1-Octadecanol, phosphate, potassium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study is of high quality with Klimisch score = 1; the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reliable, relevant and adequate data on reproductive toxicity are available for the read-across substance Phosphoric acid, dodecyl ester, sodium salt.

The read-across approach is appropriate due to similar composition of source substance and registered substance. From the available data is can be concluded that the repeated dose toxicity of substances with different alkyl moieties (C12, C14, C9-15 linear and branched) is comparable.

Phosphoric acid alkyl esters are hydrolysed unspecifically by phosphatases, e.g. acid phosphatase or alkaline phosphatase. Both enzymes are found in most organisms from bacteria to human. Alkaline phosphatases are present in all tissues, but are particularly concentrated in liver, kidney, bile duct, bone, placenta. In human and most other mammals three isoenzymes of Alkaline phosphatase exist: intestinal ALP, placental ALP, tissue non-specific ALP (present in bone, liver, kidney, skin).

Seven different forms of Acid phosphatase are known in humans and other mammals. These are also present in different tissues and organs (predominantly erythrocytes, liver, placenta, prostate, lung, pancreas).

Linear and branched primary aliphatic alcohols are oxidised to the corresponding carboxylic acid, with the corresponding aldehyde as a transient intermediate. The carboxylic acids are further degraded via acyl-CoA intermediates in by the mitochondrial beta-oxidation process. Branched aliphatic chains can be degraded via alpha- or omega-oxidation (see common text book on biochemistry).

“The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001).

Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995a,b).

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.” (OECD SIDS, 2006).

 

Thus, it can be expected, that also the effects on reproduction of the Phosphoric acid C12-alkyl ester will be similar to those of Phosphoric acid, mono- and di- C16-18 (even numbered) alkyl esters.

 

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD guideline 422 Phosphoric acid, dodecyl ester, sodium salt was administered to 12 Sprague-Dawley rats/sex/dose by daily oral gavage at dose levels of 0 (control), 250, 500, and 1000 mg/kg bw/d.

The males were exposed 14 days before mating, through the mating period, up to 1 day before termination (42 days in total). The females were exposed 14 days before mating, through the mating and gestation period, up to day 4 of lactation (42 to 45 days in total).

Administration of the test substance did not have any effect on the estrous cycle, days to copulation, copulation rate, fertility rate, or conception rate. Similarly, administration of the test substance did not have any effect on the delivery rate, gestation period, number of corpora lutea, number of implantation sites, implantation rate, stillbirth rate, number of live-born pups, live-birth rate in the mother animals, or on the sex ratio of the littermates. No abnormalities were observed in the lactating behaviour during the lactation period either. These results suggest that administration of the test substance even at 1000 mg/kg had no effect on the reproductive function, such as that shown by the copulation rate, of the males or females, or in the fertility rate, conception rate, or on the gestation maintenance, delivery, or lactating behaviour in the mother animals.

Pups showed no changes caused by the administration of the test substance regarding the observation at birth, necropsy findings on day 4 of lactation, body weight, or viability rate, which suggested that administration of the test substance even at 1000 mg/kg bw/d had no effect on the development.

The reproduction, breeding and developmental NOEL is 1000 mg/kg bw/d.

Higher-tier fertility study (two-generation study) is not required at this tonnage band, since there were no adverse effects observed in the repeated dose toxicity study in reproductive organs or tissues or any adverse effects in the screening studies for reproductive toxicity (OECD 422). Therefore, there is no data gap in fertility. There is no reason to believe that results of the screening study would not be relevant for fertility in humans and therefore, for risk assessment.

Short description of key information:
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test oral (gavage), rat (Sprague-Dawley) m/f (OECD guideline 422, GLP no data): reproduction, breeding and developmental NOEL: 1000 mg/kg bw/day (both sexes); read-across substance Phosphoric acid, dodecyl ester, sodium salt

Justification for selection of Effect on fertility via oral route:
OECD guideline study, no deviations, GLP

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study: rat (Sprague-Dawley Crl:CD® BR),  gavage, (OECD 414): NOEL developmental toxicity, embryotoxicity, fetotoxicity and teratogenicity 361 mg/kg bw/d (highest dose administered).  No compound related developmental toxicity, embryotoxicity, fetotoxicity or teratogenicity has been observed in a developmental toxicity study with Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts.  

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

316 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study is of high quality with Klimisch score = 1; the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Reliable, relevant and adequate data on prenatal developmental toxicity are available for the read-across substance Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts.

The read-across approach is appropriate due to similar composition of source substance and registered substance. From the available data is can be concluded that the repeated dose toxicity of substances with different alkyl moieties (C12, C14, C9-15 linear and branched) is comparable.

Phosphoric acid alkyl esters are hydrolysed unspecifically by phosphatases, e.g. acid phosphatase or alkaline phosphatase. Both enzymes are found in most organisms from bacteria to human. Alkaline phosphatases are present in all tissues, but are particularly concentrated in liver, kidney, bile duct, bone, placenta. In human and most other mammals three isoenzymes of Alkaline phosphatase exist: intestinal ALP, placental ALP, tissue non-specific ALP (present in bone, liver, kidney, skin).

Seven different forms of Acid phosphatase are known in humans and other mammals. These are also present in different tissues and organs (predominantly erythrocytes, liver, placenta, prostate, lung, pancreas).

Linear and branched primary aliphatic alcohols are oxidised to the corresponding carboxylic acid, with the corresponding aldehyde as a transient intermediate. The carboxylic acids are further degraded via acyl-CoA intermediates in by the mitochondrial beta-oxidation process. Branched aliphatic chains can be degraded via alpha- or omega-oxidation (see common text book on biochemistry).

“The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001).

Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995a,b).

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.” (OECD SIDS, 2006).

The Phosphoric acid alkyl esters with branched fatty alcohol chains can be considered as a worst case scenario because the metabolism of the resulting branched fatty acids occurs less efficient compared to linear fatty acids.

 

Thus, it can be expected, that also the effects on development of the Phosphoric acid C9-15, branched and linear alkyl ester will be similar to those of Phosphoric acid, mono- and di- C16-18 (even numbered) alkyl esters.

 

In a developmental toxicity study according to OECD guideline 414, Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts (36.1% a.i.) was administered to 25 female Sprague-Dawley Crl:CD® BR rats/dose by oral gavage at dose levels of 0 (control), 36.1, 180.5 and 361 mg/kg bw/d (active ingredient) from day 6 through 15 of gestation. Females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section.

No treatment-related effects on mortality, number of abortions, clinical signs, food consumption, gross pathology, intrauterine growth and survival (incl. postimplantation loss, viable litter size, mean fetal body weights, fetal sex ratios, mean numbers of corpora lutea and implantation sites) were observed.

No treatment-related fetal malformations or fetal developmental variations were observed at any dose level.

The NOEL for maternal toxicity is 36.1 mg/kg bw/d.

The NO(A)EL for maternal toxicity is 361 mg/kg bw/d (highest dose administered).

The NOEL for developmental toxicity is 361 mg/kg bw/d (highest dose administered).

The NOEL for embryotoxicity is 361 mg/kg bw/d (highest dose administered).

The NOEL for fetotoxicity is 361 mg/kg bw/d (highest dose administered).

The NOEL for teratogenicity is 361 mg/kg bw/d (highest dose administered).

There is no data gap in prenatal developmental toxicity. There is no reason to believe that results of the prenatal developmental toxicity study would not be relevant for developmental toxicity in humans and, therefore, for risk assessment.

 

Justification for selection of Effect on developmental toxicity: via oral route:
OECD guideline study, GLP

Justification for classification or non-classification

In conclusion, the results of the available data on toxicity to reproduction, developmental toxicity and teratogenicity indicate that 1-Octadecanol, phosphate, potassium salt does not need to be classified for toxicity to reproduction (fertility), developmental toxicity and teratogenicity according to Directive 67/548/EEC as well as CLP, EU GHS (Regulation 1272/2008/EC) and therefore labelling is not necessary.