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Administrative data

Description of key information

Oral: The acute oral LD50 was determined to be 1114 mg/kg bw in rats. 
Inhalation: The acute inhalation LC50 was determined to be > 1.6 mg/L in rats.
Dermal: The acute dermal LD50 was determined to be 1700 mg/kg bw in rabbits.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline outlined in study that has been applied, but procedure was similar to OECD401; well described record
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CDBR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: males: 8-9 wekkes, females 10-11 weeks
- Weight at study initiation: Males: 195 - 302 grams; Females: 188 - 223 grams
- Fasting period before study: yes (overnight)
- Housing: Single housed during the test period.
- Diet (e.g. ad libitum): Certified Rodent Checkers #5002 (mash), ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-76° F
- Humidity (%): 40-70% relative humidity
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test material was heated in a water bath at 46° Celsius (group 1) and 47° Celsius (groups 2 and 3) untilliquified.
The undiluted test material was administered by a single oral intubation via syringe and a stainless steel, straight, ball tipped feeding needle.
Individual animal doses were calculated by dividing the specified dose level by the density (1.02 g/ml) to arrive at the dose volume. The dose volume was then multiplied by the animal's fasted body weight to arrive at the dose.
Doses:
0, 600, 1300, 2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Animals were examined for viability twice daily for two weeks.
Body weights were recorded the day prior to dosing (pretest), on the day of dosing (Day 0), on Days 7 and 14, and at death for animals succumbing prior to termination.
After the Day 14 observations, all surviving animals were sacrificed and analyzed by gross necroscopy.
Statistics:
The oral median lethal dose (LD50) was calculated using the standard Litchfield Wilcoxon technique (Litchfield and Wilcoxon, 1949) with equal weighting of the data values.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 114 mg/kg bw
Based on:
test mat.
95% CL:
> 877 - < 1 416
Mortality:
1/10 at 600, 6/10 at 1300 and 9 at 2000 mg/kg (see table below)
All mortalities occurred prior to Day 3, with the majority at day 0
Clinical signs:
Adverse clinical effects were observed in all groups primarily from Day 0 to Day 4. Abnormal clinical signs noted during the study included hypoactivity, hyperactivity, hypothermia, aggressive behavior, ataxia, abnormal production of stool, oral, nasal and ocular discharge, emaciation, food consumption decrease, prostration, breathing abnormalities, and staining of the fur. All surviving animals were free of abnormalities from Day 6 through study termination,
Body weight:
All surviving animals exhibited weight gain relative to their prefast values at termination.
Gross pathology:
Postmortem examination of those animals found dead revealed lung discoloration and tissue consolidation, staining of the fur, liver discoloration, nasal and/or oral discharge. Abnormal content of the stomach and small intestine were also noted. These abnormal contents appeared to be test material. No abnormalities were observed in any animal surviving to termination.

 

Male

Female

Combined

600

1

0

1

1300

2

4

6

2000

4

5

9

LD50

1236

1049

1114

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 114 mg/kg bw
Quality of whole database:
GLP and guideline study

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is comparable with the inhalation hazard test described in the Annex of OECD Guideline 403 (adopted 1981) with acceptable restrictions mostly due to reduced documentation and no GLP
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Analytical purity of the test substance not reported
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Mean weight at study initiation: 160.5 g (calculated from the raw data)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Vapour was generated by bubbling 200 l/h dry air (no CO2) through the test substance column of about 5 cm above a fritted glass disc in a glass cylinder. The glass cylinder was heated in a water bath to two different temperatures, 20 and 50°C. Concentrations stated in the raw data were 1.12, 1.36 and 1.6 mg/L generated by heating the water bath to 50°C, and 0.2 and 0.3 mg/L generated by heating the water bath to 20°C.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
8 h
Concentrations:
0.2, 0.3, 1.12, 1.36 and 1.6 mg/L
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: clinical signs were recorded several times on the day of administration and at least once per workday for the individual animals; weighing on day 0 before administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, mean body weight
Statistics:
not performed
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.6 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
8 h
Mortality:
No mortality was observed.
Clinical signs:
No clinical signs were observed.
Body weight:
No effect on the body weight gain was observed.
Gross pathology:
No abnormalities were noted.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
acceptable

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Approximately 24 hours prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair. The prepared site was approximately 10% of the body surface and remained intact. The dose was based on the sample weight as calculated from the specific gravity. The test article was applied to the prepared dermal site, one time, by syringe type applicator on a g/kg basis. The test site was covered with a gauze patch, secured with non-irritating tape and gentle pressure was applied to the gauze to aid the distribution of the test article over the area. The torso was wrapped with plastic which was secured with non-irritating tape. At 24 hours, the patches were removed. The residual test article was gently washed off with distilled water prior to dermal observations.
Duration of exposure:
24 hours
Doses:
1000, 1600, 2000, 2500 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The test sites were scored for dermal irritation at 24 hours post dose and on days 7 and 14 using the numerical Draize scale. Additional signs were described. The animals were observed 1, 2 and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for 14 days for mortality. Body weights were recorded pretest, weekly and at death or termination. All animals were examined for gross pathology. Abnormal tissues were preserved in 10% buffered formalin for possible future microscopic examination.
Statistics:
The LD 50, 95% Confidence Limits, dose response curve and slope were calculated by the method of
Litchfield, J.T., Jr., & Wilcoxon, F., JPET 96:99, 1949.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 700 mg/kg bw
Based on:
test mat.
95% CL:
> 1 300 - < 2 200
Sex:
female
Dose descriptor:
LD50
Effect level:
1 800 mg/kg bw
Based on:
test mat.
95% CL:
> 1 300 - < 2 500
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 700 mg/kg bw
Based on:
test mat.
95% CL:
> 1 300 - < 2 200
Mortality:
1000 mg/kg bw: 0/5 males, 0/5 females
1600 mg/kg bw: 3/5 males, 3/5 females
2000 mg/kg bw: 3/5 males, 2/5 females
2500 mg/kg bw: 4/5 males, 4/5 females
Clinical signs:
The deaths occurred by day 4 and were preceded by physical signs of diarrhea, lethargy, ptosis, dyspnea, negative righting reflex, ataxia, few feces, yellow nasal discharge, red discharge and soiling of the anogenital area, convulsions and mucoid diarrhea. Necropsy of the dead animals revealed abnormalities of the lungs, liver, spleen, pleural cavity, eyes, treated skin, kidneys, heart and gastrointestinal tract, as well as soiling of the anogenital area, wetness of the nose/mouth area, wetness of the anogenital area and red staining of the anogenital area.
Physical signs noted in survivors included lethargy, ptosis, yellow nasal discharge, diarrhea, ataxia, dyspnea, few feces, emaciation, soiling of the anogenital area, red discharge, ocular discharge, red staining of the anogenital and mucoid diarrhea.
Body weight:
Body weight changes of survivors were generally normal, although instances of weight loss were noted in survivors of all groups.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
The LD50 was determined to be 1700 mg/kg bw (males/females combined)
Executive summary:

Five healthy male and five healthy female New Zealand Albino rabbits were dosed dermally with the test substance at 1000, 1600, 2000 and 2500 mg/kg of body weight. The test article was kept in contact with the skin for 24 hours. Dermal responses were recorded on days 1, 7 and 14. Animals were observed for toxicity and pharmacological effects at 1, 2 and 4 hours post dose and once daily for 14 days. All animals were observed twice a day for mortality. Body weights were recorded pretest, weekly and at death or termination in the survivors. All animals were examined for gross pathology. The deaths occurred by day 4 and were preceded by physical signs of diarrhea, lethargy, ptosis, dyspnea, negative righting reflex, ataxia, few feces, yellow nasal discharge, red discharge and soiling of the anogenital area, convulsions and mucoid diarrhea. Necropsy of the dead animals revealed abnormalities of the lungs, liver, spleen, pleural cavity, eyes, treated skin, kidneys, heart and gastrointestinal tract, as well as soiling of the anogenital area, wetness of the nose/mouth area, wetness of the anogenital area and red staining of the anogenital area. Physical signs noted in survivors included lethargy, ptosis, yellow nasal discharge, diarrhea, ataxia, dyspnea, few feces, emaciation, soiling of the anogenital area, red discharge, ocular discharge, red staining of the anogenital and mucoid diarrhea. Body weight changes of survivors were generally normal, although instances of weight loss were noted in survivors of all groups. Necropsy results of survivors revealed abnormalities of the treated skin, gastrointestinal tract, lungs, liver and kidneys. The LD 50's and 95 Confidence Limits are: males · 1700 (1300 · 2200) mg/kg; females · 1800 (1300 · 2500) mg/kg; and males & females combined · 1700 (1300 - 2200) mg/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 700 mg/kg bw
Quality of whole database:
acceptable

Additional information

Oral:

An oral study was conducted according to guideline OECD 401 with GLP. Groups of 5 rats per sex and dose were administered with 1000, 1442, 2080, 3000 mg/kg bw of the test substance. Common signs of hunched posture, lethargy and pilo-erection were noted in all animals treated with 1000 or 1442 mg/kg bw and in the majority of surviving animals treated with 2080 mg/kg bw during the day of dosing. Decreased respiratory rate was also noted in all animals treated with 1442 mg/kg bw during this period. All animals treated with 1000 and 1442 mg/kg bw appeared normal one to two days after treatment. All surviving animals treated with 2080 mg/kg bw appeared normal six days after treatment. Reduced bodyweight gain was noted in 2 females treated with 1442 mg/kg bw and 2 males treated with 2080 mg/kg bw. Abnormalities noted at necropsy of decedents were abnormally red lungs, dark or pale liver and haemorrhage of the small intestine including incidents of pale kidneys and haemorrhage of the glandular gastric epithelium in animals treated with 2080 mg/kg bw. No abnormalities were noted at necropsy of surviving animals killed at the end of the study. The acute oral LD50 of the test substance was found to be 1864 mg/kg bw for male and female animals. (Safepharm, 1989).

In another key study by Exxon (1994), Vinyl Caprolactam (MRD-93-524) was administered via oral intubation to five male and female rats at dose levels of 600, 1300, and 2000 mg/kg. Adverse clinical effects were observed in all groups, primarily from Day 0 to Day 4. Abnormal clinical signs noted during the study included hypoactivity, hyperactivity, hypothermia, aggressive behavior, ataxia, abnormal production of stool, oral, nasal, and ocular discharge, emaciation, food consumption decrease, prostration, breathing abnormalities, and staining of the fur. The LD50 observed in this study was 1236 (males), 1049 mg/kg (females) and 1114 mg/kg (combined).

 

Another oral supporting study of lower reliability was conducted equivalent or similiar to guideline OECD 401 without GLP (BASF, 1963)

. The observed clinical signs were staggering, abdominal and lateral position, dyspnea, and slight convulsions and narcotic-like state in some cases. These clinical signs were reversible within 2-4 days in survivors. Abnormalities noted at necropsy of decedents were dilatation of the urinary bladder, fatty infiltration of the liver and capsular hemorrhages of the thymus. No abnormalities were detected in sacrificed animals. The acute oral LD50 of the test substance was found to be 1400 mg/kg bw for male and female animals.

These results are further supported by a study conducted by Consumer Product testing in 1979 (non-guideline). Since all animales dies in a range-finding study (500 mg/kg-30 g/kg; 1 animal each dose), three female and male rats were treated with 100 -2520 mg/kg in the main study. Clinical signs and gross pathology are only poorly recorded; the LD50 in this study was 830 mg/kg.

 

Inhalation:

An inhalation study comparable with OECD Guideline 403 (adopted 1981) was conducted in rats. 3 males and 3 females were exposed for 8 hrs to an atmosphere containing the test item at concentrations of 0.2, 0.3, 1.12, 1.36 and 1.6 mg/L. No mortality and clinical signs was observed. No effect on the body weight gain were observed. No pathological changes were observed at necropsy. The acute inhalation LD50 of the test substance was found to be > 1.6 mg/L for male and female animals. (BASF, 1963)

Dermal:

An acute dermal GLP study was conducted according to OECD Guideline 402 (Acute Dermal Toxicity) in rabbits (ISP, 1993). Five healthy male and female New Zealand Albino rabbits were dosed dermally with the test substance at 1000, 1600, 2000 and 2500 mg/kg of body weight. The deaths occurred by day 4 and were preceded by physical signs of diarrhea, lethargy, ptosis, dyspnea, negative righting reflex, ataxia, few feces, yellow nasal discharge, red discharge and soiling of the anogenital area, convulsions and mucoid diarrhea. Necropsy of the dead animals revealed abnormalities of the lungs, liver, spleen, pleural cavity, eyes, treated skin, kidneys, heart and gastrointestinal tract, as well as soiling of the anogenital area, wetness of the nose/mouth area, wetness of the anogenital area and red staining of the anogenital area. Physical signs noted in survivors included lethargy, ptosis, yellow nasal discharge, diarrhea, ataxia, dyspnea, few feces, emaciation, soiling of the anogenital area, red discharge, ocular discharge, red staining of the anogenital and mucoid diarrhea. Body weight changes of survivors were generally normal, although instances of weight loss were noted in survivors of all groups. Necropsy results of survivors revealed abnormalities of the treated skin, gastrointestinal tract, lungs, liver and kidneys. The LD50 was determined to be 1700 mg/kg bw (males/females combined).

A second dermal study was performed as limit test comparable to OECD Guideline 402 (Acute Dermal Toxicity) in rats with acceptable restrictions mostly due to reduced documentation and no GLP. The only test dose of 2000 mg/kg bw did not cause mortality, symptoms or necropsy findings in 5 rats after 14 days. The acute oral LD50 of the test substance was found to be >2000 mg/kg bw for male and female animals. (BASF, 1988).

A third dermal study was performed comparable to OECD Guideline 402 (Acute Dermal Toxicity) in rabbits with acceptable restrictions mostly due to reduced documentation and no GLP. The only test dose of 400 mg/kg bw did not cause mortality, symptoms or necropsy findings. (BASF, 1978)


Justification for selection of acute toxicity – oral endpoint
The Key study with the lowest LD50 was selected (GLP and Guideline study).

Justification for selection of acute toxicity – inhalation endpoint
The Key study was selected (Inhalation Risk Test).

Justification for selection of acute toxicity – dermal endpoint
The Key study was selected (GLP and Guideline study).

Justification for classification or non-classification

N-Vinylcaprolactam is harmful after oral and dermal administration (EU: R21/22; CLP acute oral/dermal Cat. 4, H302/H312) according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.

Classification for acute inhalation toxicity is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.