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EC number: 203-207-6 | CAS number: 104-49-4
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- The study was performed to a recognised guideline on an analogous material. Please refer to Section 13.2 "OTher Assessment reports" for full justification, reference "pPDI+TDI READ ACROSS JUSTIFICATION".
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
- Justification for study design:
- Guideline study.
Test material
- Reference substance name:
- m-tolylidene diisocyanate
- EC Number:
- 247-722-4
- EC Name:
- m-tolylidene diisocyanate
- Cas Number:
- 26471-62-5
- Molecular formula:
- C9H6N2O2
- IUPAC Name:
- 2,4-diisocyanato-1-methylbenzene, 2,6-diisocyanato-1-methylbenzene
- Test material form:
- not specified
- Details on test material:
- 80:20 % mixture of the 2,4- and 2,6-isomers, over 99% pure (Dow Chemical USA).
Constituent 1
- Specific details on test material used for the study:
- As above.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- As per guideline recommendations.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Kingston, NY
- Diet: ad libitum, certified ground rodent chow #5002, Ralton-Purina
- Water: ad libitum, tap water
- Acclimation period: 2 weeks
- Weight at study initiation:
(P) ♂ 200.2 - 204.7 g; ♀ 141.4 - 146.6 g;
(F1) ♂ 127.5 - 141.2 g; ♀ 111.6 - 121.0 g
- Age at study initiation: 6 weeks
ENVIRONMENTAL CONDITIONS
- Temperature: 62 - 76 °F (Room temperature)
- Humidity (%): 40 - 70
- Photoperiod: 12 hrs dark / 12 hrs light
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Male and female Sprague-Dawley weanling rats F0 (28 animals/sex/group) were exposed to TDI vapour at different concentrations, 6 hours/day, 5 days/week, for 10 weeks.
Animals were paired randomly within groups for 3 weeks to produce the F1 generation. Exposures of females continued through mating and the first 19 days of gestation and were discontinued from gestation day 20 through the fourth day postpartum. Exposures of females resumed on day 5 postpartum and continued through postnatal day 20. Exposures of F0 males were continuous from the mating period through delivery of the first F1 litters. At weaning, 28 weanlings/sex/group F1 were randomly selected to produce the F2 generation. F1 weanlings were exposed to the same TDI protocol as the F0 generation.
In addition, 10 F1 weanlings/sex/group were necropsied for gross lesions. F0 males were necropsied following delivery of the first F1 litters. F0 females were necropsied after the F1 pups were weaned.
The selected F1 weanings were exposed to the same exposure concentration of TDI as their parents for 12 weeks. After their pre-breed exposure, F1 animals were paired as described above to produce the F2 generation. Mating, gestation, lactation, necropsy of the F1 parents and selected F2 weanlings and historic examination of selected F1 adults tissues were performed as described above except that no F2 animals were selected as parents. Remaining non-selected F1 and F2 pups at weaning were euthanised and discarded after the necropsy of the selected pups.
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: TDI vapour was generated using a glass evaporator system. Rats were exposed to TDI vapours in 4320 L chambers.
- Temperature, humidity, pressure in air chamber: Temperature measurements were obtained from the inside surface of each evaporator during the exposure regimen.
- Air flow rate: 1000 L/min (for the 0.0 and 0.3 ppm chambers), or 1500 L/min (for the 0.02 and 0.08 ppm chambers)
- Air change rate: ≥ 14 / h
TEST ATMOSPHERE
- Brief description of analytical method used: Throughout the study, TDI atmosphere were monitored by placing probes in the breathing zone of the animals approximately six times per each 6 h exposure. Control chamber atmosphere was measured six times daily for the first 11 exposure days and once per day thereafter. Atmospheres were monitored by paper tape devices based upon modified Marcali method.
Two Autostep Isocyanate paper tape monitoring devices (GMD) System, Inc., Hendersonville, PA), one for 0.00, 0.02, 0.08, and one for 0.3 ppm were used to measure TDI concentrations in the exposure chamber atmospheres.
- Samples taken from breathing zone: yes - Details on mating procedure:
- - M/F ratio per cage: 1 / 1
- Proof of pregnancy: vaginal sperm and/or dropped or vaginal copulation plug
- After successful mating each pregnant female was caged: individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The 2,4- and 2,6-TDI isomer concentrations in the exposure chamber atmospheres were measured prior to the onset of the F0 exposure period and on exposure day 143. Samples were obtained and reverse-phase HPLC was used to separate and quantify the 2,4- and 2,6-TDI isomers.
- Duration of treatment / exposure:
- 10 week pre breed exposure,
3 week exposure during mating,
19 day eposure during gestation,
(dams not exposed day 20 - 24), 16 days during lactation. - Frequency of treatment:
- pre breed exposure: 6 h/day, 5 days/week
during mating: 6 h/day, 7 days/week until day 19 of gestation. Then exposed again 6 h/day, 7 days/week to day 20 postnatal. At day 21, litters weaned. Parents for second generation selected and exposed 6 h/day, 5 days/week for 12 weeks prior to mating. Exposure during mating and subsequently, as above. - Details on study schedule:
- F1 parental animals not mated until weaning [3-4] weeks after selected from the F1 litters (At weaning, 28 weanlings/sex/group F1 were randomly selected to produce the F2 generation. F1 weanlings were exposed to the same TDI protocol as the F0 generation.).
Animals were paired randomly within groups for 3 weeks to produce the F1 generation. Exposures of females continued through mating and the first 19 days of gestation and were discontinued from gestation day 20 through the fourth day postpartum. Exposures of females resumed on day 5 postpartum and continued through postnatal day 20. Exposures of F0 males were continuous from the mating period through delivery of the first F1 litters. At weaning, 28 weanlings/sex/group F1 were randomly selected to produce the F2 generation. F1 weanlings were exposed to the same TDI protocol as the F0 generation.
The selected F1 weanings were exposed to the same exposure concentration of TDI as their parents for 12 weeks. After their pre-breed exposure, F1 animals were paired as described above to produce the F2 generation.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.02 ppm (nominal)
- Remarks:
- 0.15 mg/m³
- Dose / conc.:
- 0.08 ppm (nominal)
- Remarks:
- 0.58 mg/m³
- Dose / conc.:
- 0.3 ppm (nominal)
- Remarks:
- 2.18 mg/m³
- Dose / conc.:
- 0 mg/m³ air (nominal)
- Remarks:
- 0, 0.2, 0.79, 0.29 mg/m3
Basis:
other: analytical concentration by inhalation
- No. of animals per sex per dose:
- 28 pups/sex/group
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- As per guideline.
- Positive control:
- No.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: pups pnd 0, 1, 4, 7, 14, 21
BODY WEIGHT: Yes
- Time schedule for examinations:
dams gd 0, 7, 14, 21 and pnd 1, 4, 7, 14;
pups pnd 1, 4, 7, 14, 21, 28 - Oestrous cyclicity (parental animals):
- Not detailed
- Sperm parameters (parental animals):
- Not detailed
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
Survival indices were calculated at day 0, 4, 7, and 14 after birth and at weaning.
GROSS EXAMINATION OF DEAD PUPS:
Yes, for external and internal abnormalities. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals, after the last litters in each generation were produced.
- Maternal animals: All surviving animals, after the last litter of each generation was weaned.
GROSS NECROPSY
- Gross necropsy consisted of external surfaces, all orifices, cranial cavity, carcass; external and cut surfaces of the brain and spinal cord, the thoracic, abdominal, and pelvic cavities and their viscera, and cervical tissues and organs.
HISTOPATHOLOGY / ORGAN WEIGHTS
Selected tissues from 10 F0 animals/sex/group in the high exposure and control groups were examined for histopathological lesions.
Tissues: pituitary, liver, kidneys (2), upper and lower respiratory tract (including nasal turbinates), vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate, and other tissues with gross lesions identified as being potentially treatment related.
Tissues from the upper respiratory tract from 10 animals/sex from the mid- and low-exposure groups also were examined for histopathological lesions. - Postmortem examinations (offspring):
- A gross internal examination was performed on any pup appearing abnormal or dying on test, and ten pups randomly selected for each sex from each test group of the Fl and F2 generations.
SACRIFICE
- Remaining non-selected F1 and F2 pups at weaning were euthansised and discarded after the necropsy of the selected pups.
- 10 F1 weanlings/sex/group were necropsied for gross lesions.
GROSS NECROPSY
- Gross necropsy consisted of external surfaces, all orifices, cranial cavity, carcass; external and cut surfaces of the brain and spinal cord, the thoracic, abdominal, and pelvic cavities and their viscera, and cervical tissues and organs. - Statistics:
- The unit of comparison was the male, the female or the litter. Results of the quantitative continuous variables e.g., body weights, food consumption, organ weights, etc. were intercomparted for the 3 treatment groups and one control group by use of Levene’s test for equal variances, analysis of variance (ANOVA) and t-tests. Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by the Mann-Whitney U-test for pairwise comparisons when appropriate. Frequency data such as the various indices were compared using the Fisher’s exact-test. For all statistical tests, the fiducial limit of 0.05 (two-tailed) was used as the criterion for statistical significance.
- Reproductive indices:
- The reproductive indices were calculated for F0 and F1 males and females for each breed (F0 to produced F1 litters and F1 to produce F2 litters).
a. Mating index (%) = Number of females with copulation plugs/Number of females cohabited x 100
b. Fecundity index (%) = Number of pregnancies/Number of plug-positive females x 100
c. Fertility index (female) (%) = Number of females pregnant/ Total number of females cohabitated x 100
d. Fertility index (male) (%) = Number of males shown to be fertile/Total number of males mated x 100
e. Gestational index = Number of females with live litters/Number of females pregnant
f. Live birth index = Number of live pups at birth/Total number of pups born - Offspring viability indices:
- The viability indices were calculated for F0 and F1 males and females for each breed (F0 to produced F1 litters and F1 to produce F2 litters).
a. 4-Day survival index = Number of pups surviving 4-day (pre-cull)/Total number of live pups at birth
b. 7-Day survival index = Number of pups surviving 7-days/Total number of live pups at 4-days (post-cull)
c. 14-Day survival index = Number of pups surviving 14-days/Total number of live pups at 7-days (post-cull)
d. 21-Day survival index = Number of pups surviving 21-days/Total number of live pups at 14-days (post-cull)
e. Lactation index = Number of pups surviving 21 days/ Total number of live pups at 4-days (post-cull)
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- See below
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- See below
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- 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
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- See below
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- > 0.3 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 0.02 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other:
- Remarks:
- minimal irritation to respiratory tract
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- not examined
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- 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:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Reproductive function / performance (P1)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- not examined
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- See below
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
During the 12-week prebreed exposure of F1 animals, animals from the 0.30 ppm group exhibited reduced body weights (both sexes) and weight gain (males only). The only treatment-related clinical signs were observed in F1 females and included perinasal encrustation and red-tinged fur. F2 pup body weights and weight gain per litter were reduced at 0.080 and 0.30 ppm during lactation.
Effect levels (F1)
- Key result
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 0.3 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- See below
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- not examined
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F2)
- Developmental immunotoxicity:
- not examined
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
F0:
F0 females exhibited no differences among groups for body weight gains.
In F0 males, body weight gain was reduced at 0.3 ppm only for the first exposure week, with increased body weight gains for the fifth and ninth treatment weeks also at 0.3 ppm. Terminal F0 male body weight gains were significantly increased at 0.02, 0.08 and 0.3 ppm (data not shown). Final body weights (week 14) were significantly increased at 0.3 ppm (6.5 %,Table 1). Clinical signs of toxicity (nasal discharge in males and red-tinged fur in females) were observed in the high-exposure F0 group. There were no treatment-related gross lesions observed in necropsy.
Histopathology revealed a significant increase in the incidence of rhinitis in the nasal turbinates of F0 animals (both sexes) exposed to 0.08 and 0.3 ppm and hyperplasia and dysplasia of the respiratory epithelium of F0 males at 0.3 ppm. The incidence of hyperplasia was also significantly increased in F0 females at 0.3 ppm. Treatment-related histopathologic lesions were limited to the upper respiratory tract with tissues located deeper in the respiratory tract being less affected.
F1-pups:
The F1 litters exhibited equivalent litter sizes and body weights per litter throughout lactation (data not shown). Perinatal deaths (postnatal days 0-4) were decreased (survival was increased) at 0.3 ppm (Table 2).
There were no treatment-related gross lesions in F1 animals that were necropsied.
F1 males had a significant increase in the incidence of rhinitis at all exposure concentrations; in females, this increase was apparent only at the two higher doses. In the high-exposure group (males), there was a significant increase in the incidence of submucosal lymphoid infiltrates in both the larynx and the trachea as well as a significant increase in the incidence of intracellular eosinophilic droplets. There were no treatment-related effects in the trachea or larynx of F1 females. During the 12-week prebreed exposure of F1 animals, animals from the 0.3 ppm group exhibited reduced body weights (both sexes) and weight gain (males only). The only treatment-related clinical signs were observed in F1 females and included perinasal encrustation and red-tinged fur. F2 pup body weights and weight gain per litter were reduced at 0.08 and 0.3 ppm during lactation.
F1-adult:
Males at 0.3 ppm exhibited reduced body weights and weight gain, females at 0.3 ppm also exhibited reduced body weights but not weight gain. Though final body weight were not reduced in both genders. Treatment-related clinical signs were observed in F1 females (but not in F1 males) at 0.08 and 0.3 ppm (perinasal encrustation and red-tinged fur). Histopathology revealed lesions limited to rhinitis in F1 males at all exposure levels and in F1 females at 0.08 and 0.3 ppm.
F2-pups:
F2 pup body weights and weight gain per litter were slightly reduced (< 8 %) at 0.08 and 0.3 ppm during lactation. Only in the high dose group reduced bw was persisting through day 21 (7 %)
Perinatal deaths were reduced (survival was increased) at 0.02 and 0.3 ppm, but lactational survival indices were unaffected by treatment.
There were no treatment-related gross lesions in F2 animals that were necropsied.
Table 1: Final body weights (week 14) of F0 adult males
ppm |
0 |
0.02 |
0.08 |
0.3 |
Mean +/-SD |
557.7 +/-52.75 |
584.9 +/-51.58 |
585 +/-51.26 |
596.4 +/-53.42 |
Table 2: Litter viability F1-generation on days 0 - 4 precull
ppm |
0 |
0.02 |
0.08 |
0.3 |
#dead (d 0-4) |
17 |
16 |
11 |
7 |
Applicant's summary and conclusion
- Conclusions:
- On the basis of the results observed, the test substance is not classsified as toxic for reproduction.
- Executive summary:
On the basis of the results observed, the test substance is not classsified as toxic for reproduction.
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