Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Read across from Toluene diisocyanate: two generation reproduction toxicity study: similar to OECD TG 416, CD rats, inhalation, doses 0, 0.02, 0.08 and 0.3 ppm, NOAEC for reproductive toxicity 0.3 ppm for rats (corresponds to 3.5 mg/m³ for TRIDI).


Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
Please refer to Read-across statement in section 13
Vehicle:
air
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related clinical signs of toxicity in F0 males included an increased incidence of nasal discharge at 0.3 ppm. F0 females exhibited an increased incidence of red-tinged fur about the head at 0.3 ppm. Periocular encrustation, perinasal encrustation, and/or red nasal discharge were observed in all exposure groups of F0 males and females, including the control group, and appeared to be associated with the inhalation treatment conditions per se rather than exposure to the test chemical vapour.
Mortality:
mortality observed, treatment-related
Description (incidence):
Two F0 adult animals died during the conduct of this study: one female and one male. One F0 female at 0.02 ppm died of an abnormal pregnancy with uterine bleeding. The cause of death of the one F0 male at 0.3 ppm, found dead on study day 85, was not determined, although the animal had microscopic lesions of the respiratory tract similar to those of other animals in its exposure group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the 10-week prebreed exposure and 3-week mating periods of the F0 animals, male body weights were equivalent across all treatment groups. Final male body weights (week 14) were statistically increased at 0.3 ppm. Male F0 weight gains at 0.3 ppm were reduced for the first exposure week and were significantly increased for treatment weeks 4–5 and 8–9; terminal F0 male body weight gains were significantly increased at 0.02, 0.08, and 0.3 ppm. Female F0 body weights exhibited no significant differences among groups during the prebreed exposure period or during the final exposure week. F0 female weight gains exhibited a similar equivalence across treatment groups for the prebreed exposure period. During the final week of exposure (week 18–19), females at 0.3 ppm exhibited a significantly increased weight gain.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related histopathologic lesions were limited to the upper respiratory tract, with tissues located deeper in the respiratory tract being less affected. In both F0 males and females at 0.3 ppm, the most frequently observed lesions were rhinitis and alterations (dysplasia and hyperplasia) of the respiratory (nasal) epithelium in the nasal turbinates. Increased incidences of rhinitis were also observed in nasal turbinates of F0 males and females at 0.08 and 0.02 ppm, relative to the F0 control males (one) and females (none). At 0.02 ppm, three F0 males exhibited rhinitis, one minimal multifocal and two mild multifocal; three F0 females at 0.02 ppm also exhibited rhinitis, one minimal multifocal and two mild (one each focal and multifocal).
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There was no effect of treatment on reproductive organs or functions.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There was no effect of treatment on reproductive organs or functions.
Reproductive performance:
no effects observed
Description (incidence and severity):
Maternal F0 gestational and lactational body weights and weight gain were equivalent across all exposure groups. Reproductive parameters of F0 parents to produce F1 offspring were unaffected by treatment. Gestational length was unaffected by exposure to the test chemical. F1 live birth and survival indices were unaffected by treatment. F1 litter sizes, sex ratio (% males), and pup body weights and weight gains (by litter and by sex by litter) were equivalent across all treatment groups from lactational day 1 through 21. No treatment-related lesions were observed in the F1 pups, which died during the lactation period.
Dose descriptor:
NOAEL
Effect level:
0.3 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Critical effects observed:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In F1 males, there were no significant treatment- or concentration-related changes in incidence of clinical observations. Although perinasal encrustation was observed across all treatment groups in F1 females, the incidence was significantly increased at 0.3 ppm. The incidence of red-tinged fur, although occasional in TDI-exposed F1 males, was significantly increased in F1 females at 0.08 and 0.3 ppm from 17 to 22 weeks (study days 120–155) of exposure. The red-tinged fur is from chromo- dacryorrhea, red-brown material (porphyrin) secreted from the Harderian gland and distributed about the face and neck by normal grooming activity (Seely, 1987). It is a relatively non-specific indication of stress. It is likely that this stress-related finding is associated with the longer duration of females’ exposure to TDI.
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the 12-week prebreed exposure of the F1 animals randomly selected to be parents of the F2 generation, the males at 0.3 ppm exhibited reduced body weights relative to the controls for the first 4 weeks of exposure. For weekly intervals 0–1 and 1–2, as well as the final week of exposure (week 15–16), body weight gains were significantly reduced at 0.3 ppm. F1 males at 0.02 ppm exhibited significantly increased body weight gain relative to controls for weekly intervals 12–13 and 13–14 of the mating period. The F1 females exhibited reduced body weights at 0.3 ppm for the first 2 weeks of exposure, as well as week 6 of exposure. There were no significant differences among groups for F1 female weight gain.
Sexual maturation:
no effects observed
Description (incidence and severity):
Maternal F1 gestational and lactational body weight and body weight changes were unaffected for all time points measured. Gestational length was unaffected by exposure. F2 pup live birth and survival indices were unaffected by treatment. F2 litter size and sex ratio (% males) were unaffected by treatment. At 0.3 ppm, F2 pup body weight per litter exhibited reductions (males, females, and all pups) beginning on pnd 14 and persisting through day 21 for male pups. Body weights of female pups and all pups/litter were also reduced on lactation day 14 at 0.08 ppm. Pup body weight gains per litter (males, females, and all pups) were reduced at 0.08 and 0.3 ppm for pnd 4 to 7, and at 0.3 ppm pup body weight gain reductions persisted (males, females, and all pups) through pnd 14.
Gross pathological findings:
no effects observed
Description (incidence and severity):
3 F1 females were sacrificed prior to scheduled sacrifice and included one animal at 0.08 ppm on study day 94 due to traumatic injury, and one animal each at 0.3 ppm and 0.08 ppm due to early deliveries during exposure.
After delivery (F1 males) or weaning (F1 females) of the F2 litters, all surviving F1 parental animals were necropsied. No gross treatment-related lesions were observed. Selected tissues were examined histologically on 10 animals/sex from high exposure and control animals. The one target tissue, the upper respiratory tract, including nasal turbinates, larynx, and trachea, was also examined microscopically from 10 animals/sex from all groups. As with F0 parents, histologic lesions were limited to the upper respiratory tract (nasal cavities, larynx, and trachea). Although dysplasia and/or hyperplasia of the nasal respiratory epithelium were present in F1 parents at 0.08 and 0.3 ppm, the frequency of occurrence was not significantly increased relative to the control frequency. Rhinitis was observed with increased frequencies in all TDI-exposed groups of F1 males and females (with no rhinitis observed in the control animals). 7 of the 10 F1 males and 4 of the 10 F1 females examined at 0.02 ppm exhibited rhinitis; in the 7 males with rhinitis, 6 were classified as minimal multifocal and 1 as moderate multifocal; in the 4 females with rhinitis, 1 was minimal focal, 1 was mild multifocal, and 2 were moderate multifocal (Table 4). Mononuclear cell infiltration of liver tissue, although present in controls and significantly increased in F1 females at 0.3 ppm, was not deemed treatment related. No treatment-related gross lesions were observed in F2 pups that died during lactation, or in the ten/sex/group subjected to necropsy at weaning.
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
Necropsy of 10 randomly selected F1 pups/sex/group indicated no treatment-related gross findings.
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
0.02 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
clinical signs
mortality
body weight and weight gain
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Reproductive effects observed:
no

    TABLE1        
    Chamber Analyses        
   Target concentrations (ppm)     
  0.00 0.02 0.08 0.3
Analytical concentrations (ppm)a        
Paper tape method <MDLS 0.020±0.0026 0.079 ± 0.0088 0.29 ± 0.023
Corrected by modified Marcali method <MDL 0.018±0.0023 0.070 ± 0.0077 0.23 ± 0.020
A/T ratio'        
Paper tape method 1.00 0.99 0.97
Corrected by modified Marcali method 0.90 0.88 0.77
Nominal Concentrations (ppm)d 0.045 ± 0.0049 0.127 ± 0.017 0.39 ± 0.027
A/N ratioe        
Paper tape method 0.44 0.64 0.74
Corrected by modified Marcali method 0.38 0.56 0.60
2,4-Isomer/2,6-isomer ratio7 1.7:1.0 2.2:1.0 3.0:1.0
Temperature (°C)g 24.1±1.17 24.7 ± 0.99 24.2 ± 0.92 25.0 ± 1.02
Relative humidity (%)g 49.5±4.80 46.0 ± 4.18 47.6 ± 4.49 47.6 ± 5.33
aGrand mean of 230 (0.02 ppm) or 235 (0.08 and 0.3 ppm) daily means ± standard deviation.      
bLess than the minimum detection limit of 0.002 ppm.         
cAnalytical to target concentration ratio.            
dGrand mean of 229 (0.02 ppm), 234 (0.08 ppm), or 235 (0.3 ppm) daily means ± standard deviation.      
eAnalytical to nominal concentration ratio.            
fIsomer ratio of the test chemical is 4.0:1.0 (80%/20%); these data are from "grab" samples taken during the exposures (see text).   
gGrand mean of 233 (0.0 ppm), 230 (0.02 ppm) or 234 (0.08 and 0.3 ppm) daily means for temperature and relative humidity ± standard deviation.

Significant treatment-related histologic findings were limited to changes in the upper respiratory tract, including minimal to moderate rhinitis at all exposure levels in F0 and F1 adult males and females. At 0.02 ppm, there were three (of ten) F0 males, seven F1 males, three F0 females, and four F1 females; at 0.08 ppm, there were eight (of ten) F0 males, five F1 males, six F0 females, and four F1 females; at 0.30 ppm, there were nine (of ten) F0 males, nine F1 males, nine F0 females, and nine F1 females, relative to the control incidence of no F1 males and F0 and F1 females, and one F0 male, out of ten/sex/group examined in each generation.

Rhinitis is a typical response of the rodent to an irritant material, and similar effects have been reported in response to well-known irritants such as chlorine (Barrow et al., 1979), acrolein (Feronet al., 1978), sulfur dioxide (Giddens and Fairchild, 1972), and acetaldehyde (Kruysse et al., 1975). The rat is regarded as the most sensitive of the commonly used laboratory species in its response to these irritants.

Because the rhinitis is localized in the most anterior portion of the upper respiratory tract, the proximate site of contact of TDI, this finding can be viewed as an essentially localized, nonspecific response to exposure to an irritating vapour. Other histologic findings only at 0.3 ppm, specifically dysplasia and/or hyperplasia of the nasal respiratory epithelium, were indicative of more severe irritant effects of TDI.

       TABLE2              
       productive Parameters              
   F0 (TDI, ppm)          F1 (TDI, ppm)     
  0.0 0.02 0.08 0.30 0.0 0.02 0.08 0.30
No. mating pairs 28 28 28 28 28 28 28 28
Mating index" 96.4 100.0 96.4 100.0 89.3 100.0 92.9 100.0
Fecundity index" 88.9 78.6 96.3 89.3 88.0 75.0 80.8 89.3
Fertility index"-' 85.7 78.6 92.9 89.3 78.6 75.0 75.0 89.3
Gestational index" 100.0 95.5 100.0 100.0 100.0 100.0 100.0 100.0
Gestational length, days 21.9 ± 0.3c 21.9 ± 0.4 21.9 ± 0.3 22.0 ± 0.06 21.9 ± 0.3 22.0 ± 0.6 22.0 ± 0.4 22.2 ± 0.5
No. live litters, pnd0 24 21 26 25 22 21 21 25
No. live litters, pnd21 23 20 25 24 21 21 20 25
Live birth index 97.7 ± 6.31c 97.0 ± 5.96 98.2 ± 4.71 98.7 ± 3.41 97.4 ± 4.67 95.2 ± 10.21 96.8 ± 7.76 98.5 ± 4.31
Survival indices"                
4-day (pnd0—4precull) 94.6 ± 20.35c 93.8 ± 21.71 93.9 ± 19.80 94.5 ± 20.12 94.3 ± 21.30 97.3 ± 3.95 93.9 ± 21.70 97.3 ± 6.16
7-day (pnd4postcull-7) 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00 100.00 ± 0.00
14-day (pnd7-14) 100.0 ± 0.00 100.0 ± 0.00 99.5 ± 2.50 99.5 ± 2.55 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00
21-day (pnd14-21) 100.0 ± 0.00 99.4 ± 2.80 100.0 ± 0.00 99.5 ± 2.55 99.4 ± 2.73 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00
Lactation index (pnd 4-21 postcull) 100.0 ± 0.00 99.4 ± 2.80 99.5 ± 2.50 99.0 ± 3.53 99.4 ± 2.73 100.0 ± 0.00 100.0 ± 0.00 100.0 ± 0.00
Indices                
Mating index(%) = (Number of females with copulation plugs/ Number of females cohabited) *100                 
Fecundity index(%) = (Number of pregnancies / Number of plug-positive females)*100
Fertility index (female)(%) =(Number of females pregnant / Number of females cohabited)*100                 
Fertility index (male)(%) = (Number of males shown to be fertile / Total number of males mated)*100                
Gestational index(%) = (Number of females with live litters / Number of females pregnant)*100             
Live birth index(%) = (Number of live pups at birth / Total number of pups born)*100                
Survival indices(%) = (Number of live pups indicated on postnatal day / Total number of live pups on previous index day)*100 ; from 7-day through lactation index, based on postcull survivors.  
Lactation index(%) = (Number of pups surviving 21 days / Total number of live pups at 4 days(postcull))*100         
Fertility index is the same for both males and females; mating was 1:1 with no change in partners
Data are presented as mean ± SD

No reproductive parameters were affected during either generation (F1 or F2). During the breeding phases for the F0 and F1 females, there were no treatment-related changes in gestational body weights or lactational body weights. F2 (but not F1) litters exhibited reduced body weights at 0.3 ppm for lactational days 14 and 21, and at 0.08 ppm for lactational day 14 only. Lactational body weight gains were reduced in F2 (but not F1) litters at 0.08 ppm for lactational days 4–7 and at 0.3 ppm for lactational days 4–7 and 7–14. Reduced pup body weight gain per litter at 0.08 and 0.3 ppm, observed during the lactation period (only for the F2 generation), initially occurred during the interval lactational days 4–7, when removal of the dams from the nest was reinstated for exposures (beginning on lactational day 5) in all groups. Removal of the dams for more than 6 h/day reduced pups' access to their food supply (the lactating dam) and was most likely compounded by the dams’ discomfort at 0.08 and 0.3 ppm upon return to the nest after the daily exposures. The effects at 0.08 ppm were resolved during the last week of lactation. There were no effects on F1 or F2 offspring body weights or weight gains at 0.02 ppm.

TABLE 3
Offspring Litter Size, Sex Ratio, Body Weights, and Weight Gain during Lactation
   F1 offspring (TDI, ppm)          F2 offspring (TDI, ppm)     
0.0 0.02 0.08 0.30 0.0 0.02 0.08 0.30
pnd 0                
No. live litters 24 21 26 25 22 21 21 25
No. total pups/litter 13.8±2.51° 14.1 ± 2.14 13.1 ± 3.19 14.2±3.53 13.9 ± 3.35 12.8 ± 3.36 13.6±2.91 13.6±2.66
No. live pups/litter 13.5±2.30 13.6±1.94 13.0±3.34 14.0±3.49 13.5 ± 3.38 12.4 ± 3.65 13.1 ± 3.05 13.4±2.74
% males/litter 49.6±12.9 48.0±12.4 45.6 ± 14.5 50.7 ± 15.7 48.6 ± 13.3 50.8 ± 15.3 48.6 ± 20.2 46.5±12.5
pnd 1                
No. live litters 23 21 26 24 22 21 21 25
Pup body weight/litterb 7.20±0.72 7.06 ± 0.78 7.04 ± 0.75 6.73 ± 0.71 7.08 ± 1.06 7.09 ± 1.03 7.04 ± 0.70 7.10±0.75

pnd 4(precull)

               
No. live litters 23 20 25 24 21 21 20 25
No. pups/litter 13.3 ± 2.40 13.5 ± 1.96 13.0±2.94 14.3± 2.18c 13.2±3.35 12.1 ± 3.65 13.2±2.86 13.0±2.74
% males/litter 50.3 ± 13.0 47.8±12.3 45.5 ± 14.6 53.0 ± 11.9 48.8 ± 13.7 51.4±15.8 50.1 ± 20.0 46.1±12.5
Pup body weight/litter 10.19±1.00 9.71 ± 1.12 9.96 ± 1.37 9.46 ± 1.27 10.19±1.82 10.48 ± 1.88 9.93 ± 1.13 10.28 ± 1.28
Pup weight gain/litter, pnd 1-4b 2.99 ± 0.73 2.60 ± 0.80 2.92 ± 0.74 2.72 ± 0.70 3.09 ± 1.02 3.39 ± 1.07 2.89 ± 0.83 3.18 ± 0.74
pnd 7                
No. live litters 23 20 25 24 21 21 20 25
No. pups/litterd 8.0 ± 0.00 8.0 ± 0.00 7.9 ± 0.28 8.0 ± 0.00 7.8 ± 1.09 7.5 ± 1.50 7.8 ± 1.12 8.0 ± 0.20
% males/litter 50.0 ± 6.5 48.8 ± 3.8 46.2 ± 9.5 50.5 ± 4.5 50.8 ± 5.4 50.4 ± 7.7 51.9±14.2 50.3 ± 3.9
Pup body weight/litter 14.89 ± 1.25 14.42±1.56 14.91 ± 1.59 14.02 ± 1.66 15.38 ± 2.41 15.25 ± 2.13 14.23 ± 1.66 14.68 ± 1.46
Pup weight gain/litter, pnd 4-7 4.70 ± 0.60 4.71 ± 0.72 4.95 ± 0.66 4.57 ± 0.78 5.19 ± 0.92 4.77 ± 0.72 4.29±1.08** 4.39 ± 0.93*
pnd 14                
No. live litters 23 20 25 24 21 21 20 25
No. pups/litter 8.0 ± 0.00 8.0 ± 0.00 7.9 ± 0.33 8.0 ± 0.20 7.8 ± 1.09 7.5 ± 1.50 7.8 ± 1.12 8.0 ± 0.20
% males/litter 50.0 ± 0.0 48.8 ± 3.8 45.9 ± 9.5 50.7 ± 3.9 50.8 ± 5.4 50.4 ± 7.7 51.9±14.2 50.3 ± 3.9
Pup body weight/litter 28.14±2.17 27.74 ± 3.21 28.72 ± 2.42 26.71 ± 2.67 29.79 ± 3.56 29.35 ± 3.50 27.51 ± 2.24* 27.33 ± 2.13*
Pup weight gain/litter, pnd 7-14 13.25 ± 1.92 13.32±2.10 13.81 ± 1.53 12.69±1.80 14.41 ± 1.64 14.10±1.94 13.28 ± 1.25 12.66±1.42**
pnd 21                
No. live litters 23 20 25 24 21 21 20 25
No. pups/litter 8.0 ± 0.00 8.0 ± 0.00 7.9 ± 0.33 7.9 ± 0.28 7.7 ± 1.10 7.5 ± 1.50 7.8 ± 1.12 8.0 ± 0.20
% males/litter 50.0 ± 6.5 48.4 ± 4.0 45.9 ± 9.5 51.0±4.0 50.5 ± 5.69 50.4 ± 7.7 51.9±14.2 50.3 ± 3.9
Pup body weight/litter 46.17±3.87 45.74 ± 4.59 46.99 ± 3.86 44.51 ± 4.88 49.03 ± 5.79 48.97 ± 6.20 46.18 ± 3.68 45.47± 3.64e
Pup weight gain/litter, pnd 14-21 18.04 ± 2.19 18.00±1.92 18.27 ± 2.10 17.76±2.66 19.23 ± 2.88 19.62 ± 2.99 18.67 ± 1.83 18.14±1.81
aData are presented as mean ± S.D.
bPup body weight and weight gain in grams, sexes combined.
cThe mean number of pups/litter was higher on pnd 4 than on pnd 0, since one litter with seven live pups, present on pnd 0 (so n= 25) had no live pups on pnd 4 (so n = 24).
dLitters culled to eight pups on pnd 4.
ePup body weight per litter was significantly reduced (p < 0.05) for male pups only, not for female or total pups per litter.
*p< 0.05 versus control group value.
**p< 0.01 versus control group value.

Continued inhalation exposure to TDI vapour for two generations in CDt (Sprague-Dawley) rats resulted in parental toxicity at 0.02, 0.08, and 0.3 ppm, evidenced by occasional body weight and weight gain depression and clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities in both sexes and both generations at 0.02, 0.08, and 0.3 ppm. Postnatal toxicity, consisting of reduced body weights and body weight gains, occurred only in F2 litters at 0.08 and 0.3 ppm. There was no effect of treatment on reproductive organs or functions. No adult no observable adverse effect level (NOAEL) was identified, although the rhinitis observed at 0.02 ppm was considered a mild, nonspecific response to an irritant. The reproductive NOAEL was at least 0.3 ppm, and the postnatal toxicity NOAEL was 0.02 ppm in rats, under the conditions of this study.

Table 4 F0         
Incidence of Rhinitis in F0 and F1 parental animals                     
   F0(TDI, ppm)          Fl(TDI, ppm)        
  0.0 0.02 0.08 0.30 0.0 0.02 0.08 0.30
Males                        
No. examined 10 10 10 10 10 10 10 10
Rhinitis 1 3 8 9 0 7 5 9
Minimal 0 1 0 0   6 3 2
Focal   0       0 0 1
Multifocal   1       6 3 1
Diffuse   0       0 0 0
Mild 1 2 4 6   0 1 3
Focal 0 0 0 0     0 0
Multifocal 1 2 4 3     1 3
Diffuse 0 0 0 3     0 0
Moderate 0 0 4 3   1 1 4
Focal     0 0   0 0 0
Multifocal     4 2   1 1 4
Diffuse     0 1   0 0 0
Females                        
No. examined 10 10 10 10 10 10 10 10
Rhinitis 0 3 6 9 0 4 5 9
Minimal   1 2 2   1 4 5
Focal   0 0 0   1 0 0
Multifocal   1 2 2   0 4 5
Diffuse   0 0 0   0 0 0
Mild   2 3 4   1 1 3
Focal   1 0 0   0 0 0
Multifocal   1 2 4   1 1 3
Diffuse   0 1 0   0 0 0
Moderate   0 1 3   2 0 1
Focal     0 0   0   0
Multifocal     0 3   2   0
Diffuse     1 0   0   1
Note. The upper respiratory tracts, including the nose, nasal turbinates, larynx, and trachea, from ten parental animals/sex/group/generation, were examined histopathologically. The findings for rhinitis are presented by incidence, degree (minimal, mild, or moderate), and distribution (focal, multifocal, or diffuse).
Conclusions:
The study on toluene diisocyanate was performed according to the OECD Guideline 416 without deviations and according to the good laboratory practice principles, it is considered to be of high quality (reliability Klimisch 2). The criteria of validity of the test system are fulfilled. There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm.
Executive summary:

The toxicity to reproduction of toluene diisocyanate was investigated in CD rats according to OECD TG416 (Märtins, 1989). The test substance was administered to the rats via inhalation (0, 0.02, 0.08 or 0.3 ppm, 6 h/day, 5 day/week) for a total of 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapour, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
3.5 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
30
Species:
rat
Quality of whole database:
well-documented study, which meets basic scientific principles
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The toxicity to reproduction of toluene diisocyanate was investigated in CD rats according to OECD TG416 (Tyll 1999). The test substance was administered to the rats via inhalation (0, 0.02, 0.08 or 0.3 ppm, 6 h/day, 5 day/week) for a total of 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. 28 weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapour, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEC) was not determined for adult toxicity; the NOAEC for reproductive toxicity was at least 0.3 ppm (corresponds to 3.5 mg/m³ for TRIDI), and the NOAEC for postnatal toxicity was 0.02 ppm.

Effects on developmental toxicity

Description of key information

Read across from Toluene diisocyanate, according to EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen), CD rats, inhalation,  doses 0.00, 0.02, 0.10, or 0.50 ppm,  NOAEL 0.1 ppm (corresponds to 1.2 mg/m³ for TRIDI) for maternal and developmental toxicity.

Read across from monomeric MDI: developmental study of Buschmann et al., 1996 (no info on GLP) performed according to OECD 414, rats, no significant treatment related effects were observed when rats were exposed to 9 mg/m³ (0.8 ppm) monomeric MDI, (correpsonding to 3.0 mg/m³ NCO) on gestation days 6 -15. Conservatively, a no embryotoxic effect level of 3 mg/m³ was determined.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to Read-across statement in section 13
Dose descriptor:
NOAEL
Effect level:
0.1 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
0.1 ppm
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Fetal body weight per litter (males, females, or all fetuses) was unaffected by exposure.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
The number of nonviable implants per litter (total, early or late resorptions, or dead fetuses) and the percent live fetuses per litter were not significantly changed by treatment.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio (% males) per litter was unchanged by exposures.
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
There were no significant differences in the incidence of any individual malformation, of malformations by category (external, visceral, or skeletal), or of total malformations. There were no significant differences in the incidence of individual external or visceral variations, of variations by category, or of total variations.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Out of 111 skeletal variations observed in the present study, six exhibited statistically significant differences in incidence in one or more toluene diisocyanate-exposed groups relative to the incidence in the control group. Only one of these, poorly ossified cervical centrum 5, exhibited an increased incidence at 0.50 ppm relative to that in controls, indicative of possible minimal fetotoxicity. This finding was observed in the absence of any other indication of developmental toxicity. The five remaining significant findings did not indicate fetotoxicity and did not appear treatment related. They included reductions in the incidence of bilobed thoracic centra 11 and 13 and wavy rib at 0.50 ppm, and reductions in the incidence of some (1– 4) proximal phalanges of the forelimb unossified and of all proximal phalanges of the hindlimb unossified at 0.02 ppm.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no significant differences in the incidence of any individual malformation, of malformations by category (external, visceral, or skeletal), or of total malformations. There were no significant differences in the incidence of individual external or visceral variations, of variations by category, or of total variations.
Dose descriptor:
NOAEC
Effect level:
0.1 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Table 2: Chamber analysis
Exposure Parameters        
Target Concentration, ppm 0.00 0.02 0.10 0.50
Analytical Concentration, ppm a  < MDL b 0.021 ±0.0018 0.12 ± 0.017 0.48 ± 0.038
A/T Ratio c  -   1.05  1.20  0.96
 Nominal Concentration, ppm a  -  0.049 ± 0.0038  0.18 ± 0.017   0.67 ± 0.025
 A/N Ratio d  -   0.44  0.67  0.72 
 Temperature, °C a 22.6 ± 0.43 23.3 ± 0.44  23.5 ± 0.33 23.9 ± 0.19
Relative Humidity, %a  54.4 ± 0.86  50.9 ± 1.65  52.1 ± 0.98  50.1 ± 1.41
aGrand mean of daily means ± standard deviation.
bLess than the minimum detection limit of 1 ppb.
cAnalytical to target concentration ratio.
dAnalytical to nominal concentration ratio.

Table 3:  Maternal Toxicity Parameters       
   TDI vapour, ppm
0.00 0.02 0.10 0.50
No. females on study 25 25 25 25
No. females at scheduled sacrificea 25 (100.0) 25 (100.0) 25 (100.0) 25 (100.0)
No. (%) gravid 22 (88.0) 21 (84.0) 23 (92.0) 23 (92.0)
No. (%) fully resorbed litters 0 (0.0) 1 (4.8) 0 (0.0) 0 (0.0)
No. (%) dams with viable fetuses 22 (100.0) 20 (95.2) 23 (100.0) 23 (100.0)
Maternal Body Weight Changes        
Day 0 to 6 (pre-exposure period) 36.1±8.05b 33.3 ± 7.98 33.7 ± 8.43 40.1 ± 8.29
Day 6 to 9 12.3 ± 3.90 9.2±3.76* 9.4 ± 2.89* 1.8 ± 5.31***
Day 9 to 12 16.7 ± 4.35 16.9 ± 4.74 17.7 ± 4.95 11.3 ± 8.23*
Day 12 to 16 24.1 ± 4.88 20.8 ± 7.10 22.5 ± 6.03 15.8 ± 8.23*
Day 6 to 16 (exposure period) 53.1 ± 7.37 46.4 ± 11.66 49.5 ± 9.96 28.9 ± 17.59***
Day 16 to 21 (post exposure period) 89.1 ± 11.63 76.3 ± 18.67* 88.4 ± 13.23 95.3 ± 18.07
Day 0 to 21 (gestation) 178.3 ± 20.25 156.0 ± 32.02* 171.5 ± 18.42 164.4 ± 28.79
Maternal Feed Consumption (g/animal/day)        
Day 0 to 6 (pre-exposure period) 22.91± 3.434b 21.44 ± 2.909 22.37 ± 4.045 22.28 ± 2.129
Day 6 to 15 (exposure period) 23.10±2.524 22.69 ± 2.123 23.17 ± 2.481 19.62 ± 2.006***
Day 15 to 21 (post exposure period) 26.64 ± 2.537 25.22 ± 2.009 26.60 ± 2.801 25.48 ± 3.267
Maternal Water Consumption (g/animal/day)        
Day 0 to 6 (pre-exposure period) 36.45±7.331b 34.88 ± 8.247 38.71 ± 12.623 41.67 ± 11.249
Day 6 to 15 (exposure period) 43.71 ± 9.743 42.03 ± 9.802 42.77 ± 11.509 39.14±10.374
Day 15 to 21 (post exposure period) 51.71 ± 8.897 54.91 ± 15.653 51.80±11.350 52.39 ± 11.772
aNo females died, aborted, delivered early, or were removed from study.         
bData are presented as mean ± SD.            
*p < 0.05 compared to control.            
**p < 0.01 compared to control.            
***p < 0.001 compared to control.            

Table 4: Maternal Organ Weights
   TDI Vapour, ppm        
  0.00 0.02 0.10 0.50
No. Dams 22 217 23 23
 Initial body weight (g)  223.08 ± 10.89a 220.65 ± 10.58  222.30 ± 9.05  224.16 ± 7.97
Body weight at sacrifice (g)  401.43 ± 24.34  376.63 ± 34.45*   393.80 ± 20.77   388.53 ± 31.40
Gravid uterine weight (g) 106.68 ± 12.22  92.50 ± 28.19  101.31 ± 18.21   101.25 ± 22.40 
 Corrected body weight (g)b  294.74 ± 19.25  284.14 ± 16.41 292.49 ± 15.81 287.28 ± 21.82 
Corrected body weight change (g)c 71.66 ± 14.11   63.49 ± 14.55   70.20 ± 12.43 63.12 ± 17.90 
 Liver weight (g) 14.35 ± 1.58  13.34 ± 2.80  14.33 ± 1.37  13.98 ± 1.53 
 Relative liver weight (%)d 4.86 ± 0.39  4.70 ± 0.5 4.90 ± 0.39 4.87 ± 0.48
aData are presented as mean ± SD.
bCorrected body weight = body weight at sacrifice minus gravid uterine weight.
cCorrected body weight change = corrected body weight minus initial body weight.
dCalculated as a percentage of the corrected body weight.
*p < 0.05 compared to control.

Table 5: Gestational Parameters
   TDI Vapour, ppm     
  0.00 0.02 0.10 0.50
No. dams 22 21 23 23
Corpora lutea/dam 17.4±3.8a 17.6±5.6 17.1±3.6 16.3±2.8
Total implants/litter 15.3±1.8 13.0±3.8* 14.3±3.0 14.3±3.4
% preimplantation loss/litterb 10.2±14.0 18.6±19.0 14.6±18.8 12.1±19.01
Viable implants/litter 14.5±1.7 12.3±4.0* 13.5±2.8 14.0±3.5
Non-viable implants/litter 0.7±0.9 0.7±1.1 0.8±1.1 0.3±0.5
Early resorptions/litter 0.6±0.7 0.6±0.9 0.7±1.0 0.3±0.5
Late resorptions/litter 0.1±0.3 0.1±0.3 0.1±0.4 0.0±0.0
Dead fetuses/litter 0.0±0.0 0.0±0.0 0.0±0.2 0.0±0.0
% live fetuses/litter 95.4±5.4 89.1±23.6 94.6±6.7 97.1±5.7
No. litters 22 20c 23 23
Sex ratio (% male fetuses)/litter 49.8±12.6 44.4±15.6 54.6±16.1 46.2±14.1
Fetal body weights per litter (g)        
All fetuses 5.21±0.21 5.37±0.25 5.37±0.30 5.22±0.37
Male fetuses 5.32±0.23 5.51±0.37 5.51±0.36 5.37±0.39
Female fetuses 5.10±0.21 5.27±0.38 5.20±0.28 5.09±0.36
aData are presented as mean±SD.
bPercent preimplantation loss=[(corpora lutea - total implants)/corpora lutea]*100.
cThe N is reduced because one dam was found to be pregnant by ammonium sulfide staining of the uterus (i.e., a fully resorbed litter).
*p<0.05compared to control.

Table 6: Summarized Incidence and Frequency of Fetal Malformations and Variations
   TDI vapour, ppm     
0.00 0.02 0.10 0.50
Number examined externallya        
Fetuses 320 258 311 322
Litters 22 20 23 23
No significant malformation findings        
Number examined viscerally'b        
Fetuses 164 134 162 168
Litters 22 20 23 23
No significant malformation findings        
Number examined skeletallyc        
Fetuses 156 124 149 154
Litters 22 20 23 23
No significant malformation findings        
Significant variations        
Cervical centrum no. 5 poorly ossified        
No. (%) fetuses 13 (8.3) 18 (14.5) 29 (19.5) 36 (23.4)
No. (%) litters 8 (36.4) 12 (60.0) 14 (60.9) 18 (78.3)*
Wavy rib        
No. (%) fetuses 45 (28.8) 27 (21.8) 16 (10.7) 11 (7.1)
No. (%) litters 11 (50.0) 9 (45.0) 8 (34.8) 4 (17.4)*
All proximal phalanges (hindlimb) unossified        
No. (%) fetuses 61 (39.1) 23 (18.5) 57 (38.3) 58 (37.7)
No. (%) litters 19 (86.4) 9 (45.0)* 18 (78.3) 20 (87.0)
Summarized malformations        
External        
No. (%) fetuses 0 (0.0) 1 (0.4)d 0 (0.0) 0 (0.0)
No. (%) litters 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)
Visceral        
No. (%) fetuses 7 (4.3) 7 (5.2) 9 (5.6) 8 (4.8)
No. (%) litters 5 (22.7) 5 (25.0) 6(26.1) 7 (30.4)
Skeletal        
No. (%) fetuses 1 (0.7) 3 (2.4) 2(1.3) 1 (0.6)
No. (%) litters 1 (4.5) 3 (15.0) 2 (8.7) 1 (4.3)
Total malformations        
No. (%) fetuses 8 (2.5) 10 (3.9) 11 (3.5) 9 (2.8)
No. (%) litters 6 (27.3) 7 (35.0) 8 (34.8) 8 (34.8)
Summarized variations        
External        
No. (%) fetuses 16 (5.0) 10 (3.9) 9 (2.9) 12 (3.7)
No. (%) litters 13 (59.1) 7 (35.0) 7 (30.4) 10 (43.5)
Visceral        
No. (%) fetuses 106 (64.6) 93 (69.4) 99 (61.1) 86 (51.2)
No. (%) litters 20 (90.9) 20 (100.0) 22 (95.7) 22 (95.7)
Skeletal        
No. (%) fetuses 156 (100.0) 124 (100.0) 149 (100.0) 154 (100.0)
No. (%) litters 22 (100.0) 20 (100.0) 23 (100.0) 23 (100.0)
Total variations        
No. (%) fetuses 265 (82.8) 220 (85.3) 249 (80.1) 243 (75.5)
No. (%) litters 22 (100.0) 20 (100.0) 23 (100.0) 23 (100.0)
Note: A single fetus may be represented more than once in listing individual defects. Only live fetuses were examined.
aAll fetuses were examined externally.
bApproximately 50% of each litter were examined viscerally (Staples, 1974) and for soft tissue craniofacial defects (Wilson, 1965; van Julsingha and Bennett, 1977).
cApproximately 50% of each litter were examined for skeletal defects after staining with alizarin red S.
dOne fetus (in one litter) at 0.02 ppm exhibited multiple malformations and variations; all four of the external malformations observed (unilateral anophthalmia, cleft palate, unilateral microtia, parasitic twin on ventrum), and 11 of the 24 visceral malformations observed (it was not randomly selected for skeletal examination).
*p< 0.05 compared to control.
Conclusions:
The study on toluene diisocyanate was performed according to EPA OTS 789.4350 (Inhalation Developmental Toxicity Screen), it is considered to be of high quality (reliability Klimisch 2). The criteria of validity of the test system are fulfilled. There was only one possible indication of minor fetotoxicity at 0.50 ppm with no other indications of developmental toxicity.The NOAEL for maternal and developmental toxicity was 0.1 ppm in this study. No embrytoxicity or teratogenicity was observed at any exposure concentrations employed.
Executive summary:

The developmental toxicity of toluene diisocyanate was investigated in Sprague Dawley rats according to EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen) (Tyl, 1999). The test substance was administered to mated female rats via inhalation (0, 0.02, 0.1 or 0.5 ppm, 6 h/day, from gestation day 6 to 15). Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified. In addition resorptions and dead and live fetuses were recorded. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. The most plausible and appropriate interpretation of the initial, brief, minor, and transient decrements in weight gain at 0.02 and 0.10 ppm is that they were due to initial responses of the dams as they acclimated to exposure of an irritating vapour rather than to toxicity per se. There were also significant reductions at 0.02 ppm in maternal weight gain for gd 16–21 (p < 0.05; postexposure period), therefore, for gd 0–21 (p < 0.05, gestational period) and for body weight at sacrifice (p < 0.05; not observed at 0.10 or 0.50 ppm), accompanied by significant reductions in total implants per litter and in viable implants per litter (both p < 0.05) at 0.02 ppm. These effects at 0.02 ppm were due, at least partially, to the presence of a fully resorbed litter with one implant only in this group (the dam and her data were included in the summary tables because she was pregnant). When her data are deleted from the individual data and the revised data statistically compared to the control group values for gd 21 terminal body weight and viable implants per litter, the differences were still statistically significant but less so. It is unlikely that this cluster of interrelated effects is due to exposure to TDI for the following reasons: (1) none of the effects were observed at higher concentrations so it is not dose related; (2) the major effect, reduced body weight gain for gd 16–21, occurred after exposures were over (they ended on gd 15); (3) this last trimester is during the time of rapid fetal growth and weight gain, and so the reduced maternal weight gain was most likely due to the reduced number of fetuses per litter in this group (i.e., the fetuses grew normally but were fewer in number); and (4) the reduction in maternal weight gain for gd 16–21 for 0.02 ppm was enough to affect the gestational weight gain (gd 0–21) for maternal body weight on gd 21 but did not affect maternal weight gain during the exposure period (gd 6–16). The cause of the smaller litters at 0.02 ppm is most likely due to biologic variation, with the viable litter size (12.9) slightly below the current historical control values of 13.30 –16.24 live fetuses per litter. The maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm. No treatment-related embryotoxicity or teratogenicity was observed. The A/D ratio (Fabro et al., 1982), the ratio of the lowest doses resulting in adult and developmental toxicity, is at most 1.0, indicating no preferential susceptibility to the conceptus.

This study confirmed effects of TDI on the maternal respiratory tract, with concomitant reductions in maternal body weight, weight gain, and feed consumption at 0.50 ppm. There was only one indication of possible minor fetotoxicity at 0.50 ppm (increased incidence of reduced ossification in cervical centrum no. 5), with no other indications of developmental toxicity. There was no evidence of maternal or developmental toxicity at 0.02 or 0.10 ppm, and no evidence of embryotoxicity or teratogenicity at any exposure concentration evaluated. The present study has shown that exposure to toluene diisocyanate vapour by inhalation during major organogenesis in CD (Sprague-Dawley) rats results in maternal toxicity and minimal indication of fetotoxicity at 0.50 ppm. The no observable adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm in this study. No embryotoxicity or teratogenicity was observed at any exposure concentrations employed.

 

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to Read-across statement in section 13
Mass median aerodynamic diameter (MMAD):
ca.
Maternal examinations:



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data


BODY WEIGHT: Yes
- Time schedule for examinations: pc 1, 6 -15 and 20.


FOOD CONSUMPTION: Yes
- Food consumption: on days 6, 10, 15 and 20 p.c.


WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: on p.c. 20
- Organs examined: Number of corporea lutea, implantation sites, live and dead fetuses, early and late resorptions, pre- and postimplantation loss, and fetal and placental weights.
Ovaries and uterine content:
.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreased in all treated groups during exposure, with statistically significance from day 6 to 10 p.c. in the high and mid dose group and from day 10 to 15 p.c. in all treated groups. Food consumption returned to normal after exposure ceased.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative lung weights: statistically significant increased in the top dose (parameter not investigated in the low- and mid-conc groups).
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
1/26 animal of the control group and 2/25 of the high-conc group were not pregnant.
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
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Nr of copora lutea, implantation sites, pre- and post implantation loss, fetal and placental weights, gross and visceral anomalies, degree of ossification and life fetuses per dam: no statistically significant differences between the groups.
Dose level (mg/m³): 0/ 1/ 3/ 9
No of mated dams: 26/ 26/ 25/ 25
No of gravid females: 25/ 26/ 25/ 23
No of corpora lutea: 19.4 (2.6)/ 18.9 (3.6)/ 19.1 (2.3)/ 19.9 (3.2)
No of implantation sites (mean +/- SE): 17.8 (1.5)/ 17.0 (2.1)/ 17.3 (3.6)/ 16.7 (2.3)
No of live foetuses per dam (mean +/- SE): 17.0 (1.6)/ 16.0 (2.1)/ 16.1 (3.6)/ 16.7 (2.3)
No of postimplantation losses (mean +/- SE): 0.9 (0.9)/ 1.0 (1.2)/ 1.2 (1.4)/ 0.7 (0.7)
Placental weights (mean +/- SE): 0.57 (0.05)/ 0.59 (0.05)/ 0.60 (0.08)/ 0.58 (0.06)
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
3 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: not specified
Dose descriptor:
LOAEL
Remarks:
embryo/fetotoxicity
Effect level:
9 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: not specified
Abnormalities:
no effects observed
Fetal body weight changes:
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
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Slight dilatation of renal pelvis: low dose group: significantly increased number of fetuses with this anomaly (within the limits of biological variability of the strain; no dose-response relationship; not statistically different if comparison on a per litter base)
Incomplete ossification of nasal bones: in the mid conc group: decrease in the number of fetuses (within tan. Variation; no dose-response relation). Incomplete ossification of sacral vertebral centers: in the mid and high dose groups: decrease in the number of fetuses (within tan. Variation; no dose-response relation; not statistically different if comparison on a per litter base).
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
(investigated: bipartite hyoid, accessory cervical rib(s), accessory lumbar rib(s), shortened rib(s), wavy rib(s), tandard-shaped vertebral centra(e), bipartite vertebral centra(e), asymmetric sternebra(e), bipartite sternebra(e) on 221; 215; 210 and 199 fetuses). Asymmetric sternebra(e): in the high-conc group: slight and significant increase in litters with fetuses displaying this anomaly. However: the relevance of this is limited by the fact it represents a minor variation (common in the strain used) and the observed incidence is still within the limits of biological variability of the rat strain used (no further data available hereon, at least not in the publication).
Accessory lumbar rib(s): mid dose group: sign.decrease in the number of fetuses with this anomaly (within boil. variation; no dose-response relation; not statistically different if comparison on a per litter base).
Visceral malformations:
no effects observed
Remarks on result:
not measured/tested
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No significant treatment related effects were observed when rats were exposed to 9 mg/m³ (0.88 ppm) monomeric MDI, (corresponding to 3.0 mg/m³ NCO) on gestation days 6-15.
Conservatively, a no embryotoxic effect level of 3 mg/m³ was determined.
Executive summary:

In the developmental study of Buschmann et al.,1996 (no info on GLP) performed according to OECD 414 using monomeric MDI, gravid rats were exposed by whole-body inhalation to clean air (control) and to 1, 3, and 9 mg/m³ MDI, respectively. The lung weights in the high-dose group were significantly increased compared to the sham-treated control animals. Treatment did not influence any other maternal and/or foetal parameters investigated (maternal weight gain, number of corpora lutea, implantation sites, pre- and post implantation loss, fetal and placental weights, gross and visceral anomalies, degree of ossification), although a slight but significant increase in litters with fetuses displaying asymmetric sternebra(e) (within the limits of biological variability, normal variations) was observed after treatment with the highest dose of 9 mg/m³.

No significant treatment related effects were observed when rats were exposed to 9 mg/m³ (0.88 ppm) monomeric MDI, (corresponding to 3.0 mg/m³ NCO) on gestation days 6-15.

Conservatively, a no embryotoxic effect level of 3 mg/m³ was determined.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1.2 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
30
Species:
rat
Quality of whole database:
well-documented study, which meets basic scientific principles
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The developmental toxicity of toluene diisocyanate was investigated in Sprague Dawley rats according to EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen) (Tyl, 1999). The test substance was administered to mated female rats via inhalation (0, 0.02, 0.1 or 0.5 ppm, 6 h/day, from gestation day 6 to 15). Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gestation day 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified. In addition resorptions and dead and live fetuses were recorded. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. The most plausible and appropriate interpretation of the initial, brief, minor, and transient decrements in weight gain at 0.02 and 0.10 ppm is that they were due to initial responses of the dams as they acclimated to exposure of an irritating vapour rather than to toxicity per se. There were also significant reductions at 0.02 ppm in maternal weight gain for gestation day 16–21 (p < 0.05; postexposure period), therefore, for gestation day 0–21 (p < 0.05, gestational period) and for body weight at sacrifice (p < 0.05; not observed at 0.10 or 0.50 ppm), accompanied by significant reductions in total implants per litter and in viable implants per litter (both p < 0.05) at 0.02 ppm. These effects at 0.02 ppm were due, at least partially, to the presence of a fully resorbed litter with one implant only in this group (the dam and her data were included in the summary tables because she was pregnant). When her data are deleted from the individual data and the revised data statistically compared to the control group values for gd 21 terminal body weight and viable implants per litter, the differences were still statistically significant but less so. It is unlikely that this cluster of interrelated effects is due to exposure to TDI for the following reasons: (1) none of the effects were observed at higher concentrations so it is not dose related; (2) the major effect, reduced body weight gain for gd 16–21, occurred after exposures were over (they ended on gd 15); (3) this last trimester is during the time of rapid fetal growth and weight gain, and so the reduced maternal weight gain was most likely due to the reduced number of fetuses per litter in this group (i.e., the fetuses grew normally but were fewer in number); and (4) the reduction in maternal weight gain for gd 16–21 for 0.02 ppm was enough to affect the gestational weight gain (gd 0–21) for maternal body weight on gd 21 but did not affect maternal weight gain during the exposure period (gestation day 6–16). The cause of the smaller litters at 0.02 ppm is most likely due to biologic variation, with the viable litter size (12.9) slightly below the current historical control values of 13.30 –16.24 live fetuses per litter. The maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapour by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm. No treatment-related embryotoxicity or teratogenicity was observed. The A/D ratio (Fabro et al., 1982), the ratio of the lowest doses resulting in adult and developmental toxicity, is at most 1.0, indicating no preferential susceptibility to the conceptus.

This study confirmed effects of TDI on the maternal respiratory tract, with concomitant reductions in maternal body weight, weight gain, and feed consumption at 0.50 ppm. There was only one indication of possible minor fetotoxicity at 0.50 ppm (increased incidence of reduced ossification in cervical centrum no. 5), with no other indications of developmental toxicity. There was no evidence of maternal or developmental toxicity at 0.02 or 0.10 ppm, and no evidence of embryotoxicity or teratogenicity at any exposure concentration evaluated. The present study has shown that exposure to toluene diisocyanate vapour by inhalation during major organogenesis in CD (Sprague-Dawley) rats results in maternal toxicity and minimal indication of fetotoxicity at 0.50 ppm. The no observable adverse effect concentration (NOAEC) for maternal and developmental toxicity was 0.10 ppm in this study (corresponds to 1.2 mg/m³ for TRIDI). No embryotoxicity or teratogenicity was observed at any exposure concentrations employed.

Conclusion:

Minor fetotoxicity effects are considered to be secondary effects of treatment which occur only in the presence of significant maternal effects therefore TDI is not toxic to reproduction and not developmental toxicant.

In the developmental study of Buschmann et al.,1996 (no info on GLP) performed according to OECD 414 using monomeric MDI, gravid rats were exposed by whole-body inhalation to clean air (control) and to 1, 3, and 9 mg/m³ MDI, respectively. The lung weights in the high-dose group were significantly increased compared to the sham-treated control animals. Treatment did not influence any other maternal and/or foetal parameters investigated (maternal weight gain, number of corpora lutea, implantation sites, pre- and post implantation loss, fetal and placental weights, gross and visceral anomalies, degree of ossification), although a slight but significant increase in litters with fetuses displaying asymmetric sternebra(e) (within the limits of biological variability, normal variations) was observed after treatment with the highest dose of 9 mg/m³.

No significant treatment related effects were observed when rats were exposed to 9 mg/m³ (0.88 ppm) monomeric MDI, (corresponding to 3.0 mg/m³ NCO) on gestation days 6-15.

Conservatively, a no embryotoxic effect level of 3 mg/m³ was determined.

Justification for classification or non-classification

TRIDI is not expected to be a reproductive or developmental toxicant since systemic effects in maternal organism will prevail over any possible fetotoxic or developmental effects according to studies on category members (diisocyanates). The substance does not meet the criteria for classification and labelling in accordance with Regulation (EC) No 1272/2008.


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