m-tolylidene diisocyanate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In an two generation reproductive toxicity study according OECD 416 under GLP conditions in rats, m-tolylidene diisocyanate showed no effects on animal fertility (Tyl, 1989).

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

2.18 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

Klimisch code 1

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a two-generation reproductive toxicity study similar to OECD Guideline 416 (Tyl, 1989), m-tolylidene diisocyanate vapour was administered to male and female Sprague-Dawley weanling rats in exposure chambers at dose levels of 0, 0.02, 0.08, 0.30 ppm.

28 animals/sex/group of the first parental generation (F0) were exposed to TDI vapour at the above concentrations for 6 hours/day, 5 days/week, for a total of 10 weeks. 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.

F1-weanlings were exposed to the same exposure concentration of TDI as their parents for 12 weeks.

Cage side observations as well as clinical observation were performed on parental animals. Furthermore the body weight was examined. Post mortem examinations included gross necropsy as well as histopathology and organ weight determination.

Postmortem examinations of the pups born alive and any pup appearing abnormal or died on the test included gross necropsy consisting 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.

F0-females exhibited no differences among groups for body weight gains. In contrast, F0-males body weight gain was reduced in the first exposure week at 0.3 ppm. However, weight gain was significantly increased at the end of the study in the 0.02, 0.08, and 0.3 ppm group. 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 histopathological lesions were limited to the upper respiratory tract with tissues located deeper in the respiratory tract being less affected.

F1-pups exhibited equivalent litter sizes and body weights per litter throughout lactation. In the first 4 postnatal days, survival was increased at 0.3 ppm. There were no treatment-related gross lesions in F1 animals observed. The incidence of rhinitis was significantly increased in all dose groups (male) or in the two higher dose groups (female, respectively). Additionally, 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 at 0.3 ppm (male). No treatment-related effects in the trachea or larynx of F1 females were observed.

The final body weight was not reduced in both genders of F1-adult animals. Treatment-related clinical signs (perinasal encrustation and red-tinged fur) were observed in F1 females but not in F1 males at 0.08 and 0.3 ppm. 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 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 bodyweight  was persisting through day 21 (7 %).

Perinatal deaths were reduced (survival was increased) at 0.02 and 0.3 ppm. There were no treatment-related gross lesions in necropsied F2 animals.

Based on the effect of the test substance on the evaluated reproduction parameters, the NOAEC is ≥ 0.3 ppm. For body weight changes and the treatment related effects on the respiratory tract, the LOEC is 0.02 ppm.

 

Effects on developmental toxicity

Description of key information

In a developmental toxicity study according to OECD 414 under GLP conditions in rats (Tyl, 1988), TDI showed no embryotoxicity or teratogenicity.

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

0.73 mg/m³

Quality of whole database:

Klimisch code 1

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a developmental inhalation toxicity study similar to OECD Guideline 414, m-tolylidene diisocyanate (TDI) was administered to 25 female Sprague-Dawley rats/dose by whole body exposure at dose levels of 0, 0.02, 0.1, and 0.5 ppm for 6 hours per day from days 6 through 15 of gestation.

Detailed clinical observations were performed and body weight was for maternal animals. Food and water consumption was measured every 3 days. A gross necropsy was performed after sacrifice on gestation day 21.Examinations of the ovary and uterine content including gravid uterine weight, number of corpora lutea, implantations, early and late resorptions were also performed. The fetal examinations included external, soft tissue, skeletal and head examinations.

No maternal mortality was observed. No significant differences in the number of pregnant/dose level, number of dams aborting, pre- and post-implantation loss, number of corpora lutea, and number of resorptions were observed. The number of total implants/litter and number of viable implants were reduced at 0.02 ppm.

Maternal weight gain was significantly depressed over the exposure period in the 0.5 ppm group. Additionally, maternal weight gain was significantly reduced early in the exposure period, gd 6 - 9, at 0.02 and 0.1 ppm. Maternal food consumption was reduced at the high dose from exposure day 9 onward. In addition, food consumption was reduced at 0.02 ppm for gd 18 - 21 due to the dam with one fully resorbed litter eating at a non-pregnant rate in this group.

The only treatment related clinical signs of toxicity were audible respiration in females at 0.5 ppm and red nasal discharge at 0.02, 0.1, and 0.5 ppm.

There were no differences in maternal gross observations at necropsy as well as no differences in gravid uterine weights, or body weight change among the groups. Hydronephrosis, a typical finding in CD- rats was observed in 2 animals at 0.1 ppm and 1 animal at 0.5 ppm.

No significant differences in litter size and weights, number of viable fetuses, or sex ratio were observed. An increased incidence of poorly ossified cervical centrum 5 at 0.5 ppm (exhibited a statistically significant increase relative to controls) indicating minimal fetotoxicity. However, this observation could be described as a common rat skeletal variation. The NOAEL for maternal and developmental toxicity is 0.1 ppm.

 

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for reproductive or developmental toxicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.