ε-caprolactam

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

distribution

excretion

Principles of method if other than guideline:

The distribution of 14C-test substance was studied in female and 14.5-day-pregnant mice by whole-body autoradiography after administrating 6.5-6.7 mg test substance/kg bw (11-14 uCi/mouse) by oral intubation. Pregnant mice were frozen at 20 min, 1, 3, 9, and 24 hr after oral administration of the compound. The non-pregnant mouse was frozen at 3 hr after oral dosing.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): (Carbonyl-14C) Caprolactam
- Specific activity (if radiolabelling): 46.9 µCi/mg

Radiolabelling:

yes

Species:

mouse

Strain:

Swiss Webster

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: pregnant mice 36-45 g, one female non pregnant mouse 33.5 g

Route of administration:

oral: gavage

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single

Remarks:

6.5-6.7 mg/kg bw/day

No. of animals per sex per dose / concentration:

5

Details on dosing and sampling:

For breeding, a male mouse was allowed to remain overnight in a cage containing 4-6 female mice. The following morning the male mouse was removed and the female mice with vaginal plugs were considered to be 0.5 days pregnant at noon of this day. On day 14.5 of gestation five mice, weighing 36-45 g, were administered the 14C-test substance (6.5-6.7 mg test substance/kg bw, 11-14 µCi/mouse) by oral intubation. 20 min, 1, 3, 9 and 24 hr following the test substance treatment the mice were frozen by immersion in a dry ice/hexane bath at -75°C.
One female mouse, weighing 33.5 g was also administered 6.6 mg 14C-test substance/kg (10.3 µCi) by oral intubation and sacrificed 3 hr later.

Details on distribution in tissues:

At 20 min and 1 hr after the oral dosing, there was still considerable radioactivity within the contents of the stomach although significant amounts had already been absorbed and distributed throughout the animals. There was a noticeable increase in the radioactivity in the fetuses and brain of the mother during the first hr after dosing. Only kidney and nasal epithelium show specific tissue affinities at these early time intervals. By 1 h, there was heavy labeling within bile ducts in the liver indicating hepatic secretion of the test substance and/or metabolites. At 3 and 9 hr, the amount of radioactivity in most tissues of the mother was rapidly decreasing.
The concentration in the fetuses was greater than that in maternal tissues but it decreases with time. Maternal tissues in which radioactivity was retained are brain, nasal epithelium, lens of the eye, bone, inner ear, and Harder's gland. By 24 h almost all of the material was eliminated from the entire fetal-maternal unit. There were small residues of radioactivity in umbilical cords, amnion, yolk sac, maternal lens, and maternal Harder's gland and maternal liver. No radioactivity was retained in any other fetal tissue. There was a significant amount of radioactivity in nasal epithelium and the olfactory lobe of the brain.
In the single non-pregnant female, the sites of localization were identical in the adult tissues: brain, nasal epithelium, bone, and renal and hepatic elimination are seen.

Details on excretion:

Evidence of renal secretion and hepatic elimination into the intestinal contents was visible.

Conclusions:

The test substance was efficiently eliminated by the kidney and liver. After 24 hr, the test substance was only measured in umbilical cords, amnion, yolk sac, maternal lens, maternal Harder's gland, and maternal liver. There was no retention in any fetal tissue.

Executive summary:

The test substance was rapidly absorbed from the stomach and was distributed throughout all animals including fetuses. There was efficient elimination by the kidney and liver, material secreted by the liver into bile and intestinal contents appeared not to be reabsorbed via an enterohepatic circulation. The kinetics of distribution and elimination appeared to be the same in female and pregnant animals. The only sites of retention of radioactivity after 24 hr (excluding renal and hepatic) were in umbilical cords, amnion, yolk sac, maternal lens, maternal Harder's gland, and maternal liver. The distribution into and removal from the fetuses was typical of molecules that freely diffuse across the placenta. There was no retention in any fetal tissue. No localization was seen that would suggest a site of toxic action except for that possibility in nasal epithelium.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Short description of test conditions:
The tissue distribution and excretion of the test substance was studied in male Fischer 344 rats given a single oral dose of 0.18 mg/kg body weight. The rats were dosed by oral intubation and killed with ether after 0.5, 1, 2, 3, 4, 6, 15 or 24 hr (five animals at a time).

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): (Carbonyl-14C)caprolactam
- Radiochemical purity (if radiolabelling): >99%
- Specific activity (if radiolabelling): 5.32mCi/mmol

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Wilmington, MA
- Mean weight at study initiation: 124±19 g

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Labelled test substance was diluted with unlabelled compound to yield a mixture containing 0.143 mg/ml and 6-8 μCi/ml. The solvent vehicle was distilled water. The concentration of the test substance in the dosing solution was verified by high-pressure liquid chromatography and the specific activity by liquid scintillation spectroscopy.

Duration and frequency of treatment / exposure:

single

Remarks:

Doses / Concentrations:
0.18 ± 0.018 mg/kg bw (mean ± SD)

No. of animals per sex per dose / concentration:

40

Details on dosing and sampling:

PHARMACOKINETIC STUDY (distribution, excretion)
Animals were killed with ether after 0.5, 1, 2, 3, 4, 6, 15 or 24 hr (five animals at a time) of dosing.
The animals were housed individually in glass Roth-type metabolism cages (Bellacour Company, Laurelton, NY) which allowed separate collection of urine and feces, expired carbon dioxide was trapped in ethanolamine. Organ and tissue samples were taken at autopsy for quantification of radioactivity. Urine was collected on ice at the intervals indicated above. The contents of the urinary bladder were combined with the urine collected from each animal. The residual radioactivity in the urinary collection funnels of the metabolism cages was rinsed with water into separate containers and the radioactivity determined. The radioactivity in the fecal samples was also determined.


METABOLITE CHARACTERISATION STUDIES
The 6- and 24-hr urine samples collected from animals were subjected to analysis by high-pressure liquid chromatography. Metabolites were quantitated by determination of radioactivity in fractions collected from the HPLC eluate.

Details on distribution in tissues:

The concentrations of radioactivity in the tissues of the rats following administration are shown in Table 1. With the exception of the stomach, bladder, kidneys and fat, the concentrations of radioactivity in the tissues were similar to that in the blood.
The concentration of radioactivity in the fat was consistently lower than that in the blood or other tissues, indicating a low affinity of the test substance and/or its metabolites for adipose tissue.
Disappearance of radioactivity from the stomach was monophasic and followed first-order kinetics (r > 0.96) with an elimination half-life of 1.87 hr. The high concentration of radioactivity found in the stomach was not surprising, since the animals were orally dosed. The concentration of radioactivity in the small intestine generally exceeded that of the blood by less than 40%. The increase was statistically significant only at the 0.5, 1.0, 3.0 and 24 hr observations (P < 0.05). Also, except at the latter times, the concentration of radioactivity in the small intestine never approached that in the stomach. The high concentrations of radioactivity observed in the kidneys and bladder reflect the importance of the urine as a route of excretion. The concentration of radioactivity in the liver did not significantly exceed that in the blood (P < 0.05), except after 24 hr. With the exception of the stomach, the concentration of radioactivity in all tissues was greatest 1 hr after dosing. Subsequently, the decrease in concentration of radioactivity in all tissues except the large intestine was monophasic and followed first order kinetics. The half-life of disappearance of radioactivity from the blood was 2.98 hr (r > 0.99).

Details on excretion:

Twenty-four hours after dosing, 77.6 ± 0.7% (mean ± SEM) of the administered radioactivity was excreted in the urine, 3.5 ± 1.1% in the feces and 1.5 ± 0.1% in the expired air of the animals. Elimination of radioactivity in the urine and expired air was most rapid during the initial 6 hr following dosing, after which excretion continued at a much reduced rate.

Metabolites identified:

yes

Details on metabolites:

As shown in Table 2, 78% of the radioactivity excreted in the urine 6 hr after the oral administration was in the form of a major metabolite (MI). A lesser quantity of another metabolite (MII) was also found. The relative proportions of MI, MII, and the parent compound were not significantly different in the 24-hr urine.

Table 1. Distribution of radioactivity in male rats at intervals following the oral distribution of 0.18 mg (¹⁴C) test substance /kg bw.

Tissue	Time after dosing (h)
	0.5	1	2	3	4	6	15	24
Liver	104±12	151±13	96±9	70±6	60±5	49±9	3.2±1	2±0.1
Spleen	91±8	140±12	100±7	71±7	60±4	44±7	1.6±0.1	1±0.1
Stomach*	1907±286	1538±397	735±196	931±235	719±258	690±135	1.7±0.1	0.7±0.1
Small intestine*	119±9	158±9	110±5	85±7	67±6	54±9	2.9±0.2	1.2±0.1
Large intestine*	64±6	93±3	77±2	72±6	66±7	64±5	37±9	8±0.9
Pancreas	101±9	116±4	78±9	58±5	50±6	35±6	1.5±0.1	2±1.3
Kidneys	130±13	247±19	189±5	171±9	146±18	105±18	4.1±0.2	1.4±0.02
Bladder	378±155	1240±223	1136±287	1201±230	573±235	797±192	56±13	-
Adrenals	74±16	162±35	70±6	59±7	61±9	41±7	-^a	-
Testes	75±8	93±13	77±2	63±10	59±4	44±6	6.7±0.2	1.1±0.3
Epididymis	72±9	112±16	77±3	57±4	51±2	41±6	3±0.2	-
Thyroid	75±18	155±48	93±17	84±15	79±2	38±4	-	-
Pituitary	115±35	146±28	104±6	73±14	48±19	-	-	-
Thymus	85±10	128±13	86±5	58±5	49±3	37±6	2±0.1	-
Salivary gland	77±9	114±10	85±4	53±4	45±4	36±6	2±0.1	0.6±0.03
Lymph nodes^b	66±17	90±6	62±6	54±3	57±6	32±6	-	-
Heart	91±10	116±4	90±5	58±6	48±4	38±7	1.3±0.1	0.4±0.1
Aorta	100±12	131±10	79±4	79±7	79±18	39±7	-	-
Lungs	78±16	135±11	93±5	63±6	52±4	46±8	2.1±0.1	0.9±0.1
Sternum	68±6	106±10	73±3	52±4	42±3	30±6	1.3±0.1	0.6±0.1
Muscle	75±8	112±11	78±3	54±4	46±3	35±5	1.1±0.1	0.3±0.04
Brain	69±8	81±8	77±4	54±5	47±3	37±6	1.4±0.1	0.4±0.05
Eyes	69±7	103±3	82±3	69±6	58±4	48±6	3.3±0.3	1.9±0.1
Skin	71±9	107±8	74±3	57±5	47±4	42±7	2.6±0.1	1.1±0.1
Fat^c	18±2	41±7	15±4	21±2	25±3	13±1	1.5±0.1	2.4±0.2
Blood	88±9	128±9	95±6	62±6	53±4	40±7	2.6±0.9	0.7±0.1

Values are the means ± SEM of 5 determinations

* including contents

^aThe level of radioactivity was too low for accurate measurement

^bLymph nodes were excised from the serosal surface of the small intestine

^cFat was taken from the supratesticular fat pad

 

Table 2. The test substance and its two major metabolites in the urine of rats dosed orally with 0.18 mg [14C]test substance/kg bw*

Component	Percentage of total urinary radioactivity after dosing (h)
	6	24
Metabolite I (MI)	78.1 ± 3.6	79.3 ± 2.4
Metabolite II (MII)	16.9 ± 3.7	17.7 ± 2.1
Parent Compound	3.9 ± 1.2	2.3 ± 0.6

* Values are means ± SD for three determinations.

Conclusions:

Excretion of the test substance has been found to be rapid and predominantly via the urine, mainly in metabolized form with only a small portion of the dose being excreted unchanged.

Executive summary:

The publication describing the tissue distribution and excretion of [14C]test substance in male Fischer 344 rats given a single oral dose of 0.18 mg/kg bw is well documented and acceptable with restrictions. After 24 hr, 77.6% of the administered radioactivity was excreted in the urine, 3.5% in the feces and 1.5% in the expired air of the animals. Elimination of radioactivity in the urine and expired air was most rapid during the initial 6 hr following dosing. Analysis of the urine indicated that after 24 hr, only 2.3% of the excreted radioactivity was in the form of the parent compound. Two major urinary metabolites of the test substance (MI and MII) were detected comprising 79.3% and 17.7% of the excreted radioactivity, respectively, in the 24-hr urine.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

excretion

Principles of method if other than guideline:

Absorption and excretion of the test substance was studied in male Wistar rats given a single inhalation exposure of 0.531 and 0.02 mg/l for 2-6 h. Blood and urine was collected for the detection of the test substance.

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Caprolactam
- Physical state: crystals
- Analytical purity: pure

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Kirchborchen
- Weight at study initiation: 180-200 g

Route of administration:

inhalation: aerosol

Vehicle:

other: water 2%, alkohol/lutrol (1:1)

Details on exposure:

TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
The test atmosphere was generated using a dynamic spray-appratus as described by Kimmerle and Eben (Arch. Toxicol. 30, 115, 1973).

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: no data
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): no data

DETERMINATION TOF EXPOSURE CONCENTRATION:
During 6h exposure 3 air samples were taken of each exposure chamber. Analysis was performed by GC.

Duration and frequency of treatment / exposure:

2-6 h

Dose / conc.:

0.02 mg/L air

Dose / conc.:

0.531 mg/L air

No. of animals per sex per dose / concentration:

20 male rats

Details on dosing and sampling:

0.531 mg/l:
After 2 h of exposure, 3 rats were were killed and blood was collected.
After 4 h of exposure was terminated for all animals.
Blood was collected 4, 6, 8 and 24 h after beginning of the exposure from 3 rats at a time.
Urine was collected using metabolism cages from 5 rats immediately after termination of the exposure. Urine was collected for 3 days.

0.020 mg/l:
After 2 and 4 h of exposure, 3 rats were killed and blood was collected.
After 6 h, the inhalation was stopped for all remaining animals and blood was collected from 3 rats. Additionally, blood was collected 8, 10 and 24 h after beginning of the exposure from 3 rats (2 rats after 24 h) at a time.
Urine was collected using metabolism cages from 5 rats immediately after termination of the exposure. Urine was collected for 3 days.

Details on absorption:

The test substance was rapidly absorbed.
During 4h inhalation of 0.531 mg/l, there was rapid and constant increase in the serum-concentration that reached to the maximum concentration of 37 ug/ml after 4 h. 20 h after exposure, no test substance was detected in the serum.
Similar findings were observed with an exposure for 6h with 0.020 mg/l. 4h following onset of exposure with a maximal serum-concentration of 1.75 µg/ml was observed and no test substance was detected in the serum 18h after exposure.

Details on excretion:

The test substance was rapidly excreted via urine during the first 24 h after exposure.
Average (3 rats) concentrations of 270 and 9 ug were detected in urine during the first 24 h after exposure in the 0.531 and 0.02 mg/l dose groups, respectively.

Conclusions:

After single inhalation, the test substance has been shown to be absorbed and excreted rapidly.

Executive summary:

The test substance appears to be absorbed rapidly after single inhalation exposure with blood peak level after approx. 4 h. Excretion was also rapid with no detectable test substance in urine after 20 h.

The relation of maximal serum concentration of 21:1 is reflecting the relation of 26:1 in the inhalation atmosphere.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

Principles of method if other than guideline:

The tissue distribution and excretion of [carbonyl-14C]test substance was studied in male Fischer 344 rats given a single oral dose of 1500 mg [14C]test substance/kg bw. Tissues, blood, urine, feces and expired carbon dioxide were collected for determination of radioactivity. In addition, a separate group of six rats was pretreated with 1500 mg/kg bw unlabelled test substance orally day for 7 days. At the end of the 7-day period (24 hr after the last dose of unlabelled test substance), the animals were dosed orally with 1500 mg [14C]test substance/kg bw, killed after 6 hr and their tissues, blood, urine, feces and expired carbon dioxide were collected for determination of radioactivity. A further three animals were dosed with 1500 mg[14C]test substance/kg bw and their urines were collected after 24 hr for determination of the test substance and its metabolites.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): (Carbonyl-14C)caprolactam
- Radiochemical purity (if radiolabelling): >99%
- Specific activity (if radiolabelling): 5.32mCi/mmol

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Wilmington, MA
- Mean weight at study initiation: 124±19 g

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Labelled test substance was diluted with unlabelled compound to yield a mixture containing 0.48 mg/ml and 1.13 μCi/ml. The solvent vehicle was distilled water. The concentration of the test substance in the dosing solution was verified by high-pressure liquid chromatography and the specific activity by liquid scintillation spectroscopy.

Duration and frequency of treatment / exposure:

single

Dose / conc.:

1 500 mg/kg bw/day

No. of animals per sex per dose / concentration:

5

Details on dosing and sampling:

PHARMACOKINETIC STUDY (distribution, excretion)
Animals were killed with ether after 6 hr of dosing and their tissues, blood, urine, feces and expired carbon dioxide were collected for determination of radioactivity.


METABOLITE CHARACTERISATION STUDIES
The 6 and 24-hr urine samples collected from animals were subjected to analysis by high-pressure liquid chromatography. Metabolites were quantitated by determination of radioactivity in fractions collected from the HPLC eluate.

Details on distribution in tissues:

The concentrations of radioactivity in the tissues of the rats following administration are shown in Table 1. Most of the tissue concentrations were approximating that of the blood. The concentration of radioactivity in the fat was consistently lower than that in the blood or other tissues, indicating a low affinity of adipose tissue for the test substance and/or its metabolites. The seven-day pretreatment with the test substance had little effect on the tissue concentrations of radioactivity (Table 1).

Details on excretion:

The seven-day pretreatment with the test substance had little effect on the excretion of radioactivity. A large difference was noted, however, in the percentage of administered radioactivity excreted in the expired air. After pretreatment, 0.25 ± 0.01% (mean ± SEM) of the administered radioactivity was excreted via this route, representing a five-fold increase over the percentage excreted by the same route in non-pretreated animals (0.05 ± 0.02%). No significant difference was noted in the urinary and fecal excretion of radioactivity between pretreated and non-pretreated animals (P < 0.05).

Metabolites identified:

yes

Details on metabolites:

As shown in Table 2, 55.2% of the excreted radioactivity was found as the parent compound, with 25.1% of the radioactivity in the form of the major metabolite. By 24 hr, however, 59.5% of the excreted radioactivity was in the form of the MI metabolite, with 14.7% as the parent compound.

Table 1. The distribution of radioactivity in the tissues of non-pretreated (control) and pretreated male rats 6 hr following the oral administration of 1500 mg/kg bw

Tissue	Distribution of radioactivity (mg equivalents test substance/g tissue)
	Control rats	Pretreated rats
Liver	0.34±0.10	0.60±0.09
Spleen	0.39±0.07	0.57±0.09
Stomach^a	17.85±4.27	22.81±3.66
Small intestine^a	0.51±0.08	0.76±0.09
Large intestine^a	0.44±0.04	0.69±0.11
Pancreas	0.35±0.04	0.48±0.07
Kidneys	0.54±0.07	0.91*±0.12
Bladder	2.01±0.38	3.99±1.19
Adrenals	0.32±0.05	0.48±0.09
Testes	0.44±0.05	0.62±0.17
Epididymis	0.37±0.04	0.51±0.07
Thyroid	0.33±0.08	0.50±0.09
Thymus	0.38±0.05	0.53±0.08
Salivary gland	0.38±0.04	0.49±0.08
Lymph nodes^b	0.26±0.03	0.32±0.04
Heart	0.41±0.05	0.56±0.09
Aorta	0.34±0.04	0.53*±0.05
Lungs	0.40±0.03	0.56±0.10
Sternum	0.34±0.04	0.47±0.08
Muscle	0.39±0.05	0.52±0.08
Brain	0.41±0.05	0.48±0.07
Eyes	0.41±0.06	0.58±0.10
Skin	0.32±0.04	0.41±0.06
Fat^c	0.07±0.01	0.13±0.02
Blood	0.42±0.05	0.58*±0.09

Values are the means (±SEM) of five or six determinants. The percentage increases shown by significantly values were 69% (kidneys), 57% (aorta) and 75% (fat).

*p<0.05

^aincluding contents

^bLymph nodes were excised from the serosal surface of the small intestine

^cFat was taken from the supratesticular fat pad

 

Table 2. The test substance and its two major metabolites in the urine of rats dosed orally with 1500 mg [14C]test substance/kg bw* 

Component	Percentage of total urinary radioactivity after dosing (h)
	6	24
Metabolite I (MI)	25.1 ± 2.4	59.5 ± 4.8
Metabolite II (MII)	14.1 ± 6.4	15.7 ± 5.7
Parent Compound	55.2 ± 7.2	14.7 ± 3.5

* Values are means ± SD for three determinations.

Conclusions:

The pattern of tissue distribution of radioactivity, 6 hr after administration of the high dose differed little from that observed after the low dose (as documented in another endpoint study record), except high presence of the radioactivity in the stomach and low excretion of the radioactivity in urine. Pretreatment with the test substance for 7 days had little effect on the tissue distribution, and urinary and faecal excretion.

Executive summary:

The publication describing the disposition of [14C]-test substance given a single dose of 1500 mg/kg bw in rats is well documented and is acceptable with restrictions. The pattern of tissue distribution of radioactivity, 6 hr after administration of the high dose differed little from that observed after the low dose (as documented in another endpoint study record), except high presence of the radioactivity in the stomach and low excretion of the radioactivity in urine. Pretreatment with the test substance for 7 days had little effect on the tissue distribution, and urinary and faecal excretion.

Description of key information

Based on the studies in rats and mice, the test substance appears to be absorbed rapidly. Excretion is also rapid and predominantly via the urine, mainly in metabolized form with only a small portion of the dose being excreted unchanged.

Additional information

Oral exposure:

There are few reliable studies on the tissue distribution and excretion of radioactive labeled or unlabeled test substance in rat, mice and rabbits.

 

24 hr after a single oral dose of 0.18 mg/kg bw [14C] test substance

to male rats, 77.6% of the administered radioactivity was excreted in the urine, 3.5% in the feces and 1.5% in the expired air of the animals (Unger et al., 1981). Absorption and excretion was readily and elimination of radioactivity in the urine and expired air was most rapid during the initial 6 hr following dosing. With low doses of the test substance most of the radioactivity was absorbed in the stomach as indicated by comparably low levels of radioactivity in the small intestine.  

No indication of an enrichment of radioactivity in a specific tissue was found throughout the observation period. This is additionally demonstrated by comparable tissue/blood levels of radioactivity, a monophasic tissue clearance and a similar tissue distribution/excretion pattern of radioactivity following pretreatment with unlabeled test substance for 7 days (1.5g/kg bw [14C] test substance). In particular low liver tissue levels of radioactivity indicate that the liver may play a limited role in caprolactam metabolization.

Analysis of the urine indicated that after 24 hr, only 2.3% of the excreted radioactivity was in the form of the parent compound. Two major urinary metabolites of the test substance (MI and MII) were detected comprising 79.3% and 17.7% of the excreted radioactivity, respectively.

With increasing dosage (1500mg/kg bw) the amount of parent compound recovered in urine increased substantially (14.7.2%) indicating a saturable metabolism. The identity of both metabolites was not further specified.

 

These experiments were confirmed by a whole-body autoradiography study in which tissue distribution of gavaged [14C]-test substance was studied in female and 14.5-day-pregnant mice (Badische Corp., 1981). [14C]-test substance was rapidly absorbed from the stomach and was uniformly distributed throughout the animals including fetuses and brains. A similar tissue distribution was observed in male mice intravenously injected with [14C]-test substance (see below).

There was efficient elimination by the kidney and via bilary secretion as shown by radioactive labeling. The only sites of retention of radioactivity after 24 hr (excluding renal and hepatic) were in umbilical cords, amnion, yolk sac, maternal lens, maternal Harder's gland, and maternal liver. But there was no retention in any fetal tissue.

 

Further confirmation was provided in an oral study in which male rabbits and rats were singly dosed with 300 mg/kg bw test substance (Bayer, 1977). Absorption and excretion of the test substance was rapid with blood peak levels after approx. 4 h and excretion predominantly via urine and to a minor degree in feces.

 

Four ninhydrin-positive compounds (metabolites A, B, C and D) were identified in urine of rats exposed to 46 mg/kg bw day over a time period of 2-3 weeks (Kerschner Kirk et al., 1987). 19% of the consumed dose was recovered in the urine in the form of these 4 metabolites. Metabolites A and D, 6-amino-4-hydroxyhexanoic acid and the corresponding lactone, accounted for 87.5% of the four metabolites. Both (A and D) were shown to be a free acid and lactone pair in equilibrium under acidic conditions. Apparently hydroxylation of the lactam in the γ-position is a major metabolic pathway. 6-Aminohexanoic acid (metabolite C) represented 8.8% and the unidentified metabolite B 3.7%.

 

Inhalation exposure:

Following a single inhalation exposure of male Wistar rats to aerosols of 0.531 and 0.02 mg/l for 2-6 h, the test substance was rapidly absorbed (Bayer, 1977).

With a high exposure concentration of 0.531 mg/l a rapid increase in the test substance serum-concentration was observed. With an exposure period of 4h the peak serum-concentration of 37 µg/ml was identified after 4 h. 20 h after onset exposure, no test substance was detectable in the serum. Similar findings were observed low dose exposure atmosphere of 0.020 mg/l. With both atmospheres the test substance was rapidly excreted via urine during the first 24 h after exposure.

As with single doses, repeated inhalation exposure with 0.025 mg/l for 5 days (6 h/day) resulted in rapid test substance absorption and excretion. No test substance was detected in the plasma ahead of each of the subsequent exposures and therefore no commutation occurred (Bayer, 1977).

 

Dermal exposure:

No information is available.

 

Other routes of exposure:

Badische Corp. (1981) studied distribution of [14C]-test substance in male mice by whole-body autoradiography after administrating 6.4-6.9 mg/kg bw (7.1-8.2 µCi/mouse) intravenously. By 20 min, there was uniform distribution throughout the mouse. Apart from renal and hepatic elimination, the only sites of residual radioactivity at 9 hr in the male were nasal epithelium and the olfactory lobe of the brain. Additionally, there was significant amount of radioactivity in the lens of the eye and in Harder's gland.

 

Following a single ip. injection of the test substance (300mg/kg bw) in rats and rabbits the test substance was rapidly absorbed and excreted within 20h after application (Bayer, 1977). ε-aminocaproic acid was identified as a major metabolite in urine. In relation to urinary test substance the amount excreted in rabbits was higher compared to rats. For both, the test susbtance and ACA, renal excretion occurred predominatly during the first 48 h.

Intra-tracheal injection of the test substance (1, 10 mg/kg bw) in rats resulted in a more rapid increase of the test substancev plasma levels compared to oral or inhalation exposure.