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Key value for chemical safety assessment

Effects on fertility

Description of key information
no further studies available
Additional information

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):

Studies in Animals

"No studies have been performed to explicitly address the question of reproductive effects in animals caused by 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. However, relevant information can be found in studies on different endpoints. Histopathological results of a subacute 28-day inhalation study in rats according to OECD TG 412 (adjusted to fulfill both the TSCA § 798.2250 as well as EU Guideline 92/69/EEC) showed no effects on the reproductive organs (ovaries, oviducts and testes) at tested concentrations of up to 4.1 mg/m3. Testes and ovary weights were also not affected." The NOAEC for general toxicity is 0.24 mg/m3. For further details on general toxicity see chapter 7.5.3 (Bayer AG, 2003).

"Based on the results there are no indications for specific adverse effects on the reproductive organs following 28-day treatment with up to 4.1 mg/m3despite the fact that already at 1.05 mg/m3the substance leads to a significantly increased incidence of inflammatory as well as epithelial changes occurring in the airways of the entire respiratory tract (nasal cavity, pharynx, larynx, trachea, lungs) with typical anterior-posterior gradient in intensity." Taking into account the knowledge about the mode of action of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (local effects at sites of immediate contact clearly predominant) the lack of effect on the reproductive organs at 4.1 mg/m3and as the NOAEC for repeated dose toxicity is set at 0.24 mg/m3it seems quite unlikely that this substance might have critical effects on testis in this low dose range.

Additionally a subchronic 13 week inhalation study with Isophorone Diisocyanate has been conducted in young adult Wistar rats according to OECD Guideline 413 (Pauluhn, 2008), which showed no substance induced effects on the reproductive organs (ovaries, oviducts and testes) at tested concentrations up to 1.1 mg/m3. Additionally there were no statistically significant or conclusive dose-dependend changes in absolute or relative organ weights of the examined reproductive organs. Based on the results there are no indications for specific adverse effects on the examined reproductive organs following 13 week treatment with up to 1.1 mg/m3

For further details on general toxicity see chapter 7.5.3 of IUCLID 5 data set (Pauluhn, 2008)

The toxicological database for inhaled Isophorone Diisocyanate (IPDI) demonstrates consistently that toxicity is associated only with the portal of entry (respiratory tract), any other manifestations of toxicity are secondary to this. While no fertility study is available for IPDI, sub-chronic and subacute studies all show toxicity confined to the respiratory tract. Fertility studies with other aliphatic diisocyanates (H12MDI and HDI) show no effects on reproductive parameters, all effects are confined to the respiratory tract. Hence the databases for other aliphatic diisocyanates all show that primary toxicity for diisocyanates is to the respiratory tract, other effects, such as fetotoxicity in developmental studies, are secondary to this. This relationship applies to H12MDI and HDI when tested in fertility studies in the rat and is considered to apply equally to IPDI, i.e., if any effects were to be seen in a fertility study, these would occur only as a secondary effect of the toxicity to the respiratory system of the exposed rats. Protection against respiratory tract toxicity will protect against any secondary effects.

Using the weight of evidence, it is concluded that reproductive toxicity is not an endpoint of concern for IPDI and additional toxicity testing is not necessary.

Studies in Humans

"There are no data available."


Short description of key information:
Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"No studies have been performed to explicitly address the question of reproductive effects in animals caused by 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate." A data waiver is claimed. "Histopathological results of a subacute 28-day inhalation study in rats according to OECD TG 412 showed no effects regarding the reproductive organs in concentrations up to 4.1 mg/m3. Testes and ovary weights were also not affected." Taking into account the knowledge about the mode of action of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (local effects at sites of immediate contact clearly predominant), the lack of effect on the reproductive organs at 4.1 mg/m3, and as the NOAEC for repeated dose toxicity is set at 0.24 mg/m3 it seems quite unlikely that this substance might have critical effects on testis in this low dose range.
Additionally a subchronic 13 week inhalation study with Isophorone Diisocyanate has been conducted in young adult Wistar rats according to OECD Guideline 413, which showed no substance induced effects on the examined reproductive organs (ovaries, oviducts and testes) at tested concentrations up to 1.1 mg/m3. (see Chapter 7.5.3 of IUCLID 5 data set)

Effects on developmental toxicity

Description of key information
Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006): 
"In a nose-only inhalation study performed in accordance with OECD TG 414, 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate had no adverse effects on the development of rats up to and including a dose level of 0.929 mg/m3. A dose of 4.536 mg/m3 was maternally toxic as evidenced by effects on respiratory tract and fur as well as decreased feed intake and impaired body weight gain. All signs of developmental toxicity observed at the 4.536 mg/m3 exposure level, i.e. reduced fetal weights, delayed descensus testis, and slightly retarded ossification, were indicative of delayed fetal development and were only seen in the presence of maternal toxicity and thus considered secondary effects. There was no treatment related effect on incidence and type of fetal malformations up to and including 4.536 mg/m3." The NOAEC for both maternal toxicity and developmental toxicity was 0.929 mg/m3 (analytical).
Additional information

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):

Studies in Animals

"The developmental toxicity of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was investigated by Klaus (2004) in a vapor inhalation study conducted according to OECD TG 414 (2001). Groups of 27 female Wistar rats were exposed to 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate via nose-only inhalation, 6 hours/day on gestation days 6 to 19 at target concentrations of 0.25, 1.0 or 4.0 mg/m3(0.206, 0.929, 4.536 mg/m3analytical). The study was terminated by cesarean section on day 20. No maternal mortalities were reported. Treatment with 3‑isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate at the 4 mg/m3exposure level affected the respiratory tract and the fur of the females and comprised bradypnea, labored breathing, breathing sounds, reddish encrusted nostrils, serous nasal discharge and rough fur. Effects on water intake and excretion of urine and feces were not observed at an exposure level up to and including 4 mg/m3, while decreased feed intake (–14.7%), reduced corrected body weight (–9.2%) and impaired body weight gain (relative to initial weight: –21.7%) was evident in the 4 mg/m3exposure group as compared to control. Necropsy revealed no treatment related gross pathological findings in any group.

Intrauterine development, gestation rate, postimplantation loss, mean litter size, fetal sex distribution, and placental appearance were not affected by treatment with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate at exposure levels up to and including 4 mg/m3. Reduction of fetal weight at the 4 mg/m3exposure level was 6.8% (p < 0.01), and impairment of placental weight (–6.6%, not statistically significant but slightly below historical control data range) could not be completely excluded at this exposure level. A marginally higher number of common eye malformations in the 4 mg/m3group (1% of the fetuses and 7.7% of litters affected vs. 0.4% of fetuses and 4.2% of litters in control), well within the range of historical control data (up to 1.8% of fetuses and 20% of litters affected), was considered to be either incidental or secondary (reduced oxygen supply to offspring by maternal bradypnea). Further incidence and type of fetal malformations were unaffected by treatment. An adverse effect on incidence and type of external and visceral deviations was not evident at an exposure level up to and including 1 mg/m3, while slightly retarded descensus testis could not be completely excluded at the maternally toxic 4 mg/m3exposure level. Statistically significant fetal skeletal findings at the 4 mg/m3exposure level included retarded ossification of distal and proximal phalanges of digits and toes, of metacarpal bones, 6thsternal segment, 7thcervical vertebral body, sacral and caudal vertebral arches, and caudal vertebral bodies. All signs of developmental toxicity observed at the 4 mg/m3exposure level, i.e. reduced fetal weights, delayed descensus testis, and slightly retarded ossification, were indicative of delayed fetal development and were only seen in the presence of maternal toxicity and thus considered secondary effects." The NOAEC for both maternal toxicity and developmental toxicity was 1 mg/m3(nominal; analytical: 0.929 mg/m3) (Klaus, 2004).

Studies in Humans

"There are no data available."

Toxicity to reproduction: other studies

Additional information

no further studies available

Justification for classification or non-classification

Regarding toxicity to reproduction the substance 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is not classified according to the criteria of EC Directive 67/548/EEC.