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EC number: 212-828-1 | CAS number: 872-50-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Remarks:
- within a 2-generation-study
- 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
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- limited maternal information: body weight without information on body weight gain and food consumption; limited number of animals per group, protocol different from guidelines
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- - Source: E. I. du Pont De Nemours and Company, Richmond, Virginia, USA
- Purity: 99.9%
Impurities:
- 1.5 or isomer-dimethyl-2-pyrrolidone (986 ppm)
- N-methyl-succinimide (251 ppm)
- 2-pyrrolidinone (14 ppm)
- low boiling impurities (36 ppm), high boiling impurities (40 ppm). - Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD (SD)BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding North Wilmington, MA, USA
- Age at study initiation:
- first group (P0 generation): 21 days
- second group (unexposed mates for F1 generation): 64 days
- Weight at study initiation:
- first group: 32-50 g
- second group: 165-217 g
- Fasting period before study: not specified
- Housing:
- before exposure: individually, cages made of stainless steel wiremesh
- during exposure: individually, stainless steel cages placed within 750 or 900 liter glass and stainless steel chambers
- animal positions within the chambers were rotated daily
- Diet: ad libitum except during the inhalation exposures; Purina Certified Rodent Chow No. 5002 (Ralston Purina Company, St. Louis, MO, USA)
- Water: ad libitum, except during the inhalation exposures
- Acclimation period: not specified
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (72 ± 2°F)
- Humidity (%): 40-60
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: nitrogen carried vapors and was mixed with dilution air
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: NMP pumped through inclined tube furnace heated to 195-210°C, N2 carried vapours throught the tube
- Method of holding animals in test chamber: hold in cages
- Source and rate of air: dilution air, 700 L/min
- Temperature, humidity, oxygen concentration: 18.9 - 27.7 °C (within control animal chambers: 19.2 - 28.3°C), about 50% r.h., below 21%
- Method of oxygen monitoring: Biomarine Oxygen Analyzer (Grade 1225R)
- Treatment of exhaust air: ventilation from bottom chamber through aqueous scrubbing tower
TEST ATMOSPHERE
- Brief description of analytical method used: HP 5710A GC with nitrogen/phosphorus detector
- Samples taken from breathing zone: no - Details on mating procedure:
- P0
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: 5 days
- After 5 days of unsuccessful pairing replacement of first male by another male with proven fertilit of same treatment group.
- Further matings after two unsuccessful attempts: yes,if not mated female placed with another male of same treatment group for 5 d
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal lavage referred to as day 0 of pregnancy
F1 (on day 70 PP: postpartum)
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1 (by mating with additional control animals of the opposite sex)
- Length of cohabitation: 5 days
- After 5 days of unsuccessful pairing replacement of first male by another male with proven fertilit of same treatment group.
- Further matings after two unsuccessful attempts: yes,if not mated female placed with another male of same treatment group for 5 d
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal lavage referred to as day 0 of pregnancy - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test atmosphere measured with HP 5710A GC with nitrogen/phosphorus detector.
- Duration of treatment / exposure:
- Exposure period: males: 100 d, females: 147 - 177 d
Premating exposure period (males): 85 d
Premating exposure period (females): 85 d
Duration of test: approx. 177 d - Frequency of treatment:
- 6 h/d, 7x/wk
- Details on study schedule:
- - F1 parental animals not mated until Day 77 PP after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 35 days of age. - Dose / conc.:
- 10.3 ppm (analytical)
- Remarks:
- equivalent to 41 mg/m3
- Dose / conc.:
- 50.8 ppm (analytical)
- Remarks:
- equivalent to 206 mg/m3
- Dose / conc.:
- 116.4 ppm (analytical)
- Remarks:
- equivalent to 478 mg/m3
- No. of animals per sex per dose:
- groups of 10 males and 20 females
- Control animals:
- yes, concurrent no treatment
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- P0 upon arrival and twice more before exposure
- during exposure while in the chamber and during handling
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
- druing handling (remove from chamber and return into chamber)
- P0 males: weekly for recovery animals
- mated females: Day 1-21 gestation
- dams: pathological changes
- F1 rats on Days 1, 4, 14, and 21 PP: postpartum, weekly for males until euthanization; females until mating
- Mated F1: Days 1-21 GD: gestation day and 1 and 22 PP
BODY WEIGHT: Yes
- Time schedule for examinations:
- P0 upon arrival and twice more before exposure
- P0 males weekly until euthanization; females weekly until mating and on d1 and d21 of gestation
- F1 males: Days 1, 4, 14, and 22 PP, weekly until they were euthanized
- F1 females: Days 1, 4, 14, 21 PP, weekly until mating and on Day 1 and 21 GD and on Days 1 and 22 PP
- F2: Days 1 and 2 PP - Sperm parameters (parental animals):
- Parameters examined in P/F1 male parental generations:
testis weight - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, 4/sex/litter as nearly as possible; excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, livebirths, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
no - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after breeding for the P0 generation and on Day 85 PP for the F1 generaion.
- Female animals: All surviving animals on Day 21 PP for P0 generation and on Day 2 PP for the F1 generation.
GROSS NECROPSY
- Gross changes of reproductive organs observed for F1 generation.
- Gross pathological changes observed for the pups of the P0 generation within the developmental study part (Solomon et al., 1995).
POST-MORTEM EXAMINATIONS: Yes
- Organs examined: ovarian weight - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 and 2 days of age, respectively.
- These animals were subjected to postmortem examinations as follows:
GROSS NECROPSY
- Gross necropsy consisted of reproductive organs. - Statistics:
- Fisher's exact test with Cochran-Armitage (pregnancy rate, clinical signs, maternal deaths, mating, fertility, gestation indices, litter survival)
ANOVA and Dunnett's test (gestation length, body weight data, liver weights)
Mann-Whitney U test (nidations) - Reproductive indices:
- Female / Male Mating Index (%) = (Number copulating / Number cohoused) * 100
Female[a] / Male[b] Fertility Index (%) = (Number bearing[a] litters sired[b] / Number copulating) * 100
Gestation index (%) = (Number of litters with at least on life pup / Number of litters) * 100 - Offspring viability indices:
- Viability Index (%) = (Number of pups alive Dav 4 Pre-standardization/pooling / Dav 4 Pre-standardization/pooling) * 100
Lactation Index (%) = (Number of pups alive at Weaning [Day 21 postpartum] / Number of pups alive Day 4 after litter standardization/pooling) * 100 - Clinical signs:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- - P0 rats died during the study: two in the control group and one in the 51 ppm group
- 1/2 control rats died from injuries during handling - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Food efficiency:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- - exposure-related reduction in response to sound was noted at 116 ppm
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Dose descriptor:
- NOAEC
- Effect level:
- 51 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Behaviour
- Remarks on result:
- other: equivalent to 206 mg/m3
- Dose descriptor:
- LOAEC
- Effect level:
- 116 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Behaviour: exposure-related reduction in response to sound was noted
- Remarks on result:
- other: equivalent to 478 mg/m3
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - body weight gain of the F1 offspring was reduced when both parents inhaled 116 ppm
- Food efficiency:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Histopathological findings:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 51 ppm
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: equivalent to 206 mg/m3
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 116 ppm
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: equivalent to 478 mg/m3
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Lowest effective dose / conc.:
- 51 ppm
- Treatment related:
- no
- Conclusions:
- The toxicological significance of the apparent reduced
responsiveness of top dose animals to sound is not
established, but at most it represented a slight
narcotic effect, the parental NOAEC therefore appears to be 50 ppm vapor. In the offspring, there was a slight decrease in pup body weight at the highest concentration only.
Overall, the study provides no evidence of an adverse effect on any parameters of fertility.
Thus, it is assessed that the following NOAECs were achieved:
Reproductive performance and fertility:
116 ppm (LOAEC), equal to 478 mg/m3
Parental toxicity:
50 ppm, equal to 206 mg/m3 - Executive summary:
In a two-generation reproduction study in rats 10 males and 20 females per dose level were exposed whole body to 0, 10 ppm (41 mg/m3), 51 ppm (206 mg/m3) or 116 ppm (478 mg/m3) of NMP vapour (Solomon et al., 1995). Sprague-Dawley rats were exposed for 6h/day, 7 days/week, for a minimum of 14 weeks. Two satellite groups, where either male or female animals were exposed, were tested additionally at 478 mg/m3.
Besides, a developmental study was conducted which is described in chapter Developmental toxicity / teratogenicity.
Animals were mated after 12 weeks of exposure to NMP vapours and both parents and offspring were examined for effects on reproductive organs /reproduction. The F1 generation was not exposed after weaning and the F2 generation was produced by mating with additional rats (non-experimental animals) of the opposite sex.
There were no effects observed for the reproducibility or the reproductive organs. For the developmental effects, apart from reduced body weight of the pups at the high dose, no adverse effects were observed (Solomon et al., 1995). This observation was in line with reduced body weight gain of the F1 generation whose parents were exposed to 478 mg/m3. The effects persisted till 21 days after birth. There is no clear dose response for this effect discussed because the effects were missing for the 206 mg/m3 dose group.
For maternal toxicity a NOAEC of 51 ppm (206 mg/m3) is proposed. However, as the only effect in maternal animals was the reduced sensitivity to sound in parental animals before mating, this effect is considered to be a systemic toxicity effect.
The developmental LOAEC is 116 ppm (478 mg/m3) as effects to the pup body weight in the developmental part of the study (Solomon et al., 1995) and reduced body weight gain for the F1 generation is described in the study.
Besides, in the devlopmental part of the study, no effects apart from slightly reduced pup body weight were observed.
Table 1: Delivery and litter data of the P0 and P1 generations (ECHA, Background document to the Opinion on NMP, 2014).
|
Dose (mg / m3) |
|||||
|
0 |
41 |
206 |
478 |
478 (only females exposed) |
478 (only males exposed) |
PO generation |
|
|
|
|
|
|
Natural delivery and litter data |
|
|
|
|
|
|
Male mating index (%) |
27/30 (90) |
8/10 (80) |
9/10 (90) |
18/20 (90) |
10/10 (100) |
9/10 (90) |
Male fertility index (%) |
27/27 (100) |
8/8 (100) |
8/9 (88,9) |
17/18 (94,4) |
10/10 (100) |
8/9 (88,9) |
Female mating index (%) |
56/58 (96,6) |
18/20 (90) |
18/19 (94,7) |
40/40 (100) |
20/20 (100) |
20/20 (100) |
Female fertility index (%) |
53/56 (94,6) |
16/18 (88,9) |
15/18 (83,3) |
37/40 (92,5) |
15/20 (75) |
17/20 (85) |
Gestation index (%) |
53/53 (100) |
16/16 (100) |
15/15 (100) |
37/37 (100) |
15/15 (100) |
17/17 (100) |
Mean gestation length N |
34 |
14 |
14 |
19 |
13 |
15 |
X (days) |
22,6 |
22,5 |
22,6 |
22,7 |
22,7 |
22,6 |
SE |
0,08 |
0,14 |
0,14 |
0,11 |
0,13 |
0,12 |
Mean number of offspring/litter |
|
|
|
|
|
|
-Born |
13,7 |
14,0 |
13,7 |
14,2 |
13,9 |
14,7 |
-Born alive |
13,5 |
13,9 |
13,5 |
14,1 |
13,9 |
14,6 |
-Day 4 PP preculling |
13,4 |
13,9 |
13,3 |
13,9 |
13,6 |
14,3 |
-Day 4 PP postculling |
8,0 |
7,9 |
7,9 |
8,0 |
8,0 |
7,9 |
-Day 14 PP |
8,0 |
7,9 |
7,9 |
8,0 |
8,0 |
7,9 |
-Day 21 PP |
8,0 |
7,8 |
7,9 |
8,0 |
8,0 |
7,9 |
Viability index (%) |
99,3 |
100,0 |
98,6 |
98,3 |
98,0 |
97,7 |
Lactation index (%) |
100,0 |
98,4 |
99,0 |
100,0 |
100,0 |
100,0 |
Sex ratio (% males) |
0,53 |
0,46* |
0,43 |
0,46 |
0,48 |
0,50 |
Offspring weight/litter (g) |
|
|
|
|
|
|
-Day 1 PP |
7,5 |
7,0* |
7,1 |
6,7* |
7,1 |
7,3 |
-Day 4 PP preculling |
10,8 |
10,0* |
10,3 |
9,6* |
10,1 |
10,5 |
-Day 4 PP postculling |
10,7 |
9,9* |
10,2 |
9,6* |
9,9* |
10,6 |
-Day 14 PP |
30,8 |
27,8* |
29,5 |
28,7* |
28,6* |
32,0 |
-Day 21 PP |
49,1 |
45,6* |
47,4 |
46,9* |
47,2 |
51,6* |
F1 generation |
|
|
|
|
|
|
Male mating index (%) |
20/20 (100) |
15/16 (93.8) |
15/15 (100) |
22/22 (100) |
|
|
Male fertility index (%) |
18/20 (90) |
14/15 (93,3) |
14/15 (93,3) |
19/22 (86,4) |
|
|
Female mating index (%) |
19/20 (95) |
15/16 (93,8) |
15/15 (100) |
22/22 (100) |
|
|
Female fertility index (%) |
18/19 (94,7) |
14/15 (93,3) |
14/15 (93,3) |
19/22 (86,4) |
|
|
|
Dose (mg / m3) |
|||||
|
0 |
41 |
206 |
478 |
478 (only females exposed) |
478 (only males exposed) |
Gestation index (%) |
17/18 (94,4) |
14/14 (100) |
14/14 (100) |
19/19 (100) |
|
|
Data from exposed females mated to unexposed males |
|
|
|
|
|
|
Mean number of offspring/litter |
|
|
|
|
|
|
-Born |
14,7 |
16,1 |
15,7 |
13,9 |
|
|
-Born alive |
14,7 |
15,9 |
15,7 |
13,8 |
|
|
-Day 2 PP |
14,6 |
15,9 |
15,6 |
13,8 |
|
|
Offspring weight/litter (g) |
|
|
|
|
|
|
-Day 1 PP |
6,7 |
6,5 |
6,7 |
6,9 |
|
|
-Day 2 PP |
7,5 |
7,3 |
7,5 |
7,7 |
|
|
Mean number of offspring/litter |
|
|
|
|
|
|
-Born |
13,2 |
13,6 |
14,0 |
13,7 |
|
|
-Born alive |
13,2 |
13,5 |
14,0 |
13,6 |
|
|
-Day 2 PP |
13,2 |
13,3 |
14,0 |
13,6 |
|
|
Offspring weight/litter (g) |
|
|
|
|
|
|
-Day 1 PP |
6,4 |
6,3 |
6,4 |
6,5 |
|
|
-Day 2 PP |
7,3 |
7,2 |
7,2 |
7,3 |
|
|
* significantly different from control, p ≤ 0.05
Table 2: Final body weights, testes and ovarian weights (ECHA, Background document to the Opinion on NMP, 2014).
Concentration (mg / m3) |
N |
Final body weight (g) |
Testes weight (g) |
Relative testes weight |
Mean testes weight |
||||
PO generation |
|
|
|
|
0 |
20 |
529 (10,5) |
3,47 (0,76) |
0,66 (0,016) |
41 |
5 |
547 (9,8) |
3,56 (0,251) |
0,65 (0,041) |
206 |
5 |
559 (25,4) |
3,65 (0,113) |
0,66 (0,018) |
478 |
15 |
530 (6,7) |
3,60 (0,074) |
0,68 (0,017) |
F1 generation |
|
|
|
|
0 |
20 |
439 (11,4) |
3,36 (0,094) |
0,77 (0,013) |
41 |
16 |
448 (5,8) |
3,62 (0,139) |
0,81 (0,030) |
206 |
15 |
457 (11,4) |
3,35 (0,082) |
0,74 (0,019) |
478 |
22 |
449 (7,8) |
3,42 (0,049) |
0,77 (0,015) |
Mean ovarian weight |
||||
PO generation |
|
|
|
|
0 |
56 |
369,8 (3,41) |
142 (4,08) |
38 (1,06) |
41 |
16 |
361,8 (4,77) |
131 (6,98) |
36 (1,79) |
206 |
15 |
360,9 (7,15) |
133 (7,15) |
37 (1,79) |
478* |
36 |
369,4 (4,16) |
136 (6,08) |
37 (1,71) |
Concentration (mg / m3) |
N |
Final body weight (g) |
Testes weight (g) |
Relative testes weight |
F1 generation |
|
|
|
|
0 |
17 |
315,8 (4,65) |
189 (6,39) |
60 (2,57) |
41 |
14 |
320,5 (7,40) |
218 (9,79) |
69 (2,75) |
206 |
14 |
330,2 (8,81) |
210 (8,58) |
64 (2,25) |
478 |
19 |
318,9 (6,27) |
198 (6,55) |
62 (2,33) |
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- 1-Methyl-2-pyrrolidone (NMP): reproductive and developmental toxicity study by inhalation in the rat.
- Author:
- Solomon H.M., Burgess B.A., Kennedy Jr. G.L.,, Staples R.E.
- Year:
- 1 995
- Bibliographic source:
- Drug Chem. Toxicol., 18(4), 271-293
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- not specified
- Deviations:
- yes
- Remarks:
- only one concentration tested; part of a 2-generation study
- Principles of method if other than guideline:
- segment of a reproduction 2-generation toxicity study
- GLP compliance:
- yes
Test material
- Reference substance name:
- 1-methyl-2-pyrrolidone
- EC Number:
- 212-828-1
- EC Name:
- 1-methyl-2-pyrrolidone
- Cas Number:
- 872-50-4
- Molecular formula:
- C5H9NO
- IUPAC Name:
- 1-methylpyrrolidin-2-one
- Test material form:
- liquid
- Details on test material:
- - Source: E. I. du Pont De Nemours and Company, Richmond, Virginia, USA
- Purity: 99.9%
Impurities:
- 1.5 or isomer-dimethyl-2-pyrrolidone (986 ppm)
- N-methyl-succinimide (251 ppm)
- 2-pyrrolidinone (14 ppm)
- low boiling impurities (36 ppm), high boiling impurities (40 ppm)
Constituent 1
- Specific details on test material used for the study:
- - Source: E. I. du Pont De Nemours and Company, Richmond, Virginia, USA
- Purity: 99.9%
Impurities:
- 1.5 or isomer-dimethyl-2-pyrrolidone (986 ppm)
- N-methyl-succinimide (251 ppm)
- 2-pyrrolidinone (14 ppm)
- low boiling impurities (36 ppm), high boiling impurities (40 ppm)
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD (SD)BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding North Wilmington, MA, USA
- Age at study initiation:
- first group (P0 generation): 21 days
- second group (unexposed mates for F1 generation): 64 days
- Weight at study initiation:
- first group: 32-50 g
- second group: 165-217 g
- Fasting period before study: not specified
- Housing:
- before exposure: individually, cages made of stainless steel wiremesh
- during exposure: individually, stainless steel cages placed within 750 or 900 liter glass and stainless steel chambers
- animal positions within the chambers were rotated daily
- Diet: ad libitum except during the inhalation exposures; Purina Certified Rodent Chow No. 5002 (Ralston Purina Company, St. Louis, MO, USA)
- Water: ad libitum, except during the inhalation exposures
- Acclimation period: not specified
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (72 ± 2°F)
- Humidity (%): 40-60
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: nitrogen carried vapors and was mixed with dilution air
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: NMP pumped through inclined tube furnace heated to 195-210°C, N2 carried vapours throught the tube
- Method of holding animals in test chamber: hold in cages
- Source and rate of air: dilution air, 700 L/min
- Temperature, humidity, oxygen concentration: 18.9 - 27.7 °C (within control animal chambers: 19.2 - 28.3°C), about 50% r.h., below 21%
- Method of oxygen monitoring: Biomarine Oxygen Analyzer (Grade 1225R)
- Treatment of exhaust air: ventilation from bottom chamber through aqueous scrubbing tower
TEST ATMOSPHERE
- Brief description of analytical method used: HP 5710A GC with nitrogen/phosphorus detector
- Samples taken from breathing zone: no - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test atmosphere measured with HP 5710A GC with nitrogen/phosphorus detector.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: 5 days
- After 5 days of unsuccessful pairing replacement of first male by another male with proven fertilit of same treatment group.
- Further matings after two unsuccessful attempts: yes,if not mated female placed with another male of same treatment group for 5 d
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal lavage referred to as day 0 of pregnancy - Duration of treatment / exposure:
- males: 100 days, females: 106-110 d
- Frequency of treatment:
- 6 h/d,7d/week
- Duration of test:
- minimum of 14 weeks
Doses / concentrations
- Dose / conc.:
- 116.4 ppm (analytical)
- Remarks:
- equal to 478 mg/m3
- No. of animals per sex per dose:
- 10 males and 20 females per dose level
- Control animals:
- yes, concurrent no treatment
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- P0 upon arrival and twice more before exposure
- during exposure while in the chamber and during handling
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
- druing handling (remove from chamber and return into chamber)
- P0 males: weekly for recovery animals
- mated females: d1-d21 gestation
- dams: pathological changes
BODY WEIGHT: Yes
- Time schedule for examinations:
- P0 upon arrival and twice more before exposure
- P0 males weekly until euthanization; females weekly until mating and on d1 and d21 of gestation
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: liver, uterus - 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 resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: all per litter, except for the heads fixed in Bouin's solution
- Head and eyelid examinations: Yes: all per litter; heads fixed in Bouin's solution - Statistics:
- - One way ANOVA, significant F-value resulted in Dunnett's test, nonparametric procedures resulted in Batlett's test: body weight, body weight gain, organ weight and gestational length
- Cochran-Armitage test for trend, if significant Fisher's exact followed: incidence of clinical observations
- Fisher's exact: mating, fertility, gestation indices, and for litter survival
- Jonckheere's test, two-tailed Mann-Whitney U test: Live fetuses, dead fetuses, resorptions, percent resorptions, corpora lutea, fetal weight and incidence of alterations
- test for trend and pairwise test between control and experimental groups, Cochran-Armitage and Fisher's exact test: incidence of pregnancy, clinical signs, and matemal death
- two-way ANOVA: differences among groups
SIGNIFANCE LEVEL
- alpha = 0.05 for all, except for Bartlett's test (alpha = 0.005)
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Three P0 rats died during the study; two in the control group and one in the 51 ppm group. One of the two control rats died from an injury received during handling.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- An exposure-related reduction in response to sound was noted at 116 ppm, but not at either 10 or 51 ppm.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): - no effects compared to control animals observed
Effect levels (maternal animals)
- Dose descriptor:
- NOAEC
- Effect level:
- 116 ppm
- Based on:
- test mat.
- Basis for effect level:
- behaviour (functional findings)
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - slight but statistically significant decrease in fetal body weight was observed at 116 ppm (7% = 3.37 g versus 3.62 g in controls; p<0.025).
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- - no effects compared to control animals observed
- Details on embryotoxic / teratogenic effects:
- No significant difference in the incidence of fetal malformations, variations or retarded development was observed in the exposed rats compared to the control.
An exposure-related, slight but statistically significant decrease in fetal body weight was observed at 116 ppm (7% = 3.37 g versus 3.62 g in controls; p<0.025).
Details on study results are given in table 1.
Effect levels (fetuses)
- Dose descriptor:
- LOAEC
- Effect level:
- 116 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 116 ppm (analytical)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
- Dose response relationship:
- no
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 1: Combined results of the P0 generation of the combined 2-year-generation study and the developmental toxicity study. Groups CI and EIII for use in the developmental toxicity phase of the study.
Group |
CI/II |
EI |
EII |
EIII |
EIV |
EV |
Exposure Level (ppm) |
0 |
10 |
51 |
116 |
0 |
116 |
|
0 |
10 |
51 |
116 |
116 |
0 |
Mean Number of Offspring/Litter |
|
|
|
|
|
|
Born |
13.7 |
14.0 |
13.7 |
14.2 |
13.9 |
14.7 |
Born Alive |
13.5 |
13.9 |
13.5 |
14.1 |
13.9 |
14.6 |
Day 4 PP Preculling |
13.4 |
13.9 |
13.3 |
13.9 |
13.6 |
14.3 |
Day 4 PP Postculling |
8.0 |
7.9 |
7.9 |
8.0 |
8.0 |
7.9 |
Day 14 PP |
8.0 |
7.9 |
7.9 |
8.0 |
8.0 |
7.9 |
Day 21 PP |
8.0 |
7.8 |
7.9 |
8.0 |
8.0 |
7.9 |
|
|
|
|
|
|
|
Viability Index(%) |
99.3 |
100.0 |
98.6 |
98.3 |
98.0 |
97.7 |
Lactation Index(%) |
100.0 |
98.4 |
99.0 |
100.0 |
100.0 |
100.0 |
Sex Ratio (% Males) |
0.53 |
0.46a |
0.43 |
0.46 |
0.48 |
0.50 |
Offspring Weight/ |
|
|
|
|
|
|
Day 1 PP |
7.5 |
7.0a |
7.1 |
6.7a |
7.1 |
7.3 |
Day 4 PP Preculling |
10.8 |
10.0a |
l0.3 |
9.6a |
10.1 |
10.5 |
Day 4 PP Postculling |
10.7 |
9.9a |
10.2 |
9.6a |
9.9a |
10.6 |
Day 14 PP |
30.8 |
27.8a |
29.5 |
28.7a |
28.6a |
32.0 |
Day 21 PP |
49.1 |
45.6a |
47.4 |
46.9a |
47.2 |
51.6a |
a= Significantly different from Control Group, p ≤ 0.05 C: control group; E: exposure group
|
Applicant's summary and conclusion
- Conclusions:
- The NOAEC for maternal toxicity was 116 ppm (equivalent to 478 mg/m3) with exposure exclusively in vapor form.
Based on the reduced pup body weights the investigated concentration of 116 ppm was not a NOAEC for fetotoxicity, however, in respect to the small effect, this concentration should be considered as LOAEC for developmental toxicity. - Executive summary:
As part of a reproduction toxicity study (Solomon et al., 1995), 10 male and 20 female Sprague-Dawley rats were exposed to 0 or 116 ppm (478 mg/m3) NMP vapor starting at 34 days of age for 6h/d. For the male rats, exposure continued until day 134 of age, the end of the mating period. The females were exposed to gestation day 20 (day 140 -144). Body weights of the dams were recorded on gestation day 1 and 21, and clinical signs were monitored daily before, during and after exposure. After sacrifice, dams were examined for gross pathological changes, livers were weighed, corpora lutea were counted and resorptions were determined by staining. The fetuses were sexed and subjected to external, visceral, and skeletal examinations. The indices of reproductive performance for the NMP-exposed rats did not differ significantly from those obtained for the control rats. Rats exposed to 116 ppm (478 mg/m3) had a detectable decrease in response to sound. No other signs of NMP-related toxicity were detected among the parental rats. An exposure-related slight decrease in pup weight was detected at 116 ppm. The LOAEC for developmental toxicity was therefore 116 ppm.
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