N-(n-octyl)-2-pyrrolidinone

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

OECD415 (1Gen) with additional parameters of OECD416 (2Gen)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)

Deviations:

yes

Remarks:

Additonal to the basic design of an EOGRTS selected F1 animals (25/sex/group) were treated after weaning up to sexual maturation. Adjustment of F1 generation at PND4 to 4/sex/litter instead of 5/sex/litter; no weight of heart and thymus.

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

yes

Remarks:

extended by additional examinations as required by OECD416

Principles of method if other than guideline:

One-generation study (OECD 415; May 1983), extended by additional examinations (estrous cycle, sperm parameters, organ weight determinations, extended histopathology, signs of sexual maturation in selected pups) that are required in a two-generation study (OECD 416; Jan. 2001)

GLP compliance:

yes

Limit test:

no

Justification for study design:

Several RDT studies are available for n-octylpyrrolidone (NOP): 90d study in rats (1991), 90d study in dogs (1991), 28d study in rats (1989 and 1992). Overall, reduced food consumption and body weights, as well as hepatic findings were observed after repeated administration of high doses of n-octylpyrrolidone. Besides hepatic and thyroid findings, which could be regarded as rather adaptive than adverse, no findings (e.g. immuntoxic, neurotoxic or reprotoxic effects) were observed, triggering additional cohorts of an EOGRTS/OECD443.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach/Riss, FRG
- Age at study initiation: 34 days (43 days at study initiation)
- Mean weight at study initiation: 183 (114 - 194) g for the males , 148 (132 - 160) g for the females.
- Fasting period before study: none
- Housing: singly in type DK III stainless steel wire cages
- Diet: ground Kliba maintenance diet rat/mouse/hamster, 343 meal, supplied by Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland, ad libitum
- Water: Tap water ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: over night
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy
- After successful mating each pregnant female was caged (how): individual

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Premating exposure period (males): 75 days
Premating exposure period (females): 75 days

Frequency of treatment:

continuously

Remarks:

Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
nominal in diet

No. of animals per sex per dose:

25 males and 25 females

Control animals:

yes

Positive control:

not done

Parental animals: Observations and examinations:

N-Octylpyrrolidone was administered to groups of 25 male and 25 female healthy young Wistar rats (F0 parental generation) as a homogeneous addition to the food in different dietary concentrations, which were adjusted regularly to obtain a constant test substance intake of 0, 100, 300 and 1000 mg/kg bw/day. At least 75 days after the beginning of treatment, F0 animals were mated to produce a litter. After litter standardization on day 4 p.p. (post partum) F1 pups were reared until weaning. At this time 25 male and 25 female pups per group were selected and allowed to grow up until sexual maturity. The latter rats ("selected F1 animals") were treated with the compound after weaning (day 21 p.p.) until sacrifice at the same dose levels and in the same manner as the F0 parental animals. The study was terminated with the sacrifice and gross necropsy of all F0 and F1 animals. The state of health of the F0 and F1 rats was checked each day, and the F0 parental animals were examined for their mating and reproductive performance.
Food consumption of the F0 parents was determined regularly during premating (once weekly over a period of 6 days each), and during gestation (clays 0-7, 7-14, 14-20) and lactation periods (days 1-4, 4-7, 7-14). Food consumption of the selected F1 animals was determined once weekly after weaning (over a period of 6 days). In general, body weights of F0 parents and selected F1 animals were determined once weekly (each time for a period of 7 days). However, F0 females were weighed on days 0, 7, 14 and 20 of gestation and on days 1, 4, 7, 14 and 21 of lactation. The body weights of the selected F1 animals were additionally determined on the day of preputial separation/ vaginal opening.

Oestrous cyclicity (parental animals):

Estrous cycle data were evaluated in F0 generation females over a three week-period prior to mating and throughout the following mating period until individual evidence of mating occurred. Moreover, the estrous stage of each F0 female was determined on the day of scheduled sacrifice.

Sperm parameters (parental animals):

Various sperm parameters (sperm head counts and morphology) were assessed in all control and high dose F0 generation males, while sperm motility was examined in the F0 males of all groups at scheduled sacrifice or after appropriate staining.

Litter observations:

All F1 pups were sexed on the day of birth and were weighed on the subsequent day as well as on day 4 after birth. their viability was recorded. Standardized litters were weighed on days 7, 14 and 21 p.p. After weaning the non-selected pups were subjected to gross necropsy (including weight determinations of brain, spleen and thymus in one pup/sex/litter). The selected FI weanlings were reared and the time of sexual maturation (day of preputial separation/ vaginal opening) was determined. Thereafter, these pups were killed and examined macroscopically at necropsy.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera


HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at day of preputial separation/ vaginal opening
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination)


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera


HISTOPATHOLOGY / ORGAN WEIGTHS
Tissues were prepared for microscopic examination and weighed, respectively.

Dose descriptor:

NOAEL

Remarks:

Fertility

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no findings

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: adaptive findings (target organ: liver), thyroid findings secondary to the liver findings.

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: reduced food consumption and body weight, mainly during premating and gestation; furthermore adaptive findings comparable to findings in male.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Slightly decreased mean body weights in F1 pups of both sexes, statistically significant from day 7 until day 21 p.p. (13 % at maximum). Slightly impaired weight gain of F1 pups from day 4 p.p. until weaning (average -15 %)

Reproductive effects observed:

not specified

Results summary

The following test substance-related findings were observed:

Test group 03 (1038.9 mg/kg body weight/day)

Parental animals:

CLINICAL EXAMINATIONS / REPRODUCTIVE PERFORMANCE / CLINICAL PATHOLOGY / PATHOLOGY

- Decreased food consumption in F0 females, slightly but statistically significantly (up to 9 %) during premating from study week 6 until study week 10, from days 0 - 20 p.c. and after weaning study week 18 – 19

- Slightly decreased (up to 7 %) mean body weights in F0 females, statistically significant during premating (weeks 8-10), during gestation, on lactation days 1-4 and after weaning (weeks 18-19)

- Significantly decreased average body weight gain in F0 females during entire premating (-10 %), highest decrease during weeks 4-5 (-35 %); decreased weight gain

- during second gestation week (-18 %), regain of weight from day 4 p.p. until weaning (+58 %)

- Significantly increased absolute and relative liver weights in males and females

. Significantly increased relative weight of the thyroid glands in males

- Minimal to slight central hypertrophy of hepatocytes in the liver of three males and all females

- Higher incidence of hypertrophy/ hyperplasia in the thyroid glands of males

-Higher incidence of altered colloid in the thyroid glands of males F1 pups / selected F1 animals (reared F1weanlings)

 

offspring:

CLINICAL EXAMINATIONS / PUP ORGAN WEIGHTS / SEXUAL MATURATION

- Slightly decreased mean body weights in F1 pups of both sexes, statistically significant from day 7 until day 21 p.p. (13 % at maximum)

. Slightly impaired weight gain of F1 pups from day 4 p.p. until weaning (average -15 %)

 

Test group 02 (311.8 mg/kg body weight/day)

F0 parental animals

CLINICAL EXAMINATIONS / REPRODUGTIVE PERFORMANCE / CLINICAL PATHOLOGY / PATHOLOGY

-Decreased mean body weights (maximum -6%), statistically significant in the last 2 weeks prior to mating as well as body weight gain (average -9% during premating) in the F0 females.

- Significantly increased absolute (males, only) and relative liver weights in males and females

- Significantly increased relative weight of the thyroid glands in males

- Higher incidence of hypertrophy hyperplasia in the thyroid glands of males

- Higher incidence of altered colloid in the thyroid glands of males

 

F1 pups 1 selected F1 animals (reared F1 weanlings)

CLINICAL EXAMINATIONS / PUP ORGAN WEIGHTS / SEXUAL MATURATION

- no test substance-related findings

 

Test group 01 (103.1 mg/kg body weight/day)

F0 parental animals

CLINICAL EXAMINATIONS / REPRODUOTIVE PERFORMANCE / CLINICALPATHOLQGY / PATHOLOGY

- No test substance-related findings

 

F1 pups 1 selected F1 animals (reared F1 weanlings)

CLINICAL EXAMINATIONS / PUP ORGAN WEIGHTS / SEXUAL MATURATION

No test substance-related findings

 

CONCLUSION

There were no indications that N-Octylpyrrolidon adversely affected reproductive performance or fertility of the F0 parental animals at dose levels of 100, 300 and 1000 mg/kg body weight/day.

 

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 test substance related effect disappeared during post-weaning development of the selected F1 offspring, thus being a temporary effect on postnatal development. This slight retardation of development was present exclusively at a dose level where maternal toxicity was noted in the F0 females, too. Moreover, no other test substance-induced signs of developmental toxicity were obtained in F1 pups and selected F1 animals raised after weaning until sexual maturity. Thus, under the conditions of the present extended one-generation study the NOAEL (no observed adverse effect level) could be fixed for:

- fertility and reproductive performance of the F0 parental rats: 1000 mg/kg body weight/day In both genders

- general systemic toxicity of the test substance: 1000 mg/kg body weight/day in F0 parental males; 100 mg/kg body weight/day in F0 parental females

- developmental toxicity (growth and development of the F1 offspring until sexual maturity): 300 mg/kg body weight/day in both genders

Conclusions:

There were no indications the substance adversely affected reproductive performance or fertility of the F0 parental animals at dose levels of 100, 300 and 1000 mg/kg bw/day.
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 test substance related effect disappeared during postweaning development of the selected F1 offspring, thus being a temporary effect on postnatal development. This slight retardation of development was present exclusively at a dose level where maternal toxicity was noted in the F0 females, too. Moreover, no other test substance-induced signs of developmental toxicity were obtained in F1 pups and selected F1 animals raised after weaning until sexual maturity.

Thus, under the conditions of the present extended one-generation study the NOAEL (no observed adverse effect level) could be fixed for:
Fertility and reproductive performance of the F0 parental rats = 1000 mg/kg bw/day;
General systemic toxicity = 1000 mg/kg bw/day in F0 parental males, 100 mg/kg bw/day in F0 parental females;
Developmental toxicity (growth and development of the F1 offspring until sexual maturity) = 300 mg/kg bw/day in both genders.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Several groups of 25 male and 25 female rats were treated for 75 days with 100, 300, 1000 mg/kg bw/day of N-(n-Octyl)pyrrolidone in the diet. The test substance was administered to healthy young Wistar rats (F0 parental generation) as a homogeneous addition to the food in different dietary concentrations, which were adjusted regularly to obtain a constant test substance intake. At least 75 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 descendant generation). After litter standardization on day 4 p.p. (post partum) F1 pups were reared until weaning. At this time 25 male and 25 female pups per group were selected and allowed to grow up until sexual maturity. The latter rats ("selected F1 animals") were treated with the compound after weaning (day 21 p.p.) until sacrifice at the same dose levels and in the same manner as the F0 parental animals. The study was terminated with the sacrifice and gross necropsy of all F0 and F1 animals. The state of health of the F0 and F1 rats was checked each day, and the F0 parental animals were examined for their mating and reproductive performance.

 

There were no indications that N-(n-Octyl)pyrrolidone adversely affected reproductive performance or fertility of the F0 parental animals at dose levels of 100, 300 and 1000 mg/kg body weight/day. 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 test substance related effect disappeared during post-weaning development of the selected F1 offspring, thus being a temporary effect on postnatal development. This slight retardation of development was present exclusively at a dose level where maternal toxicity was noted in the F0 females, too. Moreover, no other test substance-induced signs of developmental toxicity were obtained in F1 pups and selected F1 animals raised after weaning until sexual maturity.

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: 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)

Short description of key information:
Extended one-generation reproduction toxicity study (OECD 443) in rats:
NOAEL (reproduction toxicity, parental generation): 1000 mg/kg bw;

Justification for selection of Effect on fertility via oral route:
GLP, OECD guideline study.

Effects on developmental toxicity

Description of key information

Teratogenicity study (OECD 414) in rats: 
- NOAEL (maternal and fetal): 200 mg/kg bw 
- NOAEL (tera): 800 mg/kg bw

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 1990 - June 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Fuellinsdorf/CH
- Age at study initiation: 11 weeks, minimum (age at pairing)
- Weight at study initiation: 179-225 g (d0 post coitum)
- Fasting period before study:
- Housing: individually in Makrolon cages
- Diet (ad libitum): Kliba (Klingentalmuehle AG, Kaiseraugst/CH)
- Water (ad libitum): tap water
- Acclimation: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40-70 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

other: bi-distilled water with 0.5% Cremophor

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- daily before administration
- amount: 10 ml/kg bw (daily adjustment)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

During the dosing period of this study, samples were taken for confirmation of concentration, homogeneity and stability on two occasions. Analyses were performed by the RCC Analytlcal Chemistry Laboratory using a method supplied by the Sponsor.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy

Duration of treatment / exposure:

day 6 - 15 post coitum

Frequency of treatment:

daily in the morning

Remarks:

Doses / Concentrations:
50, 200, 800
Basis:
nominal conc.

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: range-finding study (RCC project 277896)

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes, twice daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes, daily from day 0 - 21 post coitum
FOOD CONSUMPTION: Yes (day0-6, 6-11, 11-16, 16-21)
WATER CONSUMPTION: No data
POST-MORTEM EXAMINATIONS: Yes, gross macroscopic examination
- Sacrifice on gestation day 21
- Organs examined: all internal organs, with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of pre- and post-implantation loss: Yes

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [about half per litter]
- Skeletal examinations: Yes: [about half per litter]
- Head examinations: Yes

Statistics:

For analysis of body weights, food consumption, reproduction and skeletal examination data:
Univariate one-waY analysis of variance was used to assess the significance of intergroup differences. If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-one t- test) , based on a pooled variance estimate, was applied for the comparison between the treated groups and the control group. The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information. Individual values, means, standard deviations and t - statistics were rounded off before printing.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
HIGH DOSE GROUP (800 mg/kg bw/d):
- 2 females were found dead of day 16 or 12 post coitum, respectively (observed toxic effects noted during the days prior to death)
- ruffled fur, ventral recumbency. somnolence, apathy, dyspnea, comatose state were note during the dosing period

MID DOSE GROUP (200 mg/kg bw):
- 1 incidental death in the mid dose group
- no clinical signs of reaction to treatment

LOW DOSE GROUP (50 mg/kg bw):
- no clinical signs of reaction to treatment

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: fetal effects at maternal toxic doses

Details on embryotoxic / teratogenic effects:
- At 800 mg/kg, mean fetal body weight was statistical significantly reduced in comparison with the control group. This finding which was combined with a delay in skeletal ossification correlated with the severe maternal toxicity observed at this dosage. At 50 or 200 mg/kg, no effects of treatment with the test article on the mean fetal body weights were evident.
- At external, visceral or skeletal examination of the fetuses, no test article related abnormal findings were noted in any group.

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

Dose descriptor:

NOAEL

Effect level:

800 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

No teratogenic potenial of Surfadone LP 100 (= NOP, CAS 2687-94-7) was found in this study. The fetotoxicity (reduced mean fetal body weight, combined with delay in skeletal ossification) correlated with the severe maternal toxicity at 800 mg/kg bw exposure.

Executive summary:

SURFADONE LP 100 (N-octyl-pyrrolidone, CAS 2687-94 -7) was administered orally by gavage, once daily, to pregnant female Wistar rats from day 6 through to day 15 post coitun, at dosages of 50, 200 or 800 mg/kg bw/d in order to assess the effects on embryonic and fetal development (OECD guideline 414, GLP; Bayer AG 1991).

At 800 mg/kg, one dam died after the 7th and one after the 10th test article administration. The females of this group had marked clinical signs of reaction to treatment, reduced food consumption, slight body weight loss during the first day of dosing and reduced corrected body weight gain. The mean fetal body weight was reduced at this dosage, combined with a delay of skeletal ossification.

At 50 or 200 mg/kg, no effects of treatment with the test article on the a maternal or fetal parameters were evident.

Based on the results of this study, the NOAEL for the maternal and fetal parameters was considered to be 200 mg/kg bw/d. SURFADONE LP 100 did not reveal any teratogenic potential up to and including the highest dose level of 800 mg/kg bw/d when administered to pregnant Wistar rats under the conditions described for this study.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

800 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a teratogenicity study according to OECD guideline 414, N-(n-octyl)-2-pyrrolidone was administered orally by gavage, once daily, to pregnant female Wistar rats from day 6 through to day 15 post coitum, at dosages of 50, 200 or 800 mg/kg bw/d in order to assess the effects on embryonic and fetal development (1991_RL1). At 800 mg/kg, one dam died after the 7th and one after the 10th test article administration. The females of this group had marked clinical signs of reaction to treatment, reduced food consumption, slight body weight loss during the first day of dosing and reduced corrected body weight gain. The mean fetal body weight was reduced at this dosage, combined with a delay of skeletal ossification. At 50 or 200 mg/kg, no effects of treatment with the test article on the maternal or fetal parameters were evident.

Based on the results of this study, the NOAEL for the maternal and fetal parameters was considered to be 200 mg/kg bw/d. The NOAEL for teratogenicity was considered to be 800 mg/kg bw/d, the highest dose tested.

In the Dose Range Finder for this study (1991_RL1) with doses of 100, 500 and 750 mg/kg bw/d the findings were consistent to the results of the key study.

In a supporting study (Ext. One-Generation Study, 2001) the NOAELs were 1000 mg/kg bw/d (m/f) for fertility and reproductive performance of the F0 parental rats, 1000 mg/kg bw/d (m) and 100 mg/kg bw/d (f) for general systemic toxicity and 300 mg/kg bw/d (m/f) for developmental toxicity (growth and development of F1 offspring until sexual maturation).

Justification for selection of Effect on developmental toxicity: via oral route:
GLP OECD guideline study.

Mode of Action Analysis / Human Relevance Framework

​No information available

Justification for classification or non-classification

There are no indications given to classify N-(n-Octyl)pyrrolidone for its toxicity to reproduction or developmental toxicity/ teratogenicity.