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EC number: 269-929-9 | CAS number: 68391-11-7 The complex combination of polyalkylated pyridines derived from coal tar distillation or as high-boiling distillates approximately above 150°C (302°F) from the reaction of ammonia with acetaldehyde, formaldehyde or paraformaldehyde.
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Report date:
- 2016
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- CiToxLAB Hungary Ltd.
- Limit test:
- no
Test material
- Test material form:
- gas under pressure: refrigerated liquefied gas
- Details on test material:
- - Name of test material: Pyridine, alkyl derivs.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633, from SPF colony
- Age at study initiation: Young adult female rats, nulliparous and non-pregnant, at least approximately 11 weeks old
- Weight at study initiation: Will not exceed ± 20% of the mean weight at onset of treatment
- Housing: Type II and/or III polycarbonate cages
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 13 October 2015 To: 12 November 2015
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 400
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Justification for use and choice of vehicle (if other than water): Polyethylene glycol 400 was selected based on the previous experimental work
- Concentration in vehicle: 0, 10, 33.3, 100 mg/ml
- Amount of vehicle (if gavage): 3.0 ml/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of test formulations for concentration were performed according to a validated analytical method. Top, middle and bottom samples were taken from test item formulations two times during the study, during the first and last week of treatment.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1 male / 1 - 3 females
- Length of cohabitation: 2 hours/day
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Gestation day (GD) 6 to GD19
- Frequency of treatment:
- Daily on a 7 days/week basis
- Duration of test:
- GD0 to GD20
- No. of animals per sex per dose:
- 24 mated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were set based on available data including the results of a dose range finding study in the pregnant rat, with the aim of inducing toxic effects but no death or suffering at the highest dose and a NOAEL at the lowest dose.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At the onset of treatment (GD6) then at least weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Body weight of each animal will be recorded with precision of +/- 1 g at least on GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20.
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: The dams’ viscera were examined macroscopically for any structural abnormalities or pathological changes; stomach with the GI tract (oesophagus, small intestine including duodenum, ileum and jejunum with Peyer’s patches and large intestine including caecum, colon and rectum). The ovaries and uterus were removed and the pregnancy status ascertained. The uterus including the cervix were weighed and examined for early and late embryonic or foetal deaths and for the number of live foetuses. - 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
- Other: Placentas were examined macroscopically - Fetal examinations:
- - External examinations: Yes, plus an additional examination of the great arteries
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- The statistical evaluation of data was performed with the program package SPSS PC+4.0 (SPSS Hungary Kft, Budapest) or SAS 9.2 in the case of Provantis 9, by an appropriate statistical method (Bartlett, ANOVA/ANCOVA and Duncan, Kruskal-Wallis and Mann-Whitney U tests, T-test, Wilcoxon test, Chi2). The homogeneity of variance between groups was checked by Bartlett`s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA/ANCOVA) was be made. If the obtained result was significant Duncan’s Multiple Range test or Kruskal-Wallis test was used to assess the significance of inter-group differences. Significant results with inter-group comparisons will be further compared using Kruskal-Wallis, and Mann-Whitney U-tests.
Non pregnant females, females with no implantation, or ≤ 5 implantation sites, and females showing signs of abnormal pathology and/or misdosing will be excluded from statistical analysis; in-life individual data will be reported as applicable.
The limit for growth retarded foetuses was calculated from the average body weight of the vehicle control foetuses. A foetus was considered as growth retarded if the deviation from the mean control values was greater than minus two fold standard deviation of all control foetuses.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Observed effects include reduced food consumption, body weight, body weight gain, and adjusted/corrected body weight gain.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Observed were reduced foetal weights. This effect is most likely attributed to the effects upon the dams. Therefore, it does not represent a primary effect of treatment per se and is not relevant for classification.
There were no direct effects of the test item on external, visceral and/or skeletal development of foetuses in the study; slight retardation of ossification was associated with foetal body weight and maternal toxicity at the High dose group.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- act. ingr.
- Basis for effect level:
- other: embryotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- act. ingr.
- Basis for effect level:
- other: foetotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- act. ingr.
- Basis for effect level:
- other: teratogenecity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Summary of pregnancy data
|
Dose (mg/kg bw/day) |
|||
Parameters |
0 |
30 |
100 |
300 |
Number of mated females |
24 |
24 |
24 |
24 |
Number of non-pregnant females |
0 |
0 |
0 |
0 |
Number of females with ≤ 5 implantation sites |
0 | 0 | 0 | 0 |
Number of evaluated females |
24 |
24 |
24 |
24 |
Table 2: Summary of the intrauterine evaluation
Parameters |
Dose (mg/kg bw/day) |
|||
0 |
30 |
100 |
300 |
|
Number of evaluated dams |
24 |
24 |
24 |
24 |
Mean number of corpora lutea |
12.21 |
12.33 |
12.38 |
11.50 |
Mean number of implantations |
11.42 |
11.00 |
11.33 |
10.67 |
Preimplantation loss, mean |
0.79 |
1.33 |
1.04 |
0.83 |
Preimplantation loss (%), mean |
6.25 |
10.21 |
7.79 |
7.08 |
Early embryonic loss, mean |
0.38 |
0.50 |
0.54 |
0.38 |
Early embryonic loss (%), mean |
3.04 |
4.17 |
5.13 |
3.33 |
Late embryonic loss, mean |
0.25 |
0.00 |
0.33 |
0.67 |
Late embryonic loss (%), mean |
2.38 |
0.00 |
3.00 |
6.08 |
Dead foetuses, mean |
0.04 |
0.00 |
0.00 |
0.00 |
Postimplantation loss, mean |
0.67 |
0.50 |
0.88 |
1.04 |
Postimplantation loss (%), mean |
6.13 |
4.17 |
8.17 |
9.42 |
Total intrauterine mortality, mean |
1.46 |
1.83 |
1.92 |
1.88 |
Total intrauterine mortality (%), mean |
11.58 |
14.00 |
15.00 |
16.29 |
Viable foetuses, mean |
10.75 |
10.50 |
10.46 |
9.63 |
Note: No statistically significant differences were observed in these examined parameters of any test item treated groups when compared to the negative (vehicle) control.
Bodyweight (g)
No toxicologically significant changes were observed in the mean bodyweights or body weight gain values of the Low or Mid test item treated groups when compared to control. The High (300 mg/kg bw/day) dose group, had significantly lower bodyweight during the treatment period, correlating with the significantly lower bodyweight gain values during the study.
Sex: Female day(s) Relative to Start Date |
0 mg/kgbw/day |
30 mg/kgbw/day |
100 mg/kgbw/day |
300 mg/kgbw/day |
|
0 |
Mean |
209.3 |
210.0 |
210.0 |
211.1 |
6 |
Mean |
232.4 |
232.8 |
232.4 |
232.8 |
12 |
Mean |
253.1 |
252.2 |
249.3 |
234.9 |
20 |
Mean |
321.2 |
319.7 |
321.8 |
285.0 |
Gravid uterus weight and corrected body weight were also significantly lower in the High dose group (p < 0.05 .and p < 0.01, respectively)
In the High dose group (300 mg/kg bw/day), the corrected body weight gain and corrected net body weight gain (body weight gain during the treatment period adjusted for the gravid uterine weight) was lower by approx. 60 and 109%, respectively compared to the Control group; these difference were also statistically significant (p < 0.01). There were no effects in the Low or Mid dose groups.
Statistically significant lower foetus weight per litter was observed in the High dose group, and the number of foetuses with retarded body weight was also increased in this group.
No direct developmental toxicity including teratogenicity was observed at any dose level.
Table 3: Examination of viable foetuses
Parameters |
Dose (mg/kg bw/day) |
||||
0 |
30 |
100 |
300 |
|
|
Number of examined litters |
24 |
24 |
24 |
24 |
|
Viable foetuses, mean |
10.75 |
10.50 |
10.46 |
9.63 |
|
Male foetuses, mean |
4.63 |
5.54 |
5.67 |
4.46 |
|
Female foetuses, mean |
6.13 |
4.96 |
4.79 |
5.17 |
|
Total number of foetuses |
258 |
252 |
251 |
231 |
|
Total number of male foetuses |
111 |
133 |
136 |
107 |
|
Total number of female foetuses |
147 |
119 |
115 |
124 |
|
Mean foetal weight / litter (g) |
3.551 |
3.592 |
3.573 |
3.277** |
|
Number of foetuses with retarded body weight |
8 |
3 |
2 |
32** |
|
Number of affected litters (Runts) |
6 |
2 |
2 |
11 |
|
**: p< 0.01
Applicant's summary and conclusion
- Conclusions:
- Maternal toxicity was evident at 300 mg/kg bw/day. Therefore, the NOAEL for maternal toxicity is 100 mg/kg bw/day. The NOAEL/LOAEL for developmental effects was the same as that for maternal/systemic effects and is based on reduced foetal weights. The effect upon foetal weights is most likely attributed to the effects upon the dams. Therefore, it does not represent a primary effect of treatment per se and is not relevant for classification.
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