Benzenepropanal, 2-methyl-4-(2-methylpropyl)-

PBT assessment

PBT assessment: overall result

PBT status:

the substance is not PBT / vPvB

Justification:

PERSISTENCE (P) :

NYMPHEAL (GR-88 -0778) was shown to be INHERENTLY and ULTIMATELY Biodegradable in an OECD 302C study. Following a lag-phase of four- to five-weeks, biodegradation began and attained 44% biodegradation by Day 44, increasing to 77% by Day 60 of the incubation.

Although this is not conclusive evidence of non-persistence, data exists from an OECD 301C MITI Biodegradation study which, under the very conservative test conditions (test item test concentration = 100 mg/L, difficulties with non-fresh cultured inoculum), NYMPHEAL was shown to undergo complete 100% primary degradation to the corresponding carboxylic acid, NYMPHEAL ACID (GR-88 -1910) during the study. NYMPHEAL is a primary aldehyde and, as such, would be expected to rapidly oxidise to the corresponding carboxylic acid in the presence of oxygen in different milieu.

From an Environmental Risk Assessment (ERA) perspective, it is thus suggested that the NYMPHEAL ACID (GR-88 -1910) is in fact the relevant entity for consideration, rather than the Parent. Several additional studies have been performed on the NYMPHEAL ACID, and are presented in the relevant section, herebelow.

- Biodegradation - OECD 301F - Not Readily Biodegradable

The Parent, NYMPHEAL, is NOT P.

NYMPHEAL ACID (GR-88 -1910) is not considered to be P or vP, since the OECD 302C study on the Parent, NYMPHEAL, demonstrates rapid and significant biodegradation following a 4- to 5-week lag phase, presumably following rapid transformation of the Parent aldehyde to the Carboxylic Acid, then micro-oraganism re-adaptation to the Acid.

BIOACCUMULATION (B) :

The LogPow of NYMPHEAL was determined in an OECD 117 study to be 3.7, which is significantly below the threshold screening value of 4.5.

The LogPow of the primary metabolite, NYMPHEAL ACID (GR-88 -1910), which is considered to be the relevant moeity for the ERA, was determined to be 2.9.

NYMPHEAL (GR-88 -0778, Parent) - An In vivo Fish bioconcentration study has not been performed on NYMPHEAL (GR-88 -0778). However, In silico modelling and In vitro Fish liver S9 metabolism both predict similar BCF values, indicating low potential to bioaccumulate.

In silico Modelling NYMPHEAL :

BCFBAF(v3.01) (EPISuite v4.11) :

- Regression Based Method BCF = 128 L/kg

- Arnot-Gobas Method BCF = 175 L/kg

BCF BaseLine Model (OASIS-CATALOGIC v5.11.16) NYMPHEAL :

- BCFMax = 583 L/kg

- BCFAttenuated (metabolism, size, water solubility) = 4.79 L/kg

In vitro Fish S9 Liver Cells Metabolism NYMPHEAL :

Predicted BCF (fu = 1.0, i.e. no effect of differential binding to serum assumed) = 59.4 L/kg

Predicted BCF (fu calc, i.e. assuming different binding to serum in vivo compared with in vitro) = 66.4 L/kg

It is considered that NYMPHEAL (GR-88 -0778) is NOT B / NOT vB.

NYMPHEAL ACID (GR-88 -1910, Primary Metabolite) - NYMPHEAL transformed 100% to NYMPHEAL ACID in an OECD 301C MITI Biodegradation study. As a consequence of this, an In vivo fish bioconcentration study was performed on the NYMPHEAL ACID (GR-88 -1910) according to the OECD 305 - I test guideline. Detects of both the major- and minor-component of NYMPHEAL ACID were all below the respective Limit of Quantifications, which were respectively, < 3.4 L/kg and < 9.4 L/kg. NYMPHEAL ACID presents negligible potential to bioaccumulate in fish.

It is considered that NYMPHEAL ACID (GR-88 -1910) is NOT B / NOT vB.

TOXICITY (T) :

NYMPHEAL (GR-88-0778, Parent) - Acute studies have been performed on three trophic levels of freshwater species - OECD 201, OECD 202, OECD 203.

OECD 201 - Algal Inhibition :

ErC50 (72 hr) = 1.55 mg/L

ErC10 (72 hr) = 0.56 mg/L

NOErC (72 hr) = 0.12 mg/L

EyC50 (72 hr) = 0.72 mg/L

EyC10 (72 hr) = 0.30 mg/L

NOEyC (72 hr) = 0.12 mg/L

OECD 202 - Acute Daphnia Imobillisation :

EC50 (48 hr) = 1.01 mg/L

OECD 203 - Acute Fish Toxicity :

LC50 (96 hr) (Danio rerio) = 1.09 mg/L

SEPA 203 - Acute Fish Toxicity (Chinese study) :

LC50 (96 hr) (Gobiocypris rarus) = 3.48 mg/L

To address long-term toxicity testing to the long-term Daphnia endpoint as part of the REACH registration of NYMPHEAL (target substance) it is proposed to read-across to FLORHYDRAL (source substance). This is an analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). It is covered by scenario 2 in the ECHA Read-Across Assessment Framework [RAAF, ECHA 2017].  This read-across is based on the hypothesis that the source and target substance have similar ecotoxicological properties as a result of structural similarity (both the target- and source-substances are primary aldehydes), the same expected mode of action for aquatic toxicity and similar physicochemical properties relevant for the read-across ecotoxicological Endpoint.

In order to derive the 21-day NOEC for NYMPHEAL from the source substance and to compensate for the lower hydrophobicity of FLORHYDRAL, the ratio of the acute Daphnia toxicity value for the source substance divided by that of the target substance 48 hour EC50 has been used to calculate a safety assessment factor to derive the NYMPHEAL 21-day NOEC.

FLORHYDRAL 48hr EC50 (2.26 mg/L)  ÷  NYMPHEAL 48hr EC50 (1.01 mg/L)  =  2.238

Subsequently, the FLORHYDRAL 21-day NOEC of 0.71 mg/L (mean measured value) yields a predicted 21-day NOEC for NYMPHEAL via read-across of 0.32 mg/L.

NYMPHEAL ACID (GR-88 -1910) - A non-GLP study, respecting the spirit of GLP to the TG OECD 201, was performed on the NYMPHEAL ACID (GR-88 -1910) and an Acute Fish toxicity study per Japanese Industrial Standard (JIS K 0102:2016 -71) was performed under GLP.

OECD 201 - Algal Inhibition :

ErC50 (72 hr) > 18.3 mg/L

ErC10 (72 hr) > 18.3 mg/L

NOErC (72 hr) > = 18.3 mg/L

EyC50 (72 hr) > 18.3 mg/L

EyC10 (72 hr) > 18.3 mg/L

NOEyC (72 hr) > = 18.3 mg/L

JIS K 0102:2016 -71 - Acute Fish Toxicity :

LC50 (96 hr) (Oryzias latipes) = 57.4 mg/L

Clearly the primary metabolite, NYMPHEAL ACID (GR-88 -1910) is much less toxic than the Parent molecule. In the case of Algal Inhibition is between 12- and 152 -times less toxic, and, 53 -times less acute toxic for freshwater fish.

Both NYMPHEAL (GR-88 -0778) and NYMPHEAL ACID (GR-88 -1910) are NOT T.