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Description of key information

Several GLP guideline studies were performed: 
- EPA OPP 82-1 / 90 d study in rat (diet) with a NOEL of 600 ppm (33-65 mg/kg for males, 43-69 mg/kg for females).
- EPA OPP 82-1 / 90 d study in dogs (capsule) with a NOAEL of 30 mg/kg for males and females.
- OECD415 study / extended 1 generation study with a systemic NOAEL of 1000 mg/kg bw/d for males and 100 mg/kg bw/d for females (see IUCLID section 7.8.1).

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
Study period:
From 27 Sep 1990 to 2 July 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study run to a method comparable with current guidelines and to GLP.
Qualifier:
according to guideline
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, MI
- Age at study initiation:approximately 4 weeks
- Weight at study initiation: The weight range was 182-211 grams for the males and 127-160 grams for the females.
- Fasting period before study:
- Housing: in suspended stainless steel cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow #5002 (ground meal)
- Water (e.g. ad libitum): ad libitum fresh water (municipal source)
- Acclimation period: 14days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64-79°F
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: To:
Route of administration:
oral: feed
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): diets were prepared for seven- or fourteen-day feeding period
- Mixing appropriate amounts with (Type of food): 1% corn oil
- Storage temperature of food: at room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):Lot no.s were in report. NOV2590A, MAY2891A, JUL1691A
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test diets were analyzed for verification of test article concentration after each preparation during the first month and monthly thereafter.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
60, 600, 6000ppm (increased to 8000 ppm and again to 10000 ppm)
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
Dosage conversion ppm in diet to mg/kg bw/day:
60 ppm = 4-7 mg/kg (females) and 3-7 mg/kg (males)
600 ppm = 43-69 mg/kg (females) and 33-65 mg/kg (males)
10000ppm = 608-924 mg/kg (females) and 492-718 mg/kg (males)

The study consisted of a control and 3 treated groups with 10 animals per sex in each group. The test article was blended with rodent meal to prepare dietary concentrations of 60, 600 and 6000 ppm. Due to the lack of frank toxicity at the high-dose level, the concentration of the test was increased from 6000 to 8000 ppm on study day 29 and from 8000 to 10000 ppmon study day 43. Control animals were fed basal diet.
All animals were observed daily for clinical signs of toxicity. Body weights and food consumption were measured and recorded weekly. Clinical pathology and ophthalmology examinations were performed at or near the end of the treatment period. All tissues collected from control and high-dose animals, all tissues from animals sacrificed during the study and the lungs, liver, kidneys and gross lesions from all low- and mid-dose animals were processed for histopathological examination.
Observations and examinations performed and frequency:
All animals were observed daily for clinical signs of toxicity. Body weights and food consumption were measured and recorded weekly. Clinical pathology and ophthalmology examinations were performed at or near the end of the treatment period.
Sacrifice and pathology:
At the end of the treatment period (study days 92 and 91), all surviving rats were sacrificed. Half of the rats from each dose-sex group were sacrificed each day.
GROSS PATHOLOGY:The animals were subjected to a complete necropsy examination which included examination of the external surfaces, the cranial, thoracic, abdominal and pelvic cavities and their viscera.
HISTOPATHOLOGY: All tissues collected from control and high-dose animals, all tissues from animals sacrificed during the study and high-dose animals, all tissues from animals sacrificed during the study and the lungs, liver, kidneys and gross lesions from all low- and mid-dose animals were processed for histopathological examination.
Other examinations:
Organ weights
Statistics:
Statistical analyses were performed by a Digital VAX 11/730 computer. All tests were two-tailed with a minimum significance level of 5%. Continuous data including body weights, body weight gains, food consumption, organ weights, and clinical pathology data were analyzed by one-way analysis of variance(ANOVA). When significance was observed with ANOVA, group by group comparison was performed with Dunnett's Test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Dietary administration of the substance produced signs of systemic toxicity in both males and females at the 10000 ppm level. Reduced body weight gain and/or food consumption, increased absolute and relative liver weights and minimal to mild hepatocyte hypertrophy were observed in the 10000 ppm group. No treatment-related mortalities or clinical signs of toxicity were observed during the study and no treatment-related differences were noted in the clinical pathology, ophthalmology or gross necropsy observations for males or females in any of the study groups. No treatment-related changes were observed in body weight gain, food consumption, organ weights and histopathology for males or females in the 60 and 600 ppm groups.
Dose descriptor:
NOEL
Effect level:
600 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 600 ppm = 43-69 mg/kg (females) and 33-65 mg/kg (males)
Critical effects observed:
not specified
Conclusions:
Dietary administration of the substance for at least 90 days produced signs of systemic toxicity in both males and females at the 10000 ppm level. Reduced body weight gain and/or food consumption, increased absolute and relative liver weights and minimal to mild hepatocyte hypertrophy were observed for both males and females in the 10000 ppm group. Therefore, based on the results of this study, a level of 600 ppm was considered a no-observed-effect level (NOEL) for systemic toxicity following dietary administration of the substance for at least 90 days.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
several GLP, guideline studies

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

Mode of Action Analysis / Human Relevance Framework

​No information available

Additional information

oral

In a 90-d study N-(n-Octyl)pyrrolidone was feed to rats at dose levels of 60, 600 and 6000 ppm (about 5, 50 and > 550 mg/kg/d) (1991_RL1). The dietary concentration for the highest group was 6000 ppm for study days 1-28, 8000 ppm for study days 29-42 and 10000 ppm for the remainder of the study: mean: 553, 607 and 660 mg/kg/d for males and 645, 759 and 856 mg/kg/d for females). Dietary administration of N-(n-Octyl)pyrrolidone produced systemic effects in both males and females at the 6000-10000 ppm level: Reduced body weight gain and/or food consumption, increased absolute and relative liver weights and minimal to mild hepatocyte hypertrophy were observed. No treatment-related mortalities or clinical signs of toxicity were observed during the study and no treatment-related differences were noted in the clinical pathology, ophthalmology or gross necropsy observations for males or females in any of the study groups. No treatment related changes were observed in body weight gain, food consumption, organ weights and histopathology for males or females in the 60 and 600 ppm groups. Based on the results of this study, the NOEL was 600 ppm (about 50 mg/kg bw/d) after dietary administration of N-(n-Octyl)pyrrolidone for at least 90 days.

In a 90-d study, oral administration via capsule of N-(n-Octyl)pyrrolidone at the dose levels of 30, 90 and 240 mg/kg/day produced a dose-related systemic toxicity in dogs (1991_RL1). The liver was the target organ of target organ of toxicity as indicated by the following: a decrease in GGT, albumin and A/G ratio; an increase in alkaline phosphatase and liver weight; and the presence of hepatocellular hypertrophy.

Based on the results of this study, a dose level of 30 mg/kg/day was considered a no-adverse- effect level (NOAEL) for systemic toxicity following oral administration of the substance result for at least 90 days, since a decrease in A/G ratio and an increase in liver weight were slight and there were no corresponding histopathological changes.

In a GLP, extended One-Generation study (OECD443) several groups of 25 male and 25 female Wistar rats were treated for 75 days with 100, 300, 1000 mg/kg bw/day of N-(n-Octyl)pyrrolidone in the diet (2005_RL1). At least 75 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 descendant generation).

There were no indications that N-(n-Octyl)pyrrolidone adversely affected reproductive performance or fertility of the F0 parental animals at any dose level. Signs of general systemic toxicity were noted in the high and mid dosed F0 parental females, such as reduced food consumption and body weight, mainly during premating and gestation. Pathology identified the liver and the thyroid glands as target organs. However, the increased liver weights in mid and high dose animals as well as the occurrence of central hypertrophy/ hyperplasia in the liver of high dose animals are considered to be test substance-related but rather reflecting an adaptive effect representing microsomal enzyme induction than a toxicologically relevant and adverse finding. In addition, the thyroid findings are considered to be secondary to the observed liver findings.

The F1 pups of the high dose groups showed decreased mean body weights as well as body weight gain in either sex until weaning. This temporary slight retardation of development was present exclusively at a dose level where maternal toxicity was noted in the F0 females, too.

Thus, under the conditions of the present extended one-generation study the NOAEL (no observed adverse effect level) were as follows:

- fertility and reproductive performance of the F0 parental rats: 1000 mg/kg bw (m/f)

- general systemic toxicity of the test substance: 1000 mg/kg bw (m); 100 mg/kg bw (f)

- developmental toxicity (growth and development of F1 offspring until sexual maturation): 300 mg/kg bw (m/f).

The detailed endpoint study report can be found in chapter 7.8.1: Toxicity to reproduction.

Supporting results were observed from further repeated dose toxicity studies:

- 28-d study in rats, gavage in olive oil (OECD407) with a NOEL of 200 mg/kg bw/d for males and 50 mg/kg bw/d for females (1992_RL1).

- 28-d study in rats, gavage in corn oil with a NOEL of 55 mg/kg bw/d for males and females (1989_RL2).

dermal

Actually, there is no information available.

inhalation

Actually, there is no information available.

Justification for classification or non-classification

According to the ECHA Guidance on the Application of the CLP Criteria, 3.9.2.2 Classification criteria for substances (v4.1, June 2015), STOT-RE is assigned on the basis of findings of ‘significant’ or ‘severe’ toxicity. In this context ‘significant’ means changes which clearly indicate functional disturbance or morphological changes which are toxicologically relevant. ‘Severe’ effects are generally more profound or serious than ‘significant’ effects and are of a considerably adverse nature which significantly impact on health. Both factors have to be evaluated by weight of evidence and expert judgement.

The NOELs for 90-d studies in both rats and dogs are > 10 mg/kg bw/d and < 100 mg/kg bw/d. The LOEL of the 90-d study in rats is well above 100 mg/kg bw/d (> 500 mg/kg bw/d = 6000–10000 ppm), which is supported by the NOAEL of 100 mg/kg bw /d in females of the extended One-Generation study in rats. The significant effects seen at the LOEL of 90 mg/kg bw/d in dogs were limited to incidental cases for some blood parameters, a significant increase of liver weights and at worse a mild hepatocellular hypertrophy. Hence, these data were not considered as sufficient evidence for a STOT RE classification in Category 2.