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Inhalation route:

In a 13-week inhalation study performed according to an EPA guideline (10/ rats/sex/dose), Sprague-Dawley rats were exposed to analytical concentration of 0, 0.023, 0.066 and 0.245 mg/l caprolactam (CAP) as an aerosol for 6 hours/day, 5 days/week (whole body exposure). The particle size was on average of 2.9 µm and consequently the test aerosol was highly respirable (Reinhold et al., 1997). No compound-related deaths occurred. There were no treatment-related responses observed in ophthalmic parameters, body weights, food consumption, neurobehavioral effects, organ weights, or macroscopic findings.

The only exposure related clinical observations were transient signs of respiratory tract irritation (e.g. nasal discharge, labored breathing). At the histological level the analysis of the respiratory tract revealed various changes compared to the control exposure group. Hypertrophy/hyperplasia of goblet cells in the nasal mucosa, intracytoplasmic eosinophilic material in the epithelium of the nasal mucosa and squamous/squamoid metaplasia/hyperplasia in the larynx mucosa were observed at all exposure levels. The severity of these changes increased in dose dependent manner and recovery was incomplete within the four weeks recovery period. These effects were interpreted to be local adaptive responses to the minimal irritant effect commonly associated with inhaled particulate material. This interpretation is fully supported by the proceedings of an international expert workshop of the European Society of Toxicology (Kaufmann et al., 2009, Exp. Tox. Path., 61, 591-603):slight laryngeal squamous metaplasia that are not observed diffusely could occur spontaneously or as treatment-induced lesions and should be assessed as “non-adverse”.

Keratinisation of the metaplastic epithelium in the larynx (reversible within 4 week recovery) was observed in the highest dose group. These changes were considered to be adverse indicating a NOAEC for local effects in the upper respiratory tract, of 0.066 mg/l.

Due to the aerodynamic diameter of the aerosol tested in this experiment (2.9 µm) it can be anticipated that a major part of the test substance is reaching the alveoli of the lung. 

No systemic toxicity was observed, indicating a NOAEC of 0.245 mg/l.

 

No further valid inhalation studies were identified.

 

Oral route:

 

A distinct gender variance in systemic toxicity of CAP was observed in a 90 day continuous feeding study with Sprague-Dawley rats (TNO, 1991). Ten rats per sex and dose were fed with dose levels of 0.05. 0.1, 0.25, 0.5 and 1 % (ca. 29, 60, 146, 296, 592 mg/kg bw in males, and 35, 70, 170, 342 and 704 mg/kg bw in females).

Decreased food intake and an increased relative liver weight were reported in the high dose group of female animals (NOEL females 342 mg/kg bw).

In males more severe sign of systemic toxicity were observed, indicated by an adverse increase of relative testes (18% at 1% CAP), liver (19% at 1% CAP) and kidney weights (25% at 1% CAP). Additionally a significant growth depression was described in the high dose group, which was paralleled by a decreased in food intake (decreased food efficacy).  

Kidney toxicity was confirmed by microscopically changes at 0.1 % and above, reflecting all typical signs of a hyaline-droplet degeneration. Based on the effects in the kidneys, the NOAEL for males was found to be 29 mg/kg bw/day.

A similar gender variance was observed in a second rat strain (Wistar rats). Again ten rats per sex and dose fed for 90-day with caprolactam in dose levels of 0.1, 0.3, 1.0 and 2.0 % (ca. 71, 203, 702, 1342 mg/kg bw in males and 77, 234, 785, 1459 mg/kg bw in females) (TNO, 1990). Decreased food intake in the high dose group and an increased relative liver weight in the two highest dose levels (14% at 785 mg/kg bw, 18% at 1459 mg/kg bw) were reported in female animals (NOAEL females 234 mg/kg bw). In males relative kidney, liver and thyroid weights were 18, 13 and 22 % increased in the 2% diet dose groups, respectively. Similar to SD-rats, nephrotoxicity was accompanied by histopathological indications of a hyaline dropled degeneration starting from the 0.3% dose level. Tubular nephrosis occurred to a higher degree and incidence in all treated male rats in comparison to the control. Due to the effects on the kidney, the NOAEL in males is considered to be slightly below ca. 71 mg/kg bw/d).

An oral feeding study was performed in order to analyze the sex and rat-strain specificity of the renal toxicity of caprolactam (Allied Corp., 1983). For this dose levels up to 613 mg/kg bw/d in Fischer-rats, 903 mg/kg bw/d in Sprague-Dawley and 968 mg/kg bw/d in Wistar rats were applied. Males were generally way more susceptible for this type of nephrotoxicity, with the first indications occurring at rather low dose levels. Furthermore it was shown, that the Fischer- and Sprague-Dawley strains are more susceptible than the Wistar-strain. An almost complete reversibility of the nephrotoxicity was observed in a recovery group reanalyzed 90 days after discontinued dosage.

 

These findings in kidneys are supposed to be of no relevance for other species including humans (Haschek and Rousseaux, Fundamentals of Toxicologic Pathology, Academic Press, 1996). Moreover, the subsequent 2 year cancer bioassay with rats and mice did not reveal any type of carcinogenicity or any impairment of kidneys (NTP, 1982).

 

Surprisingly, no comparable kidney toxicity was observed in a 3-generation fertility study with Fisher-rats (Serota et al., 1981). When the respective generations were fed for 10 week premating intervals with diets containing 100, 500 and 1000 mg/kg bw, significantly reduced body weight was noted in the high dose animals. Compound-related kidney effects only consisted of histomorphologic findings (slightly increased severity of spontaneous nephropathy, accompanied by the presence of granular casts) in three of the P1 males at the 1000 mg/kg bw level.

 

The effects of low levels of subchronic dietary Caprolactam on renal function were evaluated using both sexes and three rat strains (Fischer 344, Sprague-Dawley and Wistar) that received the test compound at diet levels of 0, 0.01, 0.05, 0.10 and 0.50% for at least 90 days (Allied Corp., 1983). Low doses of subchronic dietary CAP are capable of altering renal function when the system is stressed even at very low doses, i.e. 0.01%. The male animals were more susceptible to the effects of CAP than the females and the Fischer 344 and Sprague-Dawleys more so than Wistars. This effect of CAP appears to be more of a physiological alteration than a toxic or adverse effect, in that it is reversible and does not compromise the health of the animal.

 

In a NTP 13-week range-finding study (NTP, 1982) Fischer rats were fed with CAP dose levels of ca. 42, 83, 167, 333 and 500 mg/kg bw/d.

The only compound-related findings were decreased body weights in all treatment groups. In high dose group this decrease in body weight was accompanied by a significantly lower food consumption. Due to an absent dose relationship and a presumed palatability problem this finding can not be considered as adverse. No further compound-related effects were found, resulting in a NOAEL of 500 mg/kg bw/d based on the highest test concentration.

Similarly in B6C3F1 mice dose levels of ca. 813, 1667, 2500, 3333 and 5000 mg/kg bw/d in feed resulted in a body weight depression at all dose levels without a clear dose-response relationship. The NOAEL was identified as 5000 mg/kg bw/d since no further treatment related effects were reported.

In the associated chronic main studies dose levels of 187.5 and 375 mg/kg bw/d were assayed in rats and 1071 and 2143 mg/kg bw/d in mice. Consistently, weight gain depression, accompanied by decreased food intakes were the only treatment related observations. In these chronic studies this effect was considered as adverse since a dose dependency and a biological relevance was observed in the high dose group. Therefore the NOAELs were identified as 187.5 mg/kg bw/d for rats and 1071 mg/kg bw/d for mice.

Due to the restricted amount of parameters assayed in these chronic studies (e.g. clinical chemistry) in comparison to the OECD-guideline 408, these NTP studies can not be used in order to reliably identify an overall NOAEL for caprolactam.

 

Three groups of four male and four female beagle dogs each were fed diet containing Caprolactam at levels of 0, 0.1, 0.5 and 1 % (ca. 0, 32, 164, 292 mg/kg bw/d in males and ca. 0, 33, 158, 389 mg/kg bw/d in females) (Hazleton, 1980). A biologically irrelevant decrease in the mean body weights (2-7 % less) of the high-dose females was identified as the only treatment related effect. No treatment-related changes were noted with respect to clinical signs, food consumptions, clinical laboratory studies, ophthalmologic examination, organ weight data, or gross and microscopic pathology. Based on the results, the NOAEL for males and females was considered to be 292 and 389 mg/kg bw/d, respectively.

 

Combining all the data, CAP given by feed to rats only caused specific effects in the male rat kidney. This observation was shown to be related to a rat species which is supposed to have little or no relevance for other species, including humans. No systamic effects were identified in a subchronic dog sudy. Thus no classification as STOT is required.

 

Dermal route:

The only study available for the dermal route of exposure is of limited documentation (RL 4) and reduced scientific coverage (Hohensee, 1951). Four guinea-pigs each were dermally exposed (4 x 6 cm) to 5 and 10 % aqueous solution of Caprolactam daily for 62 days. No alterations were observed, though no quantitative assessment is possible since the applied volume of the test substance is not specified. 

 

Justification for classification or non-classification

Only local respiratory irritation observed on inhalation route of exoposure. No systemic effects observed.