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EC number: 201-818-2 | CAS number: 88-30-2
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- Endpoint summary
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- Environmental data
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- 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
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
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- Specific investigations
- Exposure related observations in humans
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- Additional toxicological data

Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1982-10-13 to 1983-03-07
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 983
- Report date:
- 1983
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- α,α,α-trifluoro-4-nitro-m-cresol
- EC Number:
- 201-818-2
- EC Name:
- α,α,α-trifluoro-4-nitro-m-cresol
- Cas Number:
- 88-30-2
- Molecular formula:
- C7H4F3NO3
- IUPAC Name:
- α,α,α-trifluoro-4-nitro-m-cresol
- Test material form:
- solid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source of test material: Hoechst, Lamprecide FCL #1409, HRI No* 975297
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, ambient conditions
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Remarks:
- COBS
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Kingston, New York, USA facility of Charles River Breeding Laboratories, Wilmington, Massachusetts, USA
- Age at study initiation: 7 - 9 weeks
- Housing: stainless steel wire mesh cages (67 in²)
- Diet: ad libitum, Purina Certified Rodent Chow (#5002)
- Water: ad libitum, automatic watering system
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- VEHICLE
- Amount of vehicle: 5 mL/kg bw
- Lot/batch no.: 101F-0141, Sigma Chemical Company, St. Louis, Missouri, USA - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- Day 6 to day 15 of gestation
- Frequency of treatment:
- daily
- Duration of test:
- 20 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 25 other: mg/5 mL/kg bw
- Dose / conc.:
- 125 other: mg/5 mL/kg bw
- Dose / conc.:
- 250 other: mg/5 mL/kg bw
- No. of animals per sex per dose:
- 25 ♀/per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a range finding study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations were included.
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 9, 12, 15, 18, and 20
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: ovaries, 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 early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter - Statistics:
- The litter or dam was considered the experimental unit for evaluation, although data on individual fetuses with abnormalities also were considered. Differences were considered significant at p < 0.05.
Dam body weight on Day 0 and the corrected and uncorrected change in weight between Days 0 and 20 were analyzed by analysis of variance, and, when significant, treatment means were compared with control means using Dunnett's multiple comparison test. Dam body weights on Days 6 and 20, gravid uterine weight, and corrected weight on Day 20 were analyzed by covariate analysis using Day 0 body weight as the covariate. Dunnett's test was performed on means adjusted for the covariate where covariate analyses indicated significant differences.
Number of corpora lutea; number of implants; implantation efficiency; number -and percent of live, resorbed, and dead fetuses; and sex ratio were analyzed using the Kruskal-Wallis test. Where significant differences were indicated, Dunn's test was performed. Mean fetus weight was analyzed by covariate analysis using the number of live fetuses as the covariate. Dunnett's test was performed on means adjusted for the covariate where covariate analysis indicated significant differences.
The number of litters with fetal gross, visceral, and skeletal abnormalities was analyzed by contingency table techniques (Chi²). Where overall significant treatment differences were indicated, treated groups were compared with the control group using the Chi² statistic for the appropriate 2x2 tables, correcting the significance levels for the number of comparisons being made.
The percent of litters with fetal gross, visceral, and skeletal abnormalities was analyzed using the Kruskal-Wallis test. Where significant differences were indicated, Dunn's test was performed.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation following treatment (observed in all treatment groups). Reddish-brown vaginal discharge (associated with a placental sign) in one animal in the 25 mg/kg group. Flaccid body tone for one animal; pawing and rubbing of the cage bottom following treatment for one animal in the 125 mg/kg group. Yellow-stained muzzle and forepaws for two animals and pronation and lethargy following treatment for one animal in the 250 mg/kg group. In addition, one animal had a rough coat.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Two animals in the 250 mg/kg group died on Day 6 (the first day of treatment) and Day 12 of gestation, respectively.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences in mean body weights and weight changes between Days 0 and 20 of gestation
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Renal pelvic cavitation was noted in all groups, and indentations were observed in the cortex of the kidney for one animal each in the 25 mg/kg group and the 250 mg/kg group. In addition, one kidney in one animal was pitted, and a mottled kidney was reported for one animal in the 125 mg/kg group. Other necropsy observations included fused placentae for one animal and a darkened and slightly enlarged liver for one animal in the 125 mg/kg group.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects 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 - Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 125 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- mortality
- Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- mortality
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Unossified hyoids, unossified sternebrae, rudimentary ribs, and anomalies of the centra were found in control and treated groups in a nontreatmeht related pattern.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Unilateral renal pelvic cavitation (anomaly) was found in control and treated groups with the following incidence: one fetus from one litter in the control group; two fetuses from two litters each in the 25 mg/kg group and 125 mg/kg group; and five fetuses from four litters in the 250 mg/kg group. In addition, one fetus from one animal in the 250 mg/kg group had bilateral renal pelvic cavitation. Although these data are not statistically significant, they may indicate a fetotoxic response or be an expression of delayed development due to compound-related fetal stress. Dilated ureters (anomaly), associated with the renal pelvic cavitation, were noted in one fetus in the control group and two fetuses in the 250 mg/kg group. A dilated ureter not associated with renal pelvic cavitation was noted in one fetus from one animal in the 125 mg/kg group. Observations for the high-dose group only included one case each of a small (anomaly) and an absent testis (malformation).
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- visceral malformations
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1: Maternal Toxicity |
TMF mg/kg bw |
|||
|
0 |
25 |
125 |
250 |
Dams on study |
25 |
25 |
25 |
25 |
Dams examined on Day 20 |
25 |
25 |
25 |
23 |
Dams with implantations |
24 |
25 |
23 |
23 |
Percent with implantations |
96 |
100 |
92 |
100 |
|
|
|
|
|
Corpora lutea, Mean |
15 |
15 |
16 |
16 |
S.D. |
1.7 |
1.7 |
2.3 |
1-8 |
|
|
|
|
|
Implantations, Mean |
14 |
13 |
14 |
14 |
S.D. |
3.1 |
4.1 |
3.3 |
4.1 |
|
|
|
|
|
Implantation efficiency, Mean |
93.3 |
86.2 |
86.3 |
89.8 |
S.D. |
18.21 |
25.54 |
19.69 |
23.54 |
|
|
|
|
|
Litters with live fetuses |
24 |
25 |
23 |
23 |
Total live fetuses |
332 |
317 |
297 |
299 |
Live fetuses,Mean |
14 |
13 |
13 |
13 |
S.D. |
3.1 |
3.9 |
3.4 |
4.7 |
|
|
|
|
|
Percent live fetuses, Mean |
100.0 |
100.0 |
100.0 |
100.0 |
S.D. |
0.00 |
0.00 |
0.00 |
0.00 |
|
|
|
|
|
Fetal weight (g), Mean |
3.5 |
3.6 |
3.5 |
3.5 |
S.D. |
0.18 |
0.29 |
0.26 |
0.22 |
|
|
|
|
|
Sex ratio [(M/M+F) X 100], Mean |
51.9 |
54.7 |
48.7 |
46.7 |
S.D. |
16.35 |
15.06 |
lb.86 |
18.88 |
|
|
|
|
|
Litters with resorbed fetuses |
9 |
12 |
11 |
11 |
Total resorbed fetuses |
14 |
17 |
16 |
26 |
|
|
|
|
|
Resorbed fetuses, Mean |
1 |
1 |
1 |
1 |
S.D. |
0.9 |
0.9 |
0.9 |
2.5 |
|
|
|
|
|
Percent resorbed fetuses, Mean |
3.8 |
4.7 |
5.5 |
8.6 |
S.D. |
5.80 |
5.93 |
7.09 |
16.73 |
Table 2: Fetal abnormalities |
TMF mg/kg bw |
|||
|
0 |
25 |
125 |
250 |
Soft tissue: |
|
|
|
|
Renal pelvic cavitation |
1 (1) |
2 (2) |
2 (2) |
6 (5) |
Dilated ureters |
1 (1) |
1 (1) |
0 |
2 (2) |
Small testis |
0 |
0 |
0 |
1 (1) |
Absent testis |
0 |
0 |
|
1 (1) |
|
|
|
|
|
Skeletal |
|
|
|
|
Malformed scapulae |
1 (1) |
0 |
0 |
0 |
Malformed/bent forelimbs |
1 (1) |
0 |
0 |
0 |
Bent ribs |
1 (1) |
0 |
0 |
0 |
Number in brackets represent the number of litters affected
Applicant's summary and conclusion
- Conclusions:
- In this developmental toxicity study similar to OECD guideline 414 (Hazleton Laboratories, 1983), the test substance showed no developmental toxicity.
- Executive summary:
In a developmental toxicity study similar to OECD guideline 414 (Hazleton Laboratories, 1983), pregnant COBS® CD® (SD) Br rats (25/group) received the test substance by oral gavage at doses of 0 (corn oil vehicle), 25, 125, or 250 mg/kg bw/day on gestation days (GD) 6 - 15, inclusive. It was not specified whether doses were adjusted for percent active ingredient. On GD 20, all dams were sacrificed and all fetuses were examined for external malformations/variations. Approximately one-half of each litter was placed in Bouin’s fixative for subsequent visceral examination and the remainder stained for skeletal examination. All animals in the control, low-, and mid-dose groups survived until scheduled sacrifice. Two high-dose dams died during the treatment interval, one on GD 6 and the other on GD 12 and the study author stated that the deaths were treatment related. The only other clinical sign of toxicity was salivation which was observed in 0/25, 0/25, 2/25, and 22/25 (p < 0.01) animals in the 0, 25, 125, and 250 mg/kg bw/day groups, respectively. There were no significant differences in maternal body weights between the treated and control groups at any time during gestation. Food consumption was not measured. Therefore, the maternal toxicity LOAEL is 250 mg/kg bw/day based on mortality. The corresponding maternal toxicity NOAEL was 125 mg/kg bw/day. No treatment-related effects were observed for gravid uterine weights, number of fetuses/litter, pre- and postimplantation loss, numbers of corpora lutea/dam, number of implantations/dam, resorptions/dam, fetal body weights, or fetal sex ratios. No statistically significant differences in the incidence rates of any external, visceral, or skeletal malformations/variations were observed in the treated litters as compared to the controls.
Therefore, no treatment related teratogenic effects were abserved. The NOAEL for developmental toxicity is 250 mg/kg/day.
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