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EC number: 270-128-1
CAS number: 68411-46-1
The UVCB substance causes adverse effects on liver in rats as indicated by slight to moderate fatty changes at doses between 75 and 300 mg/kg bw, single cell necrosis and changes in clinical chemistry observed upon subacute exposure. These changes are accompanied by a liver enlargement of up to 54% in male rats. The same hazard profile was observed for a related UVCB substance. For this substance, no additional hazards were identified in the subchronic oral toxicity study.
The concentrations analysed in the formulations of Group 2, Group 3 and
Group 4 were in agreement with target concentrations (i.e. mean
accuracies between 90% and 110%). The formulations of Group 2 and Group
4 were homogeneous (i.e. coefficient of variation ≤ 10%). Group 1
(control group) did not contain the test substance.
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1%
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1%
Hepatic toxicity was noted for animals of both sexes at 225 mg/kg
bw/day. This was supported by changes in clinical pathology endpoints
(increase of ALP, bilirubin, cholesterol and decrease of albumin, total
protein and inorganic phosphate, among others), macroscopic
abnormalities (accentuated lobular pattern, enlargement and
discoloration), increased organ weights (relative weights approximately
50% and 19% higher for males and females, respectively) and microscopic
findings including hepatocellular vacuolation and hypertrophy. Taken
together, the findings at this dose level were considered to be adverse.
At 75 mg/kg bw/day, morphologic liver findings were regarded to be an
adaptive, non-adverse response based on the minimal severity of the
hypertrophy (correlated to pale discoloration) and low incidence and
minimal degree of vacuolation in the females. However, when taken
together withsimilar changes seen in clinical biochemistry parameters as
high dose animals, and an approximate
relative liver weight increase of 24% and 17% for males and females,
respectively, the findings were also considered toxicologically relevant
at 75 mg/kg bw/day.
Experimental data includes a subacute gavage study (OECD 422) and its 28-day range-finding study, a 90-day study with a related alkylated diphenylamine and its 28-day range-finding study as well as mechanistic (“metabolome”) investigations for both substances. The related UVCB substance is “reaction products with branched nonene” instead of “reaction products with 2,2,4 –trimethylpentene”
The extended dose-range finding study in male rats was performed to verify a previously used read-across and to support dose-range finding for future testing for reproductive toxicity (BASF 2013) and accordingly, 125 and 300 mg/kg bw were chosen as dose levels. Corn oil served as vehicle since the substance is not miscible with water, but miscible with oil. Since liver was expected to be the target organ, haematology, clinical chemistry and liver histopathology were investigated. As part of this study, plasma was subjected to a "metabolome" analysis (see IUCLID section 7.9.3) which investigates changes in plasma concentrations of more than 200 endogenous plasma components.
As a result of the adverse effects on liver, dose levels of 25, 75 and 225 mg/kg bw were chosen for the OECD 422 study. This study was performed at another laboratory with slightly older animals (10-12 weeks versus 6 weeks). This may explain why the liver effects were more prominent in the full study although lower doses were tested. Affected parameters are summarized in the table below.
The data was compared to results of a full 90 -day study (OECD 408) and its dose-range finder with another UVCB substance of similar composition (Reaction products with branched nonene instead of reaction products with 2,2,4 -trimethylpentene) tested at equal and higher doses (100, 300 and 1000 mg/kg bw). The composition of both UVCB substances is shown in a table in the toxicokinetic section. An overview on these results is also given in the table below.
All studies identify liver as the primary target organ for both substances. Both substances cause an adaptive enlargement of liver in combination with adverse findings such as a disturbed lipid metabolism and cellular degeneration. Single cell necrosis is seen in a few animals at the high dose groups only. Alkaline phosphatase levels are increased less than 3fold at 300 mg/kg bw and albumin levels are decreased at equal or less than 10% for subacute and 100 mg/kg bw for subchronic exposure, respectively.
As seen in table 1, the parameters affected by the two substances are identical with two exceptions. The target substance caused a slight reduction in total bilirubin levels and an increased severity of lymphoid cell infiltrates in the liver (2/5 animals at 300 mg/kg bw). But both parameters fit to the general picture of adverse effects on liver. Comparison regarding the overall toxicity shows that for some parameters, the substance is more potent than the nonylated version. The accentuated lobular pattern of the liver (6 males, 2 females), pale discoloration (7 males, 1 female) was observed at 225 mg/kg bw after 28 days whereas only 3/20 animals showed a prominent acinar pattern of liver at 1000 mg/kg bw after 90 days. This is consistent with an increase in male relative liver weight by 54% at 225 mg/kg bw after 28 days versus 27% at 300 mg/kg bw after 90 days.
In contrast, the occurrence of single cell necrosis and the fatty changes in liver was more pronounced after 90 days at comparable dose levels. Slight changes in haematology were only observed after 90 days.
All other affected parameters similarly affected at 28 and 90 days. So overall, it appears that nonylated version is less hazardous. This may be due to the simple fact that the average molecular weight is higher and therefore the dose on a molar base lower.
The mechanistic investigation showed that both substances have the most similar metabolome patterns among all substances existing in the database.
The 90-day study with the nonylated version shows that prolonging the treatment from subacute to subchronic toxicity does not introduce previously unknown effects. Therefore, the NOAEL of 25 mg/kg bw is considered adequate for deriving the DNEL and no full 90 day study for the actual substance is needed.
Liver histopathology is included in in the ongoing bridging study (BASF 2019).
Table: Comparison of the effects observed upon repeated dose treatment with reaction products with 2,4,4 -trimethylpentene (28 -days and OECD 422) and nonene (28 and 90 days)
(Substance CAS 15721 -78 -5, Bis((1,1,2,2 -tetramethylbutyl)phenyl)amine could also be added, but caused no adverse effects at 100, 300 and 1000 mg/kg bw in the OECD 408, based on the dissiminated information)
Further information on repeated dose toxicity is available from an OECD 443 guideline study using Wistar rats. Rats were treated with 0, 200, 600 and 1800 ppm of the test subtance via the feed. In this study, the NOAEL for general, systemic toxicity is below 200 ppm (about 18 mg/kg bw/d) in the F0 parental rat, and 200 ppm in F1 adult rats based on evidence for liver toxicity observed in (histo-)pathology and clinical chemistry. For more details refer to chapter 7.8. toxicity to reproduction.
Overall, regarding the target organ liver, no sufficient dose-response with respect to degenerative effects (e.g. necrosis) was observed. There were rather adaptive responses with some evidence for focal necroses with slight increases of clinical chemistry parameters showing unsufficient dose-response.
Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. There were no significant toxic effects at doses of less than 300 mg/kg bw upon oral exposure in rats. Fatty changes were at most moderate, and not severe. There was no morbidity. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the second time in Directive (EC 286/2011).
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