Registration Dossier

Administrative data

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

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Administration / exposure

Vehicle:
air

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

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.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
0.3 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

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.

Effect levels (F1)

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

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

    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).

Applicant's summary and conclusion

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.