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EC number: 248-145-0 | CAS number: 26966-75-6
- 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)
- Rationale for reliability incl. deficiencies:
- other: Guideline full report, pre-GLP.
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 979
- Report date:
- 1979
- Reference Type:
- publication
- Title:
- Teratogenesis study of o-toluenediamine in rats and rabbits
- Author:
- Becci PJ, Reagan EL, Knickerbocker MJ, Barbee SJ & Wedig JH
- Year:
- 1 983
- Bibliographic source:
- Toxicol.Appl.Pharmacol. 71: 323-9
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- no
- Remarks:
- Pre-GLP
Test material
- Reference substance name:
- 3(or 4)-methylbenzene-1,2-diamine
- EC Number:
- 248-145-0
- EC Name:
- 3(or 4)-methylbenzene-1,2-diamine
- Cas Number:
- 26966-75-6
- Molecular formula:
- C7H10N2
- IUPAC Name:
- 3(or 4)-methylbenzene-1,2-diamine
- Details on test material:
- Light brown solid crystalline.
analysis:
ortho - 97.3%
para - 0.71%
meta - 0.64%
mono - 1.28%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- All animals used in this study were sexually mature Sprague-Dawley (TAC: N (SD) FBR) rats. All were purchased from Taconic Farms, Inc.,
Germantown, NY.
All animals were individually housed in wire-mesh bottom cages in temperature controlled quarters.
Fresh tap water and ground Charles River Rat/Mouse/Hamster Formula (Agway) were available ad libitum throughout the study.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Beginning on day 6 of gestation and continuing daily through day 15 of gestation, the appropriate material was administered orally using a
plastic, disposable syringe and gavage needle to each pregnant rat. The test material was prepared fresh daily using corn oil as the vehicle at
concentrations necessary to be dosed on a 10 ml/kg basis. The positive control compound (Aspirin) was given as an aqueous suspension.
The amount of test material administered to each female was adjusted during gestation according to the most recent body weight. The dosage
regimen was as follows:
Group Minimum No. Treatment/Level
Pregnant Females
A 20 Corn Oil: 10 ml/kg/day
B 20 Aspirin: 250 mg/kg/day
C 20 Ortho-IDA: 10 mg/kg/day
D 20 Ortho-TDA: 30 mg/kg/day
E 20 Ortho-TDA: 100 mg/kg/day
F 20 Ortho-TDA: 300 mg/kg/day - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- Female rats were mated 1:l with male rats in sufficient numbers to produce at least 120 pregnant females. Observation of the vaginal sperm
plug was considered day 0 of gestation.
One male was not allowed to impregnate more than one female per treatment group. - Duration of treatment / exposure:
- day 6 through 15 of gestation
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 10, 30, 100, 300 mg/kg bw/day
Basis:
actual ingested
- Details on study design:
- On day 20 of gestation, all females were killed by a 5-10 minute exposure to chloroform vapours. The uterine contents of each female
were removed and the reproductive performance recorded. The urogenital tract of each female was examined for anatomical normality.
All females that died or were sacrificed moribund during the course of the study were weighed; the weights were recorded;
and all were subjected to a thorough uterine examination.
Examinations
- Maternal examinations:
- Body weights of females were recorded on days 0, 6, 9, 12, 15 and 20 of gestation. All animals were observed daily for changes in
general appearance and behaviour and a record maintained. - Ovaries and uterine content:
- At the time of sacrifice on day 20 (or if the animal died or was sacrificed moribund) the following observations were recorded: numbers of
corpora lutea, implantation sites, resorption sites, live and dead foetuses; sex of foetuses; and body weights of foetuses. If possible, late
resorptions were weighed ad sexed. - Fetal examinations:
- At the time of uterine examination, all foetuses were examined grossly for the presence of external congenital abnormalities.
One-half of the foetuses from each litter were placed in Boulin’s solution for detailed visceral examination employing the Wilson free-hand
slicing technique. Any foetus showing external abnormalities was selected for examination by this method.
The remaining foetuses were eviscerated, fixed in 70% isopropyl alcohol, macerated in a 2% potassium hydroxide solution, stained in
Alizarin-Red S dye, cleared in glycerine, and examined under low power magnification for skeletal anomalies and ossification variations.
Each fetus was processed, examined and stored for possible further examination in a manner retaining the identity of both dam number and
uterine position. - Statistics:
- Incidences of occurrence were expressed as percent, and comparisons between the negative control and test groups were made using either
95% confidence intervals for proportions or by computation of exact probabilities. Continuous data were analyzed using a one-way completely
random classification analysis of variance for fixed effects. Differences were deemed significant when the probability of rejecting the null
hypothesis when true was less than 0.05. The least significant difference test was then employed to determine which test group(s) differed from
the negative control. All comparisons were made using the dam or litter as the unit of observation rather than the foetus.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Reduced body weight gain at 300mg/kg/day
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 100 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- > 300 mg/kg bw/day
- Basis for effect level:
- other: teratogenicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 100 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
On day 20 of gestation, the treated females were killed and subjected to uterine examination. The reproductive performance of treated dams is summarized in Table 1. There were no significant differences in pregnancy, implantation, numbers of live foetuses, numbers of dead foetuses or numbers of resorptions per dam between any test level and the vehicle control. There were increases in the total numbers of resorption sites in the ortho-TDA groups; however, the percentage of dams affected was not increased when compared to the vehicle control. The data showed a significant reduction in foetal weight in dams treated at 300 mg/kg.
Dam body weights during gestation are summarized in Table 2. Females administered 300 mg/kg ortho-TDA exhibited significantly lower body weights on days 12, 15 and 20 of gestation when compared to the negative control. In addition these animals showed a significantly smaller weight gain through gestation. Body weights of females treated at 10, 30 or 100 mg/kg/day did not differ from the vehicle control.
Foetuses were evaluated for skeletal anomalies, and the results are summarized in Table 3. The abnormalities noted in foetuses whose dams received ortho-toluene diamine at 10, 30, 100 or 300 mg/kg/day were generally variations rather then malformations. Skeletal examinations showed a significant increase in litters with missing sternebrae, incompletely ossified vertebrae, and incomplete skull closure at the 300 mg/kg level. There was a significant increase in the percentage of litters with incomplete vertebrae at 100 mg/kg also. These findings would probably indicate a generalized retardation of maturation due to maternal toxicity rather than a frank teratogenic response.
The results of soft tissue examinations in the foetuses are summarized in Table 4. The data showed a significant increase in litters with foetuses exhibiting a hemorrhagic abdomen in the 10, 100 and 300 mg/kg groups. There was however no dose-related increase among test groups which would suggest the finding was related to mechanical damage rather than treatment with o-TDA. Other soft tissue findings did not differ significantly from the control in frequency of occurrence.
Treatment with 250 mg/kg/day of acetylsalicylic acid (aspirin) on days 6 through 15 of gestation as the positive control resulted in many noteworthy findings. Aspirin significantly increased the percentage of dams with resorption sites, reduced the number of live foetuses per dam, and reduced fetal weights (Table 1). This in turn resulted in significantly lowered dam body weights on day 20 and smaller weight gains during gestation (Table 2). Examinations of foetuses revealed several skeletal abnormalities as well as soft tissue anomalies (Tables 3 and 4).
.
Table 1. Average Litter Reproduction Data of Rats
|
Control(2) Corn oil 10 ml/kg |
Aspirin 250 mg/kg |
Ortho-Toluene Diamine |
|||
10 mg/kg |
30 mg/kg |
100 mg/kg |
300 mg/kg |
|||
No. females mated |
25 |
33 |
33 |
25 |
33 |
33 |
.. |
||||||
Pregnancies |
||||||
Total No. |
22 |
25 |
22 |
22 |
25 |
25 |
Wastage(1) |
0 |
2 |
0 |
0 |
0 |
1 |
To term (20 days) |
22 |
23 |
22 |
22 |
25 |
24 |
.. |
||||||
Implant sites |
||||||
Total No. |
235 |
235 |
241 |
223 |
276 |
269 |
Average/Dam |
10.7 |
10.2 |
11.0 |
10.1 |
11.0 |
11.2 |
.. |
||||||
Live Fetuses |
||||||
Total No. |
227 |
128 |
223 |
200 |
264 |
246 |
Average/Dam |
10.3 |
5.6* |
10.1 |
9.1 |
10.6 |
10.3 |
M/F |
116/111 |
65/63 |
121/102 |
94/106 |
131/133 |
120/126 |
Average Wt. (g) |
3.91 |
2.76* |
3.94 |
3.97 |
3.77 |
3.19* |
.. |
||||||
Resorptions |
||||||
Total No. |
8 |
106 |
18 |
23 |
12 |
22 |
Dams Affected |
6 |
20* |
5 |
6 |
8 |
8 |
Dams w/all resorbed |
0 |
6 |
1 |
1 |
0 |
0 |
.. |
||||||
Dead Fetuses |
||||||
Total No. |
0 |
1 |
0 |
0 |
0 |
1 |
Dams affected |
0 |
1 |
0 |
0 |
0 |
1 |
Dams w/all dead |
0 |
0 |
0 |
0 |
0 |
0 |
1. Dam died or aborted; data not included below.
2. All materials administered orally days 6-15 of gestation
* Significantly different from control (p less than 0.05)
.
Table 2. Dam Body Weights (g) During Gestation(1)
Day Treatment(2) |
0 |
6 |
9 |
12 |
15 |
20 |
Weight gain g |
Control |
215.3 |
236.5 |
238.1 |
249.5 |
260.5 |
321.8 |
106.5 |
Corn oil |
+/-2.5 |
+/-2.7 |
+/-3.0 |
+/-3.1 |
+/-3.7 |
+/-5.0 |
+/-3.7 |
(10 ml/kg) |
(22) |
(22) |
(22) |
(22) |
(22) |
(22) |
(22) |
.. |
.. |
.. |
.. |
.. |
.. |
.. |
.. |
Aspirin |
217.9 |
239.1 |
236.1 |
249.5 |
257.1 |
290.7* |
73.5* |
(250 mg/kg) |
+/-2.5 |
+/-3.2 |
+/-3.4 |
+/-3.7 |
+/-4.1 |
+/-6.7 |
+/-6.2 |
.. |
(23) |
(23) |
(23) |
(23) |
(23) |
(23) |
(23) |
.. |
.. |
.. |
.. |
.. |
.. |
.. |
.. |
Ortho-TDA(3) |
216.7 |
234.7 |
236.4 |
249.9 |
263.1 |
322.5 |
106.0 |
(10 mg/kg) |
+/-3.3 |
+/-3.4 |
+/-3.2 |
+/-3.1 |
+/-3.7 |
+/-5.1 |
+/-3.7 |
.. |
(22) |
(22) |
(22) |
(22) |
(22) |
(22) |
(22) |
.. |
.. |
. |
. |
. |
. |
. |
. |
Ortho-TDA |
214.8 |
237.0 |
237.1 |
249.5 |
261.2 |
317.4 |
102.6 |
(30 mg/kg) |
+/-2.6 |
+/-2.7 |
+/-2.5 |
+/2.5 |
+/-2.6 |
+/-5.5 |
+/-4.7 |
.. |
(22) |
(22) |
(22) |
(22) |
(22) |
(22) |
(22) |
.. |
. |
. |
. |
. |
. |
. |
. |
Ortho-TDA |
218.7 |
238.9 |
235.9 |
250.6 |
262.4 |
326.0 |
107.2 |
(100 mg/kg) |
+/-2.9 |
+/-2.9 |
+/-2.8 |
+/-2.7 |
+/-2.8 |
+/-3.7 |
+/-2.3 |
.. |
(25) |
(25) |
(25) |
(25) |
(25) |
(25) |
(25) |
.. |
. . |
. |
. |
. |
. |
. |
. |
Ortho-TDA |
216.6 |
237.0 |
228.7 |
233.6* |
244.5* |
305.4* |
88.8* |
(300 mg/kg) |
+/-2.6 |
+/-2.7 |
+/-3.0 |
+/-3.7 |
+/-4.7 |
+/-5.2 |
+/-5.0 |
.. |
(24) |
(24) |
(24) |
(24) |
(24) |
(24) |
(24) |
(1) All values are means +/-SEM for the number of pregnancies in ( ).
(2) All materials administered orally days 6-15 of gestation.
(3) Ortho-TDA = Ortho-toluene diamine
* Significantly different from control (p less than 0.05)
.
Table 3. Summary of Skeletal Findings in Fetuses(1)
Findings |
Corn Oil(2) 10 ml/kg |
Aspirin 250 mg/kg |
Ortho Toluene Diamine |
|||
10 mg/kg |
30 mg/kg |
100 mg/kg |
300 mg/kg |
|||
No. of fetuses examined (at term) |
120/22 |
67/17 |
117/21 |
105/21 |
134/25 |
129/24 |
... |
||||||
Sternebrae |
||||||
Incomplete ossification |
54/19 |
63/17 |
59/19 |
53/18 |
71/22 |
111/24 |
Bipartite |
1/1 |
1/1 |
- |
- |
2/1 |
1/1 |
Missing |
1/1 |
20/11* |
1/1 |
- |
3/2 |
10/8* |
.. |
||||||
Ribs |
||||||
Fused/split |
- |
6/4* |
- |
- |
- |
- |
More than 13; Rudimentary |
34/16 |
16/8* |
21/13* |
24/12 |
30/14 |
22/15 |
More than 13; Extra |
2/2 |
39/11* |
- |
2/2 |
4/2 |
2/2 |
.. |
||||||
Vertebrae |
||||||
Incomplete ossification |
22/11 |
56/17* |
24/12 |
23/13 |
40/22* |
49/20* |
.. |
||||||
Skull |
||||||
Incomplete closure |
2/2 |
8/4* |
1/1 |
- |
2/2 |
8/6* |
Missing |
- |
2/1 |
- |
- |
- |
1/1 |
.. |
||||||
Extremities |
||||||
Incomplete ossification |
- |
3/3* |
- |
- |
- |
4/2 |
.. |
||||||
Miscellaneous |
||||||
Hyoid; missing |
1/1 |
6/4* |
- |
- |
- |
- |
Hyoid; reduced |
1/1 |
8/5* |
- |
- |
1/1 |
4/3 |
(1) Numerator = number of fetuses affected; Denominator = number of litters affected.
(2) All materials administered orally days 6-15 of gestation
* Significantly different from control (p less than 0.05)
.
Table 4. Summary of Soft Tissue Abnormalities of Fetuses
Treatment(1)/Findings |
Fetuses |
Litter |
No. affected / No. observed |
||
A Corn Oil 910 ml/kg) |
||
Hemorrhagic Abdomen |
3/120 |
3/22 |
.. |
||
B Aspirin (250 mg/kg) |
||
Spina Bifida |
4/61 |
3/17* |
Encephalomeningocele |
10/61 |
5/17* |
Gastroschisis |
1/61 |
1/17 |
Hemorrhagic Abdomen |
5/61 |
3/17 |
.. |
||
C Ortho-TDA(2) (10 mg/kg) |
||
Hemorrhagic Abdomen |
8/106 |
8/21* |
One pup appears squatty |
1/106 |
1/21 |
.. |
||
D Ortho-TDA (30 mg/kg) |
||
Hemorrhagic Abdomen |
2/95 |
2/20 |
.. |
||
E Ortho-TDA (100 mg/kg) |
||
Gastroschisis |
1/120 |
1/25 |
Hemorrhagic Abdomen |
8/130 |
8/25* |
.. |
||
F Ortho-TDA (300 mg/kg) |
||
Encephalomeningocele |
1/115 |
1/24 |
Gastroschisis |
1/115 |
1/24 |
Hemorrhagic Abdomen |
14/115 |
10/24* |
Pups small |
3/115 |
2/24 |
(1) All materials administered orally days 6-15 of gestation
(2) Ortho-TDA = Ortho-toluene diamine
* Significantly different from control (p less than 0.05)
Applicant's summary and conclusion
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