Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
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
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no information on the analytical examination of doses, ophthalmoscopic and neurobehavioural examination not performed
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Broekman Institute, Stiphout, The Netherlands
- Mean weight at study initiation: male 42.6 g, female 41.2 g
- Housing: 5 per cage
- Diet (e.g. ad libitum): test compound was thoroughly mixed into the stock diet
- Water (e.g. ad libitum): tap water
Route of administration:
oral: feed
Details on oral exposure:
DIET PREPARATION
- The following percentage composition of stock diet was used: yellow maize 29.5, brewer's yeast 3, whole wheat 36, grass meal 3, soyabean-oil meal 10, soyabean oil 3, meat scraps 4, vitamin preparations 0.5, fish meal 8, trace mineralized salt 0.5, dried whey 2, and calcium phosphate 0.5. The test compound was thoroughly mixed into the stock diet by means of a modified meat cutter (Stefan).
- Rate of preparation of diet (frequency): The diets were freshly prepared once a fortnight
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
continuously
Dose / conc.:
0.05 other: % (nominal in diet)
Dose / conc.:
0.1 other: % (nominal in diet)
Dose / conc.:
0.25 other: % (nominal in diet)
Dose / conc.:
0.5 other: % (nominal in diet)
Dose / conc.:
1 other: % (nominal in diet)
Dose / conc.:
29 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
146 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
296 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
592 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
35 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
70 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
170 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
342 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
704 mg/kg bw/day (actual dose received)
Remarks:
females
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The toxicity of caprolactam (CAP) was examined in a range-finding test with weanling albino rats fed the test substance at dietary levels of 0, 0.2, 1 and 5 % for 28 days. CAP at levels of 5 % and 1 % in the diet caused growth depression and increased liver and kidney weights. Histopathological changes in liver and kidney were observed in the 5 % group in both sexes. In the 1 % group slight histopathological changes were observed only in the kidneys of males. On the basis of the present results 1% CAP is expected to be an effect level in a sub-chronic (90-day) toxicity study.
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 13 week
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters checked: haemoglobin, packed cell volume, red blood cell counts and total and differential white blood cell counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of experiment
- Animals fasted: No data
- How many animals: all
- Parameters checked: glutamic-pyruvic transaminase (SGPT), glutamic-oxalacetic transaminase (SGOT), alkaline phosphatase (SAP), total serum
protein, albumin and albumin-globulin ratio

URINALYSIS: Yes
- Time schedule for collection of urine: 13 week
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: appearance, pH, glucose, albumin, occult blood, ketones and microscopy of the sediment
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
The following organs were weighed: heart, kidneys, spleen, liver, brain, testicles/ovaries, thymus, pituitary, thyroids and adrenals
Clinical signs:
no effects observed
Description (incidence and severity):
During the course of the experiment no abnormalities of condition or behaviour were observed.
Mortality:
no mortality observed
Description (incidence):
During the course of the experiment no deaths occurred.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight growth depression occurred at the 1.0 % feeding level in both sexes. This growth depession was only biologically relevant in males (15 and 11% at week 2 and 4).
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Decreased food consumption was observed at the highest feeding level in both sexes during week 2, 3 and 4. At 0.5 % food consumption was relatively low in week 2 and 3 in both sexes. Towards the end of the experiment food consumption was comparable in all groups.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Food efficiency in males at the highest feeding level was slightly lower than in the other test groups. The food efficiency figure obtained in control males was low, probably as a result of relatively low body weights at week 4 which had disappeared not until week 10.
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological data showed no distinct differences between groups. Total leucocytes count was increased in males of some experimental groups, but there was no trend towards higher average leucocytes counts with an increase of Caprolactam in the diet.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No significant differences occurred in serum enzyme values amongst the various groups.
Urinalysis findings:
no effects observed
Description (incidence and severity):
The results of the urine analyses showed no changes in the composition of the urine which could be attributed to the feeding of Caprolactam.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The relative weight of the kidneys and testicles were increased (25 and 18%) at 1.0 % in males. The relative weight of the liver was increased in both sexes (19% in males and 14% in females) at 1.0 %. All other organ weights of test groups were comparable with the control values. The mathematically significantly decreased heart weight of females at 0.5 % is not considered of toxicological importance, because it was not observed at the 1.0 % level.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At autopsy, the kidneys of male rats showed a pale-greenish discolouration at the highest dose level. Other gross changes attributable to the ingestion of Caprolactam were not seen.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At microscopic examination pathological changes related to the ingestion of Caprolactam were found in the kidneys of males only. These changes consisted of hyaline-droplet degeneration of the proximal convoluted tubules in the kidneys of nearly all male rats at 0.1 % Caprolactam and above. Its degree was distinctly dose-related. The swollen epithelial cells of these tubules showed a granular cytoplasm,caused by large accumulations of tiny droplets of precipitated proteinaceous material. The droplets stained deeply red with Azan. At the 0.05 % level these changes were completely absent.
The other abnormalities were about equally distributed amongst test and control animals. The pathological examinations indicate that the ingestion of Caprolactam at levels of 0.1 % and above is nephrotoxic for male rats of this particular strain (SD).
Dose descriptor:
NOAEL
Effect level:
29 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOEL
Effect level:
342 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Based on hyaline-droplet degeneration of the proximal convoluted tubules in the kidneys, the NOAEL for males was found to be 29 mg/kg bw/day.
In females, the NOAEL was 342 mg/kg bw based on increase in relative liver weights.
The findings in male kidneys are supposed to be of no relevance for other species including humans (Haschek and Rousseaux, Fundamentals of Toxicologic Pathology, Academic Press, 1996). Therefore, CAP does not require any classification.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Due to the corrosivness, repeated dose toxicity testing on the substance does not need to be conducted.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Sodium caprolactamate hydrolyses under physiological conditions with the formation of epsilon-Caprolactam and sodium hydroxide. Low concentrations of sodium hydroxide will be neutralized in the stomach by gastric juice, which has a very low pH. Therefore a DNEL can be derived solely by the toxicity data of epsilon-Caprolactam by cross-reading. The difference of the mole masses between sodium caprolactamate and epsilon-Caprolactam will not be taken into consideration, with the exception of rounding up the epsilon-Caprolactam accordingly (350 vs. 342 mg/kg bw/day).

Justification for classification or non-classification

Since the substance is classified as corrosive, there is no indication for an additonal classification based on repeated dose toxicity.