Reaction mass of 2-[[4-[[3,5-dimethyl-4-(oxiran-2-ylmethoxy)phenyl]methyl]-2,6-dimethyl-phenoxy]methyl]oxirane and 1,3-bis[4-[[3,5-dimethyl-4-(oxiran-2-ylmethoxy)phenyl]methyl]-2,6-dimethyl-phenoxy]propan-2-ol and 1-[4-[[3,5-dimethyl-4-(oxiran-2-ylmethoxy)phenyl]methyl]-2,6-dimethyl-phenoxy]-3-[4-[[4-[3-[4-[[3,5-dimethyl-4-(oxiran-2-ylmethoxy)phenyl]methyl]-2,6-dimethyl-phenoxy]-2-hydroxy-propoxy]-3,5-dimethyl-phenyl]methyl]-2,6-dimethyl-phenoxy]propan-2-ol

Endpoint summary

Description of key information

Only standard information required at REACH Annex VIII to X is available for assessing the toxicokinetics for the test substance.

The available test data do not permit extensive conclusions concerning absorption, metabolism or excretion to be conclusively drawn.

Acute toxicity (via the oral route) was low, and repeated oral administration results in high mortality at 1000 mg/kg/day.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Repeated oral administration of the test substance (in an OECD 422 study) to rats provided a parental NOAEL of 300 mg/kg/day. At 100 and 300 mg/kg/day non-adverse effects were mainly localised to the liver (hepatocellular hypertrophy which was associated with higher organ weight and a minimal increase in liver enzymes at 300 mg/kg - a change considered adaptive in nature). At 1000 mg/kg/day the animals were sacrificed prior to mating due to extensive clinical signs. (The toxicity at this dose was considered to be related to sternal bone marrow atrophy, caused by test animal malnutrition rather than a direct test substance effect). The clinical signs evident at the top dose indicated that some absorption and distribution of the test substance can be expected. At 100 and 300 mg/kg/day no adverse effects were noted and it is possible that bioelimination through normal metabolic and excretory pathways allows some removal of the test substance, with the potential for these pathways to be overwhelmed at the top dose.

 

In the 90-day repeated dose study (OECD 408), administration of control article (vehicle) or 100, 300, or 600 mg/kg/day test substance to rats following daily oral (gavage) administration for 13 weeks resulted in mortality in animals administered 600 mg/kg/day. A few non-adverse inlife findings were observed in males administered ≥100 mg/kg/day and females administered ≥300 mg/kg/day, including salivation and changes in food consumption, body weight gain, grip strength, and foot splay (males only). Clinical pathology, macroscopic, and microscopic findings were consistent with liver and kidney toxicity and were primarily observed in animals administered ≥300 mg/kg/day. Additionally, a few macroscopic and microscopic findings in other tissues were observed primarily in animals administered 600 mg/kg/day. Most findings ranged from minimal to slight severity and were considered not adverse. The majority of findings recorded during the dosing phase were fully or partly reversible. Under the conditions of this study, 300 mg/kg/day is considered the no observed adverse effect level (NOAEL).The findings evident at the top dose indicated that some absorption and distribution of the test substance can be expected.

 

Acute oral toxicity of the test substance was low (LD50 cut off greater than 5000 mg/kg).

 

No treatment related changes were observed in any of the developmental or reproductive parameters in the OECD 422 study, possibly indicating low adsorption through the placenta to directly affect the foetuses and similarly as no effects were observed in pups during the short lactation phase, low exposure to the developing pups via lactation is likely.

 

In the OECD 414 study, effects on maternal body weight and food consumption resulted in lower total weight change, corrected weight change, carcass weight and gravid uterine weights were lower for dams administered 600 mg/kg/day. Although an initial reduction in body weight and food consumption was evident following 300 mg/kg/day administration, no other maternal changes were evident. As such, the no observed adverse effect level (NOAEL) for maternal toxicity was established as 300 mg/kg/day. The findings evident at the top dose indicated that some absorption and distribution of the test substance can be expected.

 

Fetal effects consisted of slightly lower but statistically significant body weights following maternal administration of 600 mg/kg/day, and higher incidences of several skeletal variations following maternal administration of 300 or 600 mg/kg/day, although only one vertebral variation (thin cartilaginous structures of the vertebra sacral arch) reached statistical significance. These effects were considered non-adverse. Based on the findings of this study, the fetal no observed adverse effect level (NOAEL) is established as 600 mg/kg/day.This was the highest dose and as no adverse effects were noted possibly indicating low adsorption through the placenta to directly affect the foetuses.

 

In the EOGRTS (OECD 443) study there no adverse findings noted for F0 and F1 males and females and F1 litters at all dose levels tested. The high dose of 250 mg/kg/day was considered to be the NOAEL for F0 and F1 systemic toxicity, F0 reproductive toxicity, F1 neonatal toxicity, and F1 immunotoxicity and brain morphometry. 

 

The substance was determined to be a skin sensitiser based on the results of a LLNA, indicating that the test substance potentially has the ability to pass through the dermal layers of the skin, and can induce proliferation of lymphocytes in the relevant draining lymph nodes.

 

The in vivo genotoxicity tests which tested for both the test substance ability to induce DNA damage in liver and duodena cells, and also clastogenic activity and/or disruption of the mitotic apparatus (by detecting micronuclei in polychromatic erythrocytes cells) in rat bone marrow, both showed a clear negative response for genotoxic effects.

 

Based on the relatively low Log Kow values (<4.5) and low aqueous solubility of the test substance, bioaccumulation of the test substance is not expected.