Sodium 2-(1-carboxylatoethoxy)-1-methyl-2-oxoethyl laurate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Type:

metabolism

Results:

Between the four rats, the range of metabolism into carbon dioxide was 68.98-71.23%

Type:

excretion

Results:

Between the four rats, the range of dose cleared through urine was 18.62-23.88%

Details on absorption:

The compound is almost completely absorbed, and approximately 20% of the dose is cleared through the urine. Very little of the radioactivity was excreted in the feces or retained in the gastrointestinal tract contents.

The compound is rapidly metabolized, the major portion of the dose being converted to CO2 , primarily within 24 hours after administration.

Metabolites identified:

no

Approximately 16 hours after dosing, one rat died. An autopsy was performed which revealed severe necrosis of the stomach. This condition was also found in the other three experimental animals at sacrifice and was especially prominent in another rat. In these animals there was extensive ulceration and is some areas the stomach wall was almost perforated. Although the death of this rat could not be definitely attributed to this condition, it is evident that sodium capryl lactylate at the concentration used caused tissue damage in all animals, and apparently exerts an irritant effect similar to that of a caustic alkali.

Percent of compound that is metabolized and converted into CO₂is below.

Hours	Rat No. 1	Rat No. 2	Rat No. 3	Rat No. 7
8	51.23 %	66.86 %	63.93%	92.37%
16	16.70%	2.10%	5.05%	7.05%
24 hours	1.44%	0.74%		1.81%
24-hour total	69.37%	69.70%	68.98%	71.23%

 

Percent of compound that is absorbed and cleared through the urine.

Hours	Rat No. 1	Rat No. 2	Rat No. 3	Rat No. 7
8	10.18%	17.41%	21.76%	16.26%
16	9.18%	1.57%	2.12%	2.13%
24	0.33%	0.11%		0.23%
24-hour total	19.69%	19.09%	23.88%	18.62%

 

The total recovery of the administered dose amounted to 94.4% for rat No. 1; 94.0% for rat No. 2; 97.0% for rat No. 3 and 93.1% for rat No. 7.

Conclusions:

Sodium capryl lactylate after oral exposure is almost completely absorbed and rapidly metabolised in the rat with the major portion of the dose being converted to CO2 primarily within 24 hours after administration. The recovery of the administered dose (radioactivity) for the 4 rats at 48 hours after dosing ranged from 93 to 97%.

Executive summary:

A single dose of sodium capryl lactylate-¹⁴C was administered by stomach tube to each of four male albino rats at the rate of 250 mg/kg. These animals had received unlabelled sodium capryl lactylate at the same dose rate daily for three days prior to the administration of the tagged material. Samples of urine, faeces and expired CO₂, collected periodically from each rat until sacrifice, and selected tissues obtained at necropsy were analysed for radioactivity.

Sodium capryl lactylate after oral exposure is almost completely absorbed and rapidly metabolised in the rat with the major portion of the dose being converted to CO₂ primarily within 24 hours after administration. The major portions of the radioactivity were recovered in the CO₂ and urine, primarily within 8 hours after dosing. The recovery of the administered dose (radioactivity) for the 4 rats at 48 hours after dosing ranged from 93 to 97%.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Type:

metabolism

Results:

40% in 4 hours at 37 °C

Table 2: Hydrolysis results

Flask	Treatment	SCL (g)	Meq. NaOH Required	Meq NaOH per gram SCL (corrected for extract blank)
1	Non-enzymatic hydrolysis	0.15	0.602	1.54
2	Extract blank	-	0.371	-
3	Enzymatic hydrolysis	15.0	32.4	2.16
Difference due to enzyme hydrolysis				0.62

Enzymatic hydrolysis was 39.6% complete (0.62 / 1.564 x 100).

Conclusions:

Intestinal contents of the rat, undergoing normal digestion, hydrolyzed sodium capryl lactylate in vitro to about 40% of the maximum possible in 4 hours at 37 °C.

Executive summary:

In this in vitro study, the hydrolysis of sodium capryl lactylate by enzymes present in the intestinal contents of the rat was determined. The small intestine of 8 rats fed first thing in the morning after an overnight fast were incubated with test substance for 4 hours at 37 °C.

In this study, intestinal contents of the rat, undergoing normal digestion, hydrolyzed sodium capryl lactylate in vitro to about 40 % of the maximum possible in 4 hours at 37 °C.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reference 3

Endpoint:

basic toxicokinetics, other

Remarks:

in vivo and in vitro

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Duration and frequency of treatment / exposure:

in vivo: single dose (oral gavage) and assessed over 48 hours
in vitro: single incubation shaking at 37 °C, aliquots taken at 0, 10, 20, 30, 45, and 60 minutes to be applied to thin-layer plate

Details on absorption:

Not reported

Details on distribution in tissues:

For both mice and guinea pigs, most of the radioactivity was found in the liver, gastrointestinal tract and kidney with only traces of radioactivity in the other tissues (lung, testes, heart and spleen). Total % found in tissues: up to 2.1% in mice and 6.7% in guinea pigs (similar at both concentrations).
See Table 2 in "Any other information on results incl. tables".

Details on excretion:

Mice:
* At 90 mg/kg CSL >97% of the radioactivity was eliminated within 48 hours, most (~77%) being excreted as 14CO2 within 24 hr. Most of the remaining radioactivity was excreted in the urine in 24 hours with only low levels of activity in the faeces and the 48-hr urine.
* At 900 mg/kg CSL, the rate of metabolism to 14CO2 over the first 7 hours was less although the total excreted in 24 hours was similar. The % radioactivity excreted in urine and faeces was similar at both dose levels.

Guinea pigs:
Similar rate and extent of conversion of 14C-CSL to 14CO2 in guinea pig to those in the mouse, but the % excreted dose in the urine of guinea pigs was less (~9%) and the total excreted by all routes in 48 hours was also less.
All of the radioactivity found in the urine was co-chromatographed as lactic acid.

See Table 1 in "Any other information on results incl. tables".

Metabolites identified:

yes

Remarks:

14CO2

Details on metabolites:

In vitro hydrolysis study using liver homogenates of rat, mouse and guinea pig showed rapid hydrolysis of [14C]-CSL. Across all three species, the overall extent of hydrolysis in the liver within 1 hour was similar with 40-60% hydrolysed.
* Slow to no hydrolysis was observed in the blood of rats, mice and one human volunteer.

The livers of all three species readily hydrolysed the compound. The initial rate was highest in the guinea pig (24.7 µmol/g liver/hour) and lowest in the mouse (7.5 µmol/g liver/hour). In all three species, the overall extent of hydrolysis in 1 hour was similar, between 40 and 60% of the compound hydrolysed.
The initial rates of hydrolysis by rat and guinea pig gastrointestinal mucosa are similar and significantly higher than that of the mouse mucosa.
The sample of human duodenal mucosa also hydrolysed CSL but the hydrolysis in 1 hour was less than the extent of hydrolysis achieved by the rat, mouse, or guinea pig mucosa.
Whole blood from rodent species hydrolysed the compound slowly: 0.8 µmol/g blood/hour (rat) and 0.27 µmol/g blood/hour (mouse). The human blood sample yielded no measurable hydrolysis.

Table 1. Excretion of radioactivity by male mice and male guinea pigs given a single oral dose of 14C-labelled CSL or DL-[U14 -C]lactate.

			Radioactivity excreted (% of dose) mean (range) after dosing
Route of excretion	Time from dosing		14C-CSL		14C-Lactate
		Dose (mg/kg)	90	900	325
		Animals/group	4	4	3
Mice
CO2	0-7		69.7 (68.4-71.0)	57.5 (50.7-65.7)	81.3 (75.8-84.9)
	7-24		7.1 (4.2-10.4)	22.3 (12.1-32.9)	8.0 (4.9-12.1)
	24-48		3.4 (1.8-5.8)	2.8 (2.5-3.2)	2.9 (2.6-3.3)
Urine	0-24		14.8 (11.8-17.5)	14.1 (11.9-16.2)	3.4 (3.0-4.5)
	24-48		0.7 (0.3-1.1)	2.1 (0.8-4.1)	0.6 (0.5-0.7)
Faeces	0-24		2.4 (2.0-3.3)	1.8 (1.3-2.1)	0.9 (0.8-1.1)
	24-48		0.3 (0.1-0.6)	0.3 (0.3-0.4)	0.2 (0.2)
Total			98.4 (97.8-99.5)	100.9 (97.2-103.6)	97.3 (96.8-97.8)
Guinea pig
CO2	0-7		63.1 (54.4-67.2)	60.5 (50.6-67.2)	77.6 (74.8-80.4)
	7-24		12.2 (8.3-22.7)	18.1 (13.2-24.4)	4.0 (3.9-4.2)
	24-48		3.5 (2.4-4.4)	3.3 (2.8-4.3)	2.5 (2.0-3.0)
Urine	0-24		9.2 (8.2-11.0)	8.1 (6.4-9.8)	3. (3.1-3.6)
	24-48		0.8 (0.6-1.3)	1.0 (0.3-2.7)	0.4 (0.3-0.4)
Faeces	0-24		3.0 (2.7-3.7)	2.3 (1.8-2.6)	1.6 (1.5-1.6)
	24-48		0.8 (0.6-1.3)	0.6 (0.4-0.7)	0.5 (0.4-0.5)
Total			92.6 (88.8-93.9)	93.9 (89.0-96.0)	89.9 (87.0-92.7)

Table 2. Tissue distribution of radioactivity in male mice and male guinea pigs 48 hours after oral dose of 14C-CSL or control

		14C-CSL		14C-Lactate
	Dose (mg/kg)	90	900	325
Tissue	Animals/group	4	4	3
Mouse
GI tract		0.67 ± 0.15	0.79 ± 0.08	0.84 ± 0.02
Liver		0.79 ± 0.18	0.91 ± 0.05	0.98 ± 0.08
Kidney		0.22 ± 0.03	0.26 ± 0.03	0.21 ± 0.03
Lung		0.04 ± 0.02	0.04 ± 0.01	0.04 ± 0.01
Testes		0.03 ± 0.01	0.03 ± 0.01	0.04 ± 0.02
Heart		0.05 ± 0.04	0.02 ± 0.01	0.03 ± 0.01
Spleen		0.03 ± 0.01	0.02 ± 0.01	0.02 ± 0.01
Total		1.82 ± 0.55	2.07 ± 0.14	2.14 ± 0.09
Guinea pig
GI tract		3.05 ± 0.12	2.01 ± 0.17	1.87 ± 0.04
Liver		2.40 ± 0.79	4.11 ± 3.06	7.87 ± 4.13
Kidney		0.26 ± 0.04	0.24 ± 0.01	0.18 ± 0.01
Lung		0.20 ± 0.05	0.16 ± 0.04	0.10 ± 0.01
Testes		0.06 ± 0.02	0.03 ± 0.01	0.07 ± 0.02
Heart		0.06 ± 0.01	0.06 ± 0.01	0.05 ± 0.02
Spleen		0.04 ± 0.01	0.05 ± 0.02	0.03 ± 0.01
Total		6.07 ± 0.77	6.66 ± 3.03	10.17 ± 4.07

Conclusions:

The in vivo experiments using mice and guinea pigs show that the metabolism and tissue distribution of radioactivity with 14C-CSL were similar to those for an equivalent dose of free 14C-lactate. The biological fate of CSL is comparable in both rodent (rat and mouse) and non-rodent (guinea pig) species. The metabolism in vivo and in vitro show that the compound hydrolyses to stearic and lactic acids by the non-specific carboxylic ester hydrolases and are eliminated along normal physiological routes. CSL is hydrolysed to normal physiological components and is unlikely to present a toxicological problem in terms of its metabolic fate in humans at the dose levels encountered in the human diet.

Executive summary:

Two toxicokinetics studies conducted in vitro and in vivo to compare the in vivo distribution, metabolism and elimination of CSL labelled with 14C-lactic acid with that of 14C-lactic acid alone in addition to an in vitro comparison of the rates of hydrolysis of CSL by gastrointestinal mucosal homogenate (rat, mouse, guinea pig and human), liver homogenate (rat, mouse, guinea pig), whole blood (rat, mouse, man). For the in vivo study, male mice and guinea pigs were given 14C-CSL by oral intubation and housed in all-glass metabolism cages. The radioactivity excreted in expired CO2, urine and faeces, and present in liver, kidneys, heart, lungs, spleen, testes and gastrointestinal tract at post-mortem examination. For the in vitro study, washed livers or intestinal mucosal scrapings from rats, mice and guinea-pigs, human duodenal mucosa, and whole blood from rats, mice, and human volunteers were incubated with 14C-CSL and assayed for 14C-labelled lactate and 14C-CSL by thin-layer chromatography. After hydrolysis plates had been developed, the areas corresponding to lactate and CSL were scraped off and counted. Based on in vivo and in vitro studies, the substance Calcium stearoyl-2 -lactylate has a similar biological fate to lactate in both rodent and non-rodent species. CSL is distributed to tissues similarly to lactate and it is hydrolysed to normal physiological components, thus unlikely to present a toxicological problem in terms of its metabolic fate in humans at the dose levels encountered in the human diet.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Description of key information

The toxicokinetic profile of test item sodium lauroyl lactylate was assessed taking existing studies from the read-across substances, calcium stearoyl lactylates (CSL) as well as sodium capryl lactylate, which are structurally and chemically similar to sodium lauroyl lactylate. For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.

 

Absorption: Sodium capryl lactylate has shown to have high absorption after oral exposure. In particular, a single oral dose of [¹⁴C]-sodium capryl lactylate was almost completely absorbed as 93 -97% of the radioactive dose was recovered as metabolites (CO₂ and urine), primarily within 8 hours after dosing.

 

Distribution: In the study of Phillips et al. (1981), the distribution, metabolism and elimination of the read-across substance CSL in rodents (rat and mouse) and non-rodents (guinea pig and human) were investigated. Total percentages found in tissues 48 hours after oral exposure to 900 mg/kg [¹⁴C]-CSL were 2.1% in mice and 6.7% in guinea pigs. For both species, most of the radioactivity was in the liver, gastrointestinal tract and kidney with only traces of radioactivity in the other tissues (lung, testes, heart and spleen).

 

Metabolism: An in vitro hydrolysis study of Phillips et al. (1981) using liver homogenates of rat, mouse and guinea pig showed rapid hydrolysis of [¹⁴C]-CSL. Across all three species, the overall extent of hydrolysis in the liver within 1 hr was similar with 40-60% hydrolysed. There was slow to no hydrolysis observed in the blood of rats, mice and one human volunteer. Overall, it was summarised by Phillips et al. that the biological fate of CSL is comparable in both rodent (rat and mouse) and non-rodent (guinea pig) species and that the metabolism both in vivo and in vitro proceeds by the hydrolysis of the compound to stearic and lactic acids by the nonspecific carboxylic ester hydrolases.

It has been demonstrated in another study by Craig et al. (1969) that intestinal contents of the rat, undergoing normal digestion, can hydrolyse sodium capryl lactylate to about 40% of the applied concentration (50 mL of 10% sodium capryl lactylate solution) in 4 hours at 37 °C. An in vivo study also by Craig et al. (1969) showed that sodium capryl lactylate after oral exposure is almost completely absorbed and rapidly metabolised in the rat with the major portion of the dose being converted to CO₂ primarily within 24 hours after administration.

Elimination: In the Phillips et al. (1981) study with CSL, with mice exposed to 90 mg/kg [¹⁴C]-CSL, >97% of the radioactivity was eliminated within 48 hr, most (~77%) being excreted as [¹⁴C]-CO₂within 24 hr. Most of the remaining radioactivity was excreted in the urine in 24 hr with only low levels of activity in the faeces and the 48-hr urine. At a higher dose of 900 mg/kg [¹⁴C]-CSL, the rate of metabolism to [¹⁴C]-CO₂over the first 7 hr was less although the total excreted in 24 hr was similar. The percentage of radioactivity excreted in urine and faeces was similar at both dose levels. Similar rate and extent of conversion of [¹⁴C]-CSL to [¹⁴C]-CO₂in guinea pig to those in the mouse, but the percentage of excreted dose in the urine of guinea pigs was less (~9%) and the total excreted by all routes in 48 hr was also less. All of the radioactivity found in the urine was co-chromatographed as lactic acid.

Similar to CSL, majority of the sodium capryl lactylate (93-97%) administered orally to rats was eliminated within 48 h as CO₂.

Taking this information into consideration altogether, it is expected that exposure to sodium lauroyl lactylate will result in its rapid absorption and undergo hydrolysis to yield lauric and stearic acids, which will be eliminated as CO₂ as expired air or lactic acid in the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential