Benzenesulfonic acid, 4-C20-24 (even numbered) sec-alkyl derivs.

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

The justification document on the read across category approach is included in IUCLID section 13.

Type:

absorption

Results:

readily absorbed

Type:

excretion

Results:

primarily via urine

Details on absorption:

The test substance is considered to be readily absorbed in the gastrointestinal tract.

Details on excretion:

The test substance is considered to be rapidly excreted primarily via urine, but also in bile and feces.

Conclusions:

No recently generated toxicokinetic data is available for the target substance. Two studies are published with the category substance LABS Na, where LABS Na was observed to be readily absorbed from the gastrointestinal tract and primarily excreted in urine (but also in bile and feces). LABS Na had no bioaccumulation potential.

Executive summary:

No recently generated toxicokinetic data is available for the target substance. The toxicokinetic assessment is mainly based on known physicochemical and toxicological characteristics of the compounds. Supporting literature data was published for one substance in the category, LABS Na. Two toxicokinetic studies are performed with this substance which were considered reliable with restrictions (Klimisch score 2):

1.    The absorption, distribution, metabolism and elimination of LABS Na (radioactively labeled with 35S) were studies in male CR rats, after administration as an aqueous solution (Michael, 1968). The compound was readily absorbed from the gastrointestinal tract (80-90% of the dose administered) and primarily excreted in the urine. Very little was found in the lymph, so transport of LABS Na is probably by way of portal venous blood. There is considered to be no bioaccumulation potential based on the study results.

2.    The disposition of radioactivity was studied in single and repeated oral doses of [14C]LABS Na to rhesus monkeys (Cresswell et al, 1978). The results confirmed that LABS Na is rapidly absorbed, then rapidly metabolized and excreted, primarily in the urine but also in the bile and feces. No accumulation or localization of radioactivity or change in elimination was observed. LABS Na did not bioaccumulate in the tissues.

Description of key information

Due to the absence of reliable experimental data with the target substance, absorption factors for the oral, dermal and inhalation route were assumed to be 50%, 50% and 100%, respectively.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

No recently generated toxicokinetic data are available. The toxicokinetic assessment is mainly based on known physicochemical and toxicological characteristics of the compounds. Supporting literature data was published for one substance in the category, LABS Na. Two toxicokinetic studies are performed with this substance which were considered reliable with restrictions (Klimisch score 2):

1.    The absorption, distribution, metabolism and elimination of LABS Na (radioactively labeled with 35S) were studies in male CR rats, after administration as an aqueous solution (Michael, 1968). The compound was readily absorbed from the gastrointestinal tract (80-90% of the dose administered) and primarily excreted in the urine. Very little was found in the lymph, so transport of LABS Na is probably by way of portal venous blood. There is considered to be no bioaccumulation potential based on the study results.

2.    The disposition of radioactivity was studied in single and repeated oral doses of [14C]LABS Na to rhesus monkeys (Cresswell et al, 1978). The results confirmed that LABS Na is rapidly absorbed, then rapidly metabolized and excreted, primarily in the urine but also in the bile and feces. No accumulation or localization of radioactivity or change in elimination was observed. LABS Na did not bioaccumulate in the tissues.

 

 Absorption

Differences in toxicity between different alkylbenzene sulfonic acid derivatives can be partially explained by differences in bioavailability. Water solubility can be considered as the preferred parameter to get an indication of differential bioavailability. In general, water soluble compounds will give rise to a relatively higher bioavailability compared to insoluble compounds such as the target substance. Testing data for water soluble compounds (such as LABS Na) can be used as indicators in read across to less soluble compounds, provided that the difference in water solubility is taken into account.

 

Oral absorption

Since alkylbenzene sulfonic acids such as the target substance are strong acids, they are completely ionized and thus expected to not readily diffuse across biological membranes leading to low oral absorption. Furthermore, based on the fact that the target substance is considered insoluble in water due to its long apolar alkyl chain, it is not expected that this substance will dissolve into the gastrointestinal fluids and thus not be absorbed through passive diffusion. However, absorption of surfactants may be enhanced due to damage to cell membranes but this is expected to be small due to its long apolar chain and this hydrophobic character. On the other hand, the target substance is considered a lipophilic substance due to its high logPow value (>4) and may therefore be taken up by micellular solubilisation. This is especially the case for poorly water soluble substances which would otherwise be poorly absorbed.

Oral absorption from the gastrointestinal tract was observed in the toxicokinetic study carried out with the structural analogue LABS Na (see above). However, this compound is a lot more water soluble, which is an important property which favours oral absorption.

No repeated dose toxicity studies are available with any of the target substances. Though, a reliable chronic oral toxicity study of LABS Na is available and can be used to estimate the oral absorption behaviour of the target substance. In this study, male and female rats were exposed to LABS Na in the diet daily for 6 months. Diarrhea, suppressed growth, increased cecal weight and degeneration of renal tubes characterized the highest dose (115 mg/kg) group. Therefore, it is expected that the target substance is absorbed to some extent after oral intake.

Based on the physicochemical properties of the test substance and the repeated dose oral toxicity study of LABS Na, the oral absorption factor of the test substance is considered 50%.

 

Respiratory absorption

Based on its low volatility (vapour pressure < 0.5kPa), the availability of the test substance for inhalation as a vapour is limited. Since it is a liquid, the test substance has the potential to readily diffuse/dissolve into the mucus lining of the respiratory tract. The highly lipophilic character of the test substance (logPow>4) implies that the substance has the potential to be absorbed directly across the respiratory tract epithelium. Lipophilic substances are taken up by micellular solubilisation particularly when the water solubility is so low that the substance would otherwise be poorly absorbed, as is the case for the test substance. Furthermore, penetration of the test substance to the lower respiratory tract is enhanced due to its low water solubility.

No repeated dose inhalation studies are available for the target substance.

Based on the observations described above, the inhalation absorption factor of the test substance is considered 100%.

                                       

Dermal absorption

Due to its low water solubility (< 1 mg/L), dermal uptake of the test substance is expected to be low because the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Furthermore, based on its high log Pow value (> 6), the transfer fate between the stratum corneum and the epidermis will be slow and limit absorption across the skin.

Acute dermal toxicity of LABS Na was determined in 5 male and 5 female rats, according to OECD guideline 402. LABS Na was administered via dermal application at 2000 mg/kg bw and exposure lasted 24hrs, after which the test substance LABS Na was removed by washing. During a 14-day observation period, no mortality was observed. There were no signs of systemic toxicity, but reversible signs of slight erythema and slight edema were noted. Based on those results, it is expected that the target substance might be classified as dermal toxicant.

On the other hand, the test substance is considered to be corrosive to skin based on the acute dermal irritation study according to OECD guideline 404 using LABS as test substance. In this study the shaved backs of 3 male and 3 female rabbits were exposed for 4 hours to 0.5 ml of LABS and observed for up to 14 days. Significant and persistent reddening was observed. Swelling was perceptible throughout and appeared to become more noticeable with time. Based on erythema and edema scoring after 24, 48 and 72 hours observation, the test substance is considered corrosive to the skin of rabbits and should be classified as corrosive category 1C according to CLP regulation.

Since the test substance is considered a skin irritant and corrosive, damage to the skin may enhance penetration.

Based on the physicochemical characteristics and experimental studies carried out with the structural analogues LABS Na and LABS, the dermal exposure factor is considered 50%.

 

Distribution

The low water solubility and the relatively high molecular weight predict that the test substance will probably not distribute through the body by diffusion through aqueous channels and pores. The substance is lipophilic (logKow>0) and therefore likely to distribute into cells. Target organs cannot be specified based on toxicological studies.

Accumulation

The test substance has a low water solubility and is lipophilic. Accumulation is expected within the body if exposures would be continuous. This accumulation will mainly take place in the adipose tissue since this accumulation site is prone to concentrate lipophilic substances. Once exposure stops, the substance will be eliminated at a rate dependent on the half-life of the product.

Based on the physicochemical properties (low water solubility, log Pow of 10.19, etc) of the test substance, no (or little) accumulation is expected within the lungs, bones or stratum corneum. This can also be confirmed by the toxicokinetic study carried out with the water soluble structural analogue LABS Na (see above), where no accumulation took place.

 

Metabolism

Based on the structure, the test substance might undergo phase I biotransformation such as hydroxylation followed by conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulphation (by the enzyme sulfotransferase). The Phase II conjugation reactions largely increase the hydrophilic character of the product. Metabolism can take place in the liver, gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Metabolism mainly takes place in the liver, causing route specific presystemic (or first pass) effects, especially after oral intake, which is deemed to be limited. Other metabolic changes may take place in the gastrointestinal flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

 

Excretion

The toxicokinetic study with LABS Na described above also indicated that the primary route of excretion of this structurally similar compound is the urine. The substances that will be excreted in the urine are most likely conjugated metabolites from Phase II biotransformation. This is most likely the case for the test substance since the metabolites will be more water soluble and thus favourable for urinary excretion in comparison to the compound itself. Most of the metabolites are filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion.

Another route of excretion of conjugated derivatives is the bile which involves active secretion rather than passive diffusion. The excretion via the bile is highly influenced by hepatic function since metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Products in the bile pass through the intestine before excretion in the faeces and can thus undergo enterohepatic recycling which will prolong their half-life.