Poly(oxy-1,2-ethanediyl), α-[2-(dide- cylmethylammonio)ethyl]- .omega.- hydroxy-, propanoate (salt) (Bardap 26)

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

Proprietary GLP guideline-compliant study

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Deviations:

no

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

The test animals were male and female Crl CD (SD)Br rats obtained from Charles River, Michigan. They were quarantined in individual cages for approximately 2 weeks. The rats were 8 weeks old at dosing and weighed 236-262 g. The rats were housed individually, and received food (Purina Rat Chow) and water ad libitum. The room temperature was maintained at 70±5°C, with a 12 hour light/dark cycle, and at least seven air changes per hour. All animals were examined during quarantine and prior to dosing to ensure they were healthy.

Route of administration:

other: oral gavage or dietary

Vehicle:

other: gavage: water, or mixed directly with diet

Details on exposure:

Experiment 1: the test substance was administered orally by gavage in distilled water.
Experiment 2: the test substance was administered orally by gavage in distilled water.
Experiment 3: non-radiolabelled test substance was administered in rodent diet for 14 days, following by a single gavage administration of 5 mg/kg bw radiolabelled Bardac 22.

Dosing solutions were prepared by placing a weighed amount of non-radiolabelled Bardac 22 into a glass vial and dissolving in sterile distilled water. An appropriate amount of 14C Bardac 22 was then added to the aqueous solution immediately prior to dosing. All gavage doses were administered at a constant volume of 10 ml/kg bw. All doses administered where in terms of actual Bardac 22 content.

Treated diet containing 100 ppm Bardac 22 was provided by Bushy Run Research Center. Treated diet containing 34 ppm was made by mixing with the 100 ppm diet with an appropriate additional amount of untreated diet. A sample of the 34 ppm was analysed at Bushy Run Research Center, and confirmed to contain 34 ppm.

Duration and frequency of treatment / exposure:

Experiments 1 and 2: Single gavage dose
Experiment 3: 14 days dietary exposure following by single gavage dose

Dose / conc.:

5 mg/kg bw (total dose)

Remarks:

Experiment 1: 5 mg/kg bw 14C Bardac 22

Dose / conc.:

50 mg/kg bw (total dose)

Remarks:

Experiment 2: 50 mg/kg bw 14C Bardac 22

Dose / conc.:

5 mg/kg bw (total dose)

Remarks:

Experiment 3: 34 ppm in diet non-radiolabelled, followed by 5 mg/kg 14C Bardac 22 by gavage

No. of animals per sex per dose / concentration:

5/sex/dose

Control animals:

no

Positive control reference chemical:

A positive control was not included.

Details on study design:

Rats were assigned to treatment groups using a weight stratified randomisation procedure.
Rats were fasted for approximately 18 hours prior to administration of 14C Bardac 22.
Three experiments were conducted. In experiments 1 and 2, rats received a single dose of radiolabelled test substance (low or high) via gavage. The post exposure period was 7 days. In experiment 3, the rats were exposed to non-radiolabelled test substance in the diet for 14 days, followed by a single gavage dose of 14C Bardac 22.

Details on dosing and sampling:

A preliminary study had indicated that no 14CO2 was generated.
Following the single doses or the last dietary dose, urine and faeces were collected for 7 days at the following time intervals: 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours. The urine was freeze trapped and faeces were frozen upon collection. All urine, wash and faecal samples were stored at -15°C. Seven days after dosing. the animals were anaesthetised and euthanised by exsanguination. An aliquot of blood was taken and centrifuged to separate the plasma. The following tissues and organs were harvested: stomach, small intestine, large intestine, gastrointestinal tract contents, bone, brain, fat, testes, seminal vesicles, prostate, ovaries, uterus, heart, kidneys, adrenal glands, thyroid glands, liver, lungs, blood, muscle, spleen, pancreas, any tissues which displayed pathology and residual carcass. Each tissue was individually weighed and stored at -15°C until radioassay.

Statistics:

Not applicable.

Preliminary studies:

In a preliminary CO2 experiment, the males expired an average of 0.045% of dosed radioactivity as volatiles which were trapped in the ethanolamine/cellusolve mixture and designated as 14CO2. The females expired on average 0.053% of dosed radioactivity. Since no significant amount of volatiles were found, the rest of the studies were performed in hanging metal cages and the excretion of radioactivity in expired air was not investigated further.

Details on distribution in tissues:

Less than 1% was recovered in tissues in all experiments.

Details on excretion:

Experiment 1:
Males: 1.65% urine; 89.11% faeces
Female: 1.42% urine; 92.13% faeces
Total Recovery: 90.82 ± 7.30% - males; 93.56 ± 6.96% females
Experiment 2:
Males: 1.19% urine; 93.88% faeces
Female: 1.74% urine; 90.11% faeces
Total Recovery: 95.09 ± 1.92% - males; 91.88 ± 4.98% females
Experiment 3:
Males: 1.17 % urine; 99.46% faeces
Female: 2.36% urine; 91.93% faeces
Total Recovery: 100.94 ± 2.68% - males; 94.47 ± 4.62% females

Metabolites identified:

yes

Details on metabolites:

4 major metabolites were identified. The only metabolism which occurred involved oxidation of the two decyl side chains to hydroxy and hydroxyketo derivatives; no modification on the methyl substituents was evidenced. All were more polar and presumed less toxic than the parent compound. It is predicted that there is no major metabolite greater than 10% of the dosed radioactivity.

There were no mortalities and no signs of toxicity in any animal.

Experiment 1: The male rats administered a single, low dose of Bardac 22 excreted an average of 1.65% of the dose in their urine and 89.11% in their faeces, and the females excreted 1.42% in urine and 92.13% in faeces. Most of the radioactivity recovered in the urine was excreted during the first 24 hours, significant amounts of radioactivity continued to be excreted in the faeces for 36 hours in males, up to 48 hours in females. An average of 90.77% of the dosed radioactivity was recovered in the urine and faeces for males, and 93.56% in females. The total residue in tissue and carcass ranged from 0.003% to 0.135% in all rats. The total recovery in male and female rats were 90.82 ± 7.30% and 93.56 ± 6.96%, respectively.

Experiment 2: The male rats administered a single, high dose of Bardac 22 excreted an average of 1.17% of the dose in their urine and 99.46% in their faeces, and the females excreted 2.36% in urine and 91.93% in faeces. Most of the radioactivity recovered in the urine was excreted during the first 48 hours in males and 72 -96 hours in females; significant amounts of radioactivity continued to be excreted in the faeces for 72 hours in males and 92 hours in females. An average of 100.64% of the dosed radioactivity was recovered in the urine and faeces for males, and 94.28% in females. The total residue in tissue and carcass ranged from 0.074% to 0.675% in all rats. The total recovery in male and female rats was 100.94 ± 2.68% and 94.47 ± 4.62%, respectively.

Experiment 3: The low-dose repeat administration male rats excreted an average of 1.19% of the dose in their urine and 93.88% in their faeces, and the females excreted 1.74% in urine and 90.11% in faeces. Most of the radioactivity recovered in the urine was excreted during the first 36 hours, significant amounts of radioactivity continued to be excreted in the faeces for 36 hours. An average of 95.07% of the dosed radioactivity was recovered in the urine and faeces for males, and 91.85% in females. The total residue in tissue and carcass ranged from 0.04% to 0.061% in all rats. The total recovery in male and female rats was 95.09 ± 19.2% and 91.88 ± 4.98%, respectively.

Metabolism study: The results indicated that there was a sex difference in the metabolism of Bardac 22 in all 3 experiments. Metabolism was more extensive in females. Additionally, a dose-dependent metabolism was observed in females, i.e. more parent was metabolised in the single low oral dose than in the single high oral dose. Approximately 90 -100% of the radioactivity was found in the faeces.

Most, if not all, the metabolism appears to be in the gut by intestinal microflora. Female rats metabolised the test substance more extensively. A dose dependent rate of metabolism was observed in female rats.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Absorption following oral administration was shown to be poor, with the large majority of the administered substance being excreted in the faeces and with evidence of metabolism by the gastrointestinal flora. Tissue residues were low and there is no evidence for bioaccumulation.

Executive summary:

Ten Sprague Dawley rats (male and female) per groups were dosed orally with radiolabelled Bardac 22 (DDAC). The study was conducted in three phases: Experiment 1 – single low gavage dose (5 mg/kg); Experiment 2 – single high gavage dose (50 mg/kg); Experiment 3 – 14-day repeated dietary exposure to 34 ppm non-radiolabelled Bardac 22 followed by a single low gavage dose (5 mg/kg bw). Following the single doses or the last dietary dose, urine and faeces were collected for 7 days. Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound.

For all 3 experiments, approximately 89-99% of the radioactivity was recovered in the faeces and 2.5% in the urine. Tissue residues were all less than 1% of the administered dose. Four major metabolites were identified. 

The majority of orally administered Bardac 22 is excreted via the faeces and appears to be metabolised in the gut of rats, apparently by microflora. Metabolism in females was greater than in males and lower doses were more extensively metabolised than higher doses in females. No tissue accumulation of the test substance was observed. Repeated dosing did not alter the uptake, distribution or metabolism of Bardac 22.

Description of key information

Data indicate that the substance is poorly absorbed following oral and dermal exposure; conservative absorption values of 10% are assumed for these routes.

A default value of 100% absorption is assumed for the inhalation route.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Some of the data summarised in this section are based on Didecyldimethylammonium Chloride, a chemical and structural analogue of N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate. In view of the chemical and structural similarities, it is considered that the available data are adequate for N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate.

Bardap 26 (containing N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate) is highly ionic and, therefore, is not readily absorbed from the gastrointestinal tract or skin. Less than 3% of an oral dose of Bardac 22 was eliminated via urine following a single oral dose (Selim, 1989) and only 0.1% of an applied dose penetrated human skin in vitro (Roper, 2001). Thus more than 90% of Bardap 26 following an oral dose is expected to be excreted in the faeces. The majority of the metabolism of Bardap 26 should occur from intestinal flora and is limited to hydroxylation of the alkyl chain.