterations in liver, one female in the high-dose main group showed moderate edema of the forestomach mucosa, which was considered to be a result of the gavage treatment.

Based on the lack of toxicologically relevant effects up to and including the highest dose level, the NOAEL is considered to be 1000 mg/kg bw/day.

Subchronic information:

Isononanoic acid, C16-18-alkyl esters was administered orally by gavage to groups of 10 male and 10 female Wistar rats at dose levels of 0 (test group 0), 100 (test group 1), 300 (test group 2) and 1000 mg/kg body weight/day (mg/kg bw/d; test group 3) over a period of 3 months according to OECD 408 under GLP (BASF SE, 2018). Corn oil served as vehicle, control animals were dosed daily with the vehicle only. In addition to the required examinations, special attention was given to the reproductive organs of male and female animals.

Prolonged prothrombin time in females, decreased calcium levels in females, increased urea and inorganic phosphate levels in females were observed at 1000 mg/kg bw/d and 300mg/kg bw/d. Additional at these doses significant absolute and relative kidney weight were increase in male animals accompanied by alpha2u-nephropathy (not relevant for humans), minimal to slight fatty changes in the kidneys of females as well as Light brown discoloration in livers of female animals were found together with a periportal fatty change in livers of all female animals (slight to severe). Only at 1000 mg/kg decreased total protein, albumin and globulin values in females were observed. For 100 mg/kg bw/d only Alpha2u-nephropathy in all male animals (not relevant for humans) were observed.

Therefore under the conditions of this study the oral administration Isononanoic acid, C16-18-alkyl esters by gavage to Wistar rats over a period of 3 months revealed adverse signs of systemic toxicity at dose levels of 100 mg/kg bw/d and above in male and 300 mg/kg bw/d and above in female animals taking clinical pathology and pathology findings into account.The findings in the male kidneys were regarded to be adverse but as this mechanism is only known to occur in the rat they were regarded not to be of human relevance.Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was set to 1000 mg/kg bw/d in male and to 100 mg/kg bw/d in female Wistar rats.

 

Conclusions for repeated dose oral toxicity,

In the subacute (28-day) repeated dose toxicity study that was performed with isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2), no treatment-related systemic effects were observed up to and including the highest dose level (Pitterman, 1993). Thus, the NOAEL was set at ≥ 1000 mg/kg bw/day.

Further subacute toxicity studies are available for the analogue substances Fatty acids, C8-16, 2-ethylhexyl esters (CAS 135800-37-2) and Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0), both resulting in a NOAEL ≥ 1000 mg/kg bw/day. However, these studies are not sufficient to cover the repeated dose toxicity endpoint for isononanoic acid, C16-18 alkyl esters due to their inappropriate duration of exposure (28 days) and the fact that they are not suitable for read-across since they are not LCAE esters with the toxicologically critical metabolite isononanoic acid. Therefore, a GLP-compliant subchronic (90-day) toxicity study in the rat via the oral route following OECD 408 with extended fertility parameters was performed leading to a no observed adverse effect level (NOAEL) for general systemic toxicity of 1000 mg/kg bw/d in male and of 100 mg/kg bw/d in female Wistar rats (BASF SE, 2018). But it should be also taken into account that the effects observed here are mainly happen due to a fatty deposite which was seen to be reversible within the Pitterman study and are explainable by the high caloric intake

Nevertheless, based on this a NOAEL of 100 mg/kg bw/d is used for DNEL derivation and Riskassessment.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Most detrimental study with lowest NOAEL and highest duration / reliability is choose as basis for effect / endpoint.

Justification for classification or non-classification

The available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.