Registration Dossier

Administrative data

Link to relevant study record(s)

basic toxicokinetics in vivo
Data waiving:
study technically not feasible
Justification for data waiving:

Description of key information

Data obtained from Read-across from caprolactam:
Short description of key information on bioaccumulation potential result:
Based on the studies in rats and mice, caprolactam 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.
Short description of key information on absorption rate:
No dermal abssorption study available.

Data obtained by Read-Across from sodium hydroxide:
NaOH is not expected to be systemically available in the body under normal handling and use conditions.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Data obtained from Read-across from caprolactam:

Oral exposure:

There are few reliable studies on the tissue distribution and excretion of radioactive labeled or unlabeled caprolactam (CAP) in rat, mice and rabbits.


24 hr after a single oral dose of 0.18 mg/kg bw [14C] CAP 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 CAP 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 CAP for 7 days (1.5 g/kg bw [14C] CAP). 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 CAP (MI and MII) were detected comprising 79.3% and 17.7% of the excreted radioactivity, respectively.

With increasing dosage (1500 mg/kg bw) the amount of parent compound recovered in urine increased substantially (14%) 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]-CAP was studied in female and 14.5-day-pregnant mice (Badische Corp., 1981). [14C]-CAP 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]-CAP (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 witch male rabbits and rats were singly dosed with 300 mg/kg bw CAP (Bayer, 1977). Absorption and excretion of CAP 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, CAP was rapidly absorbed (Bayer, 1977).

With a high exposure concentration of 0.531 mg/l a rapid increase in CAP 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 CAP was detectable in the serum. Similar findings were observed low dose exposure atmosphere of 0.020 mg/l. With both atmospheres CAP 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 CAP absorption and excretion. No CAP 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]-caprolactam 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 CAP (300 mg/kg bw) in rats and rabbits CAP was rapidly absorbed and excreted within 20 h after application (Bayer, 1977). ε-aminocaproic acid was identified as a major metabolite in urine. In relation to urinary CAP the amount excreted in rabbits was higher compared to rats. For both, CAP and ACA, renal excretion occurred predominatly during the first 48 h.

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


Data obtained by Read-Across from sodium hydroxide:

Sodium is a normal constituent of the blood and an excess is excreted in the urine. A significant amount of sodium is taken up via the food because the normal uptake of sodium via food is 3.1-6.0 g per day according to Fodor et al. (1999). Exposure to NaOH could potentially increase the pH of the blood. However, the pH of the blood is regulated between narrow ranges to maintain

homeostasis. Via urinary excretion of bicarbonate and via exhalation of carbon dioxide the pH is maintained at the normal pH of 7.4-7.5.

When humans are dermally exposed to low (non-irritating) concentrations, the uptake of NaOH should be relatively low due to the low absorption of ions. For this reason the uptake of NaOH is expected to be limited under normal handling and use conditions. Under these conditions the uptake of OH-, via exposure to NaOH, is not expected to change the pH in the blood. Furthermore the

uptake of sodium, via exposure to NaOH, is much less than the uptake of sodium via food under these conditions. For this reason NaOH is not expected to be systemically available in the body under normal handling and use conditions.

An example will be given for an inhalation exposure scenario. Assume an exposure to an NaOH concentration of 2 mg/m³, which is the TLV in the USA, and a respiratory volume of 10 m³ per day. In this case the daily exposure is 20 mg NaOH.

The amount of 20 mg NaOH is equivalent with 11.5 mg sodium which is a negligible amount compared to the daily dietary exposure of 3.1-6.0 g (Fodor et al., 1999). The amount of 20 mg NaOH is equivalent with 0.5 mmole and if this amount would be taken up in the blood stream it would result in a concentration of 0.1 mM OH- (assuming 5 litre blood per human). This is a negligible amount when it is compared with the bicarbonate concentration of 24 mM of blood. This example confirms that NaOH is not expected to be systemically available in the body under normal handling and use conditions.