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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Expert statement
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2013-03-25
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement, no study available
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement
GLP compliance:
no
Details on test animals and environmental conditions:
not applicable
Details on exposure:
not applicable
Duration and frequency of treatment / exposure:
not applicable
Remarks:
not applicable
No. of animals per sex per dose:
not applicable
Positive control:
not applicable
Details on study design:
not applicable
Details on dosing and sampling:
not applicable
Statistics:
not applicable
Details on absorption:
Generally, oral absorption is limited for molecular weights above 500 g/mol. Due to the lipophilic properties and the low water solubility of ditetradecyl peroxydicarbonate, dissolution in the gastro-intestinal fluids is limited and absorption through the mucosal surface is estimated to be slow. On the other hand, absorption of ditetradecyl peroxydicarbonate may be facilitated following micellular solubilisation by bile salts. Micelles enter the systemic circulation via the lymphatic system, bypassing the liver.
No systemic effects were observed after single and repeated administration of ditetradecyl peroxydicarbonate on rats leading to the following discussion points:
On the one hand, the potential to induce toxic effects of ditetradecyl peroxydicarbonate might be low as the potential decomposition products, myristyl alcohol and carbon dioxide, occur physiologically. On the other hand, no observed effects could be a result of no absorption. In conclusion, bioavailability after oral administration is expected to be low.
As ditetradecyl peroxydicarbonate is a solid at room temperature, it might reach the respiratory tract in its dust state. However, due to the particle size of 1000 to 4000 µm the respirable airborne fraction is negligible. Particles might deposit in the nasal region and would be sneezed out or coughed up. No absorption through the respiratory tract epithelium is expected as dissolution in the mucus is limited by the lipophilic properties and low water solubility of ditetradecyl peroxydicarbonate. Since no specific effects of systemic toxicity were observed after oral administration systemic availability is unlikely also after inhalation exposure.
Similarly, based on physico-chemical properties of ditetradecyl peroxydicarbonate the substance is not likely to penetrate through the skin to a large extent as the high log Pow value and the low water solubility do not favour dermal penetration. It is generally accepted that if a compound’s water solubility is < 1 mg/L, absorption can be anticipated to be low. Moreover, for substances with a log Pow above 6, the rate of penetration is limited by both uptake into the stratum corneum and transfer into the epidermis. However, as ditetradecyl peroxydicarbonate has been identified as a skin sensitiser in a LLNA study, penetration through the skin must have occurred although only to a small fraction of the applied dose.
Details on distribution in tissues:
Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. The volume of distribution is estimated to be low and diffusion across cell membranes is limited by the molecular weight and lipophilic properties of the substance.
The potential decomposition product, myristyl alcohol and rather its oxidised form, myristic acid, were shown to bind to serum albumin to facilitate circulation via the bloodstream (Curry, S. et al, 1999).
Based on the BCF value of ditetradecyl peroxydicarbonate and the physiologically occurrence of its potential decomposition products bioaccumulation of the substance in the body can be excluded.
Details on excretion:
As discussed above, absorption of ditetradecyl peroxydicarbonate is limited by the compound’s high lipophilicity and low water solubility. Therefore, ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces.
Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product of ditetradecyl peroxydicarbonate, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.
Details on metabolites:
Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial β-oxidation pathway. Generally, physiologically occurring myristic acid is incorporated in the phospholipid bilayer of the plasma membrane.
Thus, metabolites are not assumed to be more toxic than the parent compound which is further supported by the results obtained in the in vitro mutation and cytogenetic assays in the presence of a metabolic activation system.
Bioaccessibility testing results:
Physico-chemical properties and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route.
Conclusions:
Physico-chemical properties, particularly water solubility and octanol-water partition coefficient and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route. Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial β-oxidation pathway. The non-absorbed fraction of ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces. Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.

Description of key information

Physico-chemical properties, particularly water solubility and octanol-water partition coefficient and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route. Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial β-oxidation pathway. The non-absorbed fraction of ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces. Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

General

Dimyristylperoxydicarbonate is produced at different EU manufacturing sites. The substance represents a basic industrial chemical used as initiator to start chain reactions in the synthesis of polymers.

 

Toxicological profile of Dimyristylperoxydicarbonate

An acute oral toxicity study conducted with ditetradecyl peroxydicarbonate using rats revealed a LD50 value of > 2000 mg/kg bw. The animals achieved expected body weight gains and necropsy revealed no significant macroscopic lesion. No acute inhalation toxicity study is available as the vapour pressure of the substance is low. Experimental data of various organic peroxides show no toxic effects after dermal application up to the tested concentration limit of 2000 mg/kg bw. Based on these data the dermal LD50 value is estimated to be > 2000 mg/kg bw also for ditetradecyl peroxydicarbonate. In an in vivo skin irritation and corrosion study, ditetradecyl peroxydicarbonate did not cause any skin irritation/corrosion effects when applied to rabbit skin. An eye irritation test performed with ditetradecyl peroxydicarbonate on rabbits showed that the substance caused only slight effects on the rabbit’s eye and was not considered to be an eye irritant. A LLNA study on mice revealed that ditetradecyl peroxydicarbonate has skin sensitising potential. Ditetradecyl peroxydicarbonate did not induce a mutagenic response both, in a bacterial reverse mutation test (Ames test) and in an in vitro mammalian cell gene mutation test (HPRT assay) performed on CHO-K1-cells both in the absence and presence of metabolic activation. No induction of chromosome aberration was observed in the in vitro cytogenetic assay on human lymphocytes.

A 14 day dose range finding study using oral administration of ditetradecyl peroxydicarbonate was performed in male and female Wistar rats in order to obtain first information on the toxic potential of the test item after long-term administration to allow a dose-setting for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The chemical was administered orally (by gavage) once a day for a total of 14 days at 0 (vehicle control), 100, 300 and 1000 mg/kg bw/day. No mortality was observed through this study. Salivation was observed in male and female animals of the high and mid dose group. There were no test item-related effects on body weight and food consumption in all dose groups in comparison to control group. Hematological and clinical chemistry parameters in male or female animals were not affected by the treatment. No specific macroscopic changes indicative of test item effect were observed in the organs and tissues at any dose levels. There were no toxicologically significant differences in the examined organ weights between the control and test item treated male or female animals at any dose level. Based on these results the following three doses were selected for the aforementioned combined repeated dose toxicity study with the reproduction/developmental toxicity screening study: 100, 300 and 1000 mg/kg bw/day.

 

The main study revealed no mortality of male and female animals/dams exposed to ditetradecyl peroxydicarbonate. Test item-related salivation was observed in male animals at 1000, 300 and 100 mg/kg bw/day with variable occurrence within a group in a dose related onset and frequency after the daily treatment. No clinical signs and no changes in behaviour and physical condition were noted in any dosage group. No test item-related body weight, or body weight gain changes were observed with respect to controls at any dose level during the pre-mating, mating, post-mating, gestation and lactation periods. There were no test item related changes in the examined hematological or blood coagulation parameters in male or female animals at any dose level compared to control. No macroscopic alterations and changes in the examined organ weights were found during the necropsy in any dosage group. Histopathological examination of reproductive and other organs of both male and female animals revealed no test item-related effect. There were no differences between the control and test item treated groups in the reproductive performance of male and female animals and in delivery data of dams. No test item-related effects were observed on clinical and pathological parameters and on mean litter weight and weight gain of the offspring. No structural or visceral malformations were noted in the offspring at any dosage level. Based on these observations the respective NOAEL for male and female rats was set to 1000 mg/kg bw/day. The NOAEL for reproductive performance of the male and female rats was evaluated to be 1000 mg/kg bw/day and the NOAEL for the offspring was determined to be 1000 mg/kg bw/day.

 

Toxicokinetic analysis of Dimyristylperoxydicarbonate

Dimyristylperoxydicarbonate is a white solid at room temperature with a molecular weight of 514.8 g/mol. The water solubility of the substance is low (< 1 mg/L at 20°C). The log Pow of ditetradecyl peroxydicarbonate was measured and determined to be greater than 6.5 at 25°C. Calculated logPow was 13.0. Based on this log Pow, a BCF of 15.1 L/kg wet-wt was calculated. The vapour pressure of ditetradecyl peroxydicarbonate is low (9.15 E‑10 Pa (25 °C, calculated value). Due to the low water solubility, no data on hydrolysis are available. Ditetradecyl peroxydicarbonate decomposes to myristyl alcohol and carbon dioxide. Myristyl alcohol has a lower log Pow value than ditetradecyl peroxydicarbonate itself (approximately 6.03). Also the BCF value is lower as compared to ditetradecyl peroxydicarbonate (approximately 178.4 L/kg wet-wt). Water solubility of myristyl alcohol is comparable to ditetradecyl peroxydicarbonate (0.2 mg/L).

 

Absorption

Generally, oral absorption is limited for molecular weights above 500 g/mol. Due to the lipophilic properties and the low water solubility of ditetradecyl peroxydicarbonate, dissolution in the gastro-intestinal fluids is limited and absorption through the mucosal surface is estimated to be slow. On the other hand, absorption of ditetradecyl peroxydicarbonate may be facilitated following micellular solubilisation by bile salts. Micelles enter the systemic circulation via the lymphatic system, bypassing the liver.

No systemic effects were observed after single and repeated administration of ditetradecyl peroxydicarbonate on rats leading to the following discussion points:

On the one hand, the potential to induce toxic effects of ditetradecyl peroxydicarbonate might be low as the potential decomposition products, myristyl alcohol and carbon dioxide, occur physiologically. On the other hand, no observed effects could be a result of no absorption. In conclusion, bioavailability after oral administration is expected to be low.

As ditetradecyl peroxydicarbonate is a solid at room temperature, it might reach the respiratory tract in its dust state. However, due to the particle size of 1000 to 4000 µm the respirable airborne fraction is negligible. Particles might deposit in the nasal region and would be sneezed out or coughed up. No absorption through the respiratory tract epithelium is expected as dissolution in the mucus is limited by the lipophilic properties and low water solubility of ditetradecyl peroxydicarbonate. Since no specific effects of systemic toxicity were observed after oral administration systemic availability is unlikely also after inhalation exposure.

Similarly, based on physico-chemical properties of ditetradecyl peroxydicarbonate the substance is not likely to penetrate through the skin to a large extent as the high log Pow value and the low water solubility do not favour dermal penetration. It is generally accepted that if a compound’s water solubility is < 1 mg/L, absorption can be anticipated to be low. Moreover, for substances with a log Pow above 6, the rate of penetration is limited by both uptake into the stratum corneum and transfer into the epidermis. However, as ditetradecyl peroxydicarbonate has been identified as a skin sensitiser in a LLNA study, penetration through the skin must have occurred although only to a small fraction of the applied dose.

Taken together, physico-chemical properties and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route.

Distribution

Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. The volume of distribution is estimated to be low and diffusion across cell membranes is limited by the molecular weight and lipophilic properties of the substance.

The potential decomposition product, myristyl alcohol and rather its oxidised form, myristic acid, were shown to bind to serum albumin to facilitate circulation via the bloodstream (Curry, S. et al, 1999).

Based on the BCF value of ditetradecyl peroxydicarbonate and the physiologically occurrence of its potential decomposition products bioaccumulation of the substance in the body can be excluded.

Metabolism

Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial beta-oxidation pathway. Generally, physiologically occurring myristic acid is incorporated in the phospholipid bilayer of the plasma membrane.

Thus, metabolites are not assumed to be more toxic than the parent compound which is further supported by the results obtained in the in vitro mutation and cytogenetic assays in the presence of a metabolic activation system.

Excretion

As discussed above, absorption of ditetradecyl peroxydicarbonate is limited by the compound’s high lipophilicity and low water solubility. Therefore, ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces.

Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product of ditetradecyl peroxydicarbonate, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.

 

Summary

Physico-chemical properties, particularly water solubility and octanol-water partition coefficient and experimental data indicate a very low bioavailability of ditetradecyl peroxydicarbonate via oral, dermal and inhalation route. Assuming that a small fraction of ditetradecyl peroxydicarbonate is absorbed into the body following oral intake, it may be distributed mainly via the lymphatic system. Based on the structure of the molecule, decomposition to myristyl alcohol and carbon dioxide might occur to a little extent. Myristyl alcohol is expected to be oxidised to myristic acid which in turn might enter the mitochondrial beta-oxidation pathway. The non-absorbed fraction of ditetradecyl peroxydicarbonate might be directly excreted from the gastro-intestinal tract via faeces. Once absorbed and transported to the liver, ditetradecyl peroxydicarbonate is expected to be biliary excreted due to its high molecular weight. In case of the decomposition product, myristyl alcohol, degradation to carbon dioxide and excretion via the exhaled air is assumed.