Mono-, and di-(sec-hexadecyl)naphthalene

PBT assessment

PBT assessment: overall result

PBT status:

the substance is not PBT / vPvB

Justification:

The study substance is not persistent (P) or very persistent (vP) based on standard test guidelines.

The screening criteria for P and vP requires biodegradation half-life of >40 and >60 days, respectively, in fresh water. A ready biodegradation study carried out in freshwater with the study substance (Mobil Business Resources, Corp. 1996a) showed that it was biodegraded to 53.2% in 28 days and 64.2 % in 35 days (CO2 monitored). Other supporting ready biodegradation (OECD 301F) data also indicate that the study substance is biodegraded extensively (ExxonMobil Biomedical Science Lab, 2009a). Hence, the study substance is not persistent (P) or very persistent (vP) since it biodegrades to 50% or more in 28 days or less (i.e., biodegradation half-life less than 28 days).

The study substance is not bioaccumulative (B) or very bioaccumulative (vB), based on calculated bioconcentration (BCF) values and measured biomagnification factor (BMF) data. The low water solubility and high partition coefficient makes it extremely difficult to conduct an aqueous BCF study. The BMF was determined by a dietary exposure study with fish (Oncorhynchus mykiss), using a 12-day uptake period and a 21-depuration period. The test substance was found to have a lipid-normalized biomagnification factor of 0.28 and an elimination half-life of 38 days. In addition, key support data were provided by the calculated BCF value of 3.16 for the study substance using the US EPA EpiSuite v3.12 program (US EPA, 2000d). A further mitigating factor is the very high log Kow value (log Kow >10) which limits uptake across membranes due to bioavailability/tissue permeation constraints. These data support the conclusion that the BCF for the study substance is well below the 2000 L/kg which is the criterion for not being considered bioaccumulative (B) and is well below the 5000 L/kg which is the criterion for not being considered very bioaccumulative (vB).

The study substance is not toxic (T) based on results from chronic aquatic toxicity studies that showed no effects at levels exceeding the maximum water solubility. Read-across data from a 21 -day invertebrate chronic studies (OECD 211) with Daphnia magna (water flea) for a structurally-related material support the assessment that the study substance would not be expected to cause chronic toxicity (reproduction, survival) at the maximum water concentrations reached under the conditions of the test. No statistically significant effects were observed at the maximum water solubility limit (as WAF solution) under the conditions of the test for a structurally-related long chain alkylated naphthalene surrogate [ExxonMobil Biomed. Sci. Lab, (2003). These read-across findings indicate that the study substance would not be expected to produce chronic toxicity to Daphnia magna. See CSR Section 7.1 for additional information regarding aquatic toxicity for the study substance.

In order to meet the criterion for T, sufficient evidence must be available to show the substance is carcinogenic to man (Class 1) or to presume that human exposure to the substance may result in the development of cancer based on long-term animal studies or other relevant information (Category 2).    The data for the study substance do not provide evidence of carcinogenicity.            ADME studies using radiolabelled

sec-hexadecylnaphthalene indicate that oral absorption occurs to a low extent (~10% of radioactive dose) in rats (Huntingdon, 2002). Findings also indicated a low bioaccumulation potential in the tissues. Dermal absorption is expected to be low or very limited based on extrapolation of the poor oral bioavailability results for the study substance and the physico-chemical properties. Physico-chemical properties also support limited absorption of the parent material through the lungs. If absorbed, the results of various toxicokinetic studies conducted on long-chain alkylated naphthalenes (e.g. isopropyl and diisopropylnaphthalenes) (Hoke and Zellerhoff, 1998;

Kojima et al. 1982) suggest that the sec-hexadecyl group in the study substance precludes biotransformation of the parent molecule into reactive and harmful intermediates (i.e. aromatic epoxides). Computational cytochrome

P-450 modeling studies also predict that aromatic ring epoxidation of sec-hexadecylnaphthalene is not likely to occur due to poor substrate binding to the active site (i.e, bulky aliphatic group prevents fit) (Lewis et al 2002).

Exclusive metabolism of the side-chain alkyl group in alkylnaphthalenes (e.g., alkyl group having more than 3

carbon atoms) has been postulated to account for the relative non-toxicity reported for diisopropylnaphthalene (DIPN) and thus, the favorable health safety properties of the parent material and its biotransformation products (see Hoke et al. 1998). Long chain alkyl groups in alkylnaphthalenes are believed to exclusively shunt metabolism of the parent chemical via side chain alkyl group pathway and not via the aromatic oxidation pathway. This precludes potential arene oxide formation or harmful/reactive metabolite involvement. In

multiple genetic toxicity studies of the study substance (CSR Section 5.7), no evidence of mutagenic potential has been identified. In addition, repeated subchronic exposure to the study substance by either the oral or dermal route showed no significant treatment-related hyperplasia and/or pre-neoplastic lesions (CSR

Section 5.6). Finally, a dermal carcinogenicity study (ECB, 2000) of a surrogate alkylated naphthalene material, diisopropylnaphthalene, reported no treatment-related tumors following a two year daily dietary exposure of doses up to 1500ppm.          Therefore, the study substance does not meet the criterion for T based on carcinogenicity.

 

 

Substances known to be mutagenic to man (Category 1) or substances which should be regarded as if they are mutagenic to man (Category 2) based on sufficient animal studies or other relevant information also defines the criterion for T.  The data on the study substance do not provide evidence of mutagenicity (CSR Section

5.7).    In an in vitro bacterial test, the study substance was not mutagenic in Salmonella strains tested in the presence or absence of metabolic activation. It was also non-cytogenic in an in vitro mammalian cell assay and when tested in an in vivo mouse bone marrow micronucleus assay. Finally, it was not mutagenic in the mouse lymphoma L5178Y/TK+/- cell line, in both the presence and absence of an S9 metabolic

system. Therefore, the study substance is a non-genotoxic substance which does not meet the criterion for

T based on mutagenicity.

 

 

 

The T criterion includes substances known to impair fertility in humans or cause developmental toxicity in humans (Category 1), substances regarded as if they impair fertility in humans or cause developmental toxicity to humans (Category 2), or substances which cause concern for human fertility or for humans owing to possible

developmental toxic effects (Category 3). In each case appropriate animal or other relevant studies are needed to clearly show or support toxic effects.      The data on the study substance do not provide evidence of reproductive toxicity

 

 

Fertility: Based on qualitative weight of the evidence reasoning, it is expected that the study substance has a low order of reproductive toxicity. First, toxicokinetic data (CSR Section 5.1) and physico-chemical properties support limited absorption of the study substance by all routes of exposure. Second, data provided for all available toxicological endpoints show limited effects for reproductive endpoints. Subchronic studies with the study substance identified no effects on reproductive female organ weights, no effects on male testis weight and no macroscopic or microscopic alterations in these tissues (ExxonMobil, 1991,

1994b). Following subchronic dermal exposure to the study substance, a small but significant increase in relative epididymus weight was noted at the highest dose tested (ExxonMobil, 1994a). However, no microscopic or macroscopic changes were noted in this tissue (or in the testes as noted above) and no effects on sperm morphology or, sperm counts were noted. In addition, no increase in epididymus weight was observed in a subchronic oral limit test (ExxonMobil, 1991). Taken together, these data suggest that the slight change in epididymus weight is spurious and not indicative of an adverse reproductive effect. Third, a two generation reproductive toxicity study in which a structurally analogous alkylated naphthalene, diisopropylnaphthalene (DIPN), was administered by oral gavage during gestation reported no effects on any of the reproductive parameters examined including, pregnancy rate, litter size and survival rates (ECB, 2000). Two additional developmental toxicity studies on DIPN, including an OECD 414 test-guideline study, demonstrated no effects

on female reproductive parameters when the test material was administered during gestation (LPT, 1993). DIPN is an adequate substance for use as read across based on similar functionality and metabolism as the study substance (refer to the toxicokinetic section for more detail). Accordingly, the weight of evidence supports that the study substance does not affect fertility and therefore, this substance does not meet the criterion for T.

 

 

Developmental toxicity: Based on qualitative weight of evidence reasoning it, it is expected that the study substance has a low order of developmental toxicity. First, toxicokinetic data (CSR Section 5.1) and

physico-chemical properties support limited absorption of the study substance by all routes of

exposure. Second, three separate studies covering two different species on a structurally analogous alkylated naphthalene material, diisopropylnaphthalene, failed to demonstrate teratogenic effects at doses that were not maternally toxic (EPA, 2003; LPT, 1993; ECB, 2000). DIPN is an adequate substance for use as read across based on similar functionality and metabolism as the study substance (refer to the toxicokinetic section for more detail). In these repeated-dose developmental toxicity studies, no effects were observed on survival rates, fetal body weight, newborn growth data, litter size, or on variation and/or developmental retardations of soft tissue. Small effects noted at maternally toxic doses included decreased fetal body weight in one study (EPA,

2003) and possible (not statistically significant) treatment-related skeletal retardations in two studies (EPA,

2003; LPT, 1993). However, because these observations were noted only at dose levels inducing maternal toxicity they cannot be considered as specific effects on prenatal development. Therefore, the study substance does not meet the criterion for T based on reproductive toxicity.

Based on the criteria listed in the above-mentioned assessment, the study substance does not qualify as Toxic under Annex XIII, Section 1.1.3 of REACH.