Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study According to ECHA Practical Guide 6 the maximum score for read across is rel. 2
Justification for type of information:
ANALOGUE APPROACH JUSTIFICATION
See document attached to this endpoint study record
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
(1992)
GLP compliance:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Portage, MI
- Age at study initiation: 7-9 wks
- Weight at study initiation: Males: 312-383 g; Females: 201-248 g
- Housing: individual
- Diet: ad libitum (except during the exposure period)
- Water: ad libitum
- Acclimation period: at least 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 40 - 60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Remarks:
air
Details on exposure:
TEST SUBSTANCE GENERATION:
HDI was generated as a vapor by passing filtered, dry air through liquid HDI in a grass bubbler. During vapor generation the bubbler containing HDl was immersed in a constant temperature water bath. The vaporized material was entrained with chamber intake air flow for mixing at the chamber head. Both bubbler temperature and air flow may have been adjusted to maintain desired chamber HDl concentrations and these parameters were monitored continuously with recordings at half-hour intervals (minimum) during each six-hour exposure period.

EXPOSURE SYSTEM:
Chambers: The chambers used in this study were Hazleton H-2000 inhalation exposure chambers which are constructed of stainless steel with clear glass windows. Each chamber has an approximate volume of two cubic meters. The chambers are equipped with stainless steel, wire mesh cage-packs. Each cage-pack is fitted with removable feed troughs and an automatic watering system. The air supplied to the chamber passes through an activated charcoal trap and a HEPA filter before being conditioned to the desired temperature and relative humidity. These chambers have been used
previously for exposure of animals to HDI.

NOMINAL CHAMBER PARAMETERS (During Exposure):
Temperature: 22 ± 2°C; Relative Humidity: 50 ± 10%; Exhaust Flow: 700 ± 100 Lpm; Static Pressure: -0.25 to -1.0 inches of water relative to atmospheric.
To the extent possible these nominal values were maintained during each exposure period. During non-exposure periods (nights) nominal values for each chamber parameter were set to be maintained as Iisted above, with the exception that the range for RH shall be relaxed to be 40 - 70%. This was to accommodate expected increases in RH due to chamber handling and animal care. The increase to 70% RH is in accordance with AALAC guidelines governing care of rats.
Details on mating procedure:
Mating was accomplished by co-housing one female with one male for up to 15 consecutive days. On each day of the mating phase all animals were exposed to HDl in the inhalation chambers. Following exposure, all animals were transferred into another animal room and co-housed overnight. On each morning following co-housing, but prior to being transferred back to the inhalation chambers, the females were evaluated for evidence of insemination by the presence of sperm in the vaginal smears or an internal vaginal plug. Following this examination all animals were returned to the inhalation chambers for exposure to HDl. Inseminated females remained in the inhalation chambers through gestation day 19 (following exposure on gestation day 19 the inseminated females were transferred to plastic cages. The corresponding male remained in the inhalation chamber through mating day 15 (males were terminated on mating days 16 and 17). The day on which insemination was observed in the vaginal smear was designated day 0 of gestation for that female. Females which did not exhibit sperm in the vaginal smear or an internal vaginal plug were sacrificed following the mating phase and underwent a gross necropsy.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber samples were collected near the animal's breathing zone using two midget impingers connected in series. Samples were collected at a frequency that ensured that the average daily value was representative of the required concentration. At a minimum, three samples (one for the control
chamber) were collected per chamber per day. An acetonitrile solution (at least 10 mL per impinger) containing N-4-nitrobenzyl-N-n-propylamine (nitro reagent) was used to trap and derivatize HDl to a UV-absorbing compound. All midget impinger samples were assayed by an established high performance liquid chromatography method.
Duration of treatment / exposure:
Exposure period: males 28 days; females 50 days
Premating exposure period: males and females 14 days

Duration of test: 54 days
Frequency of treatment:
6 hours/day, 7 days/week
Details on study schedule:
During a 4-day lactation phase the exposure to HDI was also discontinued for the dams. Deviation in the exposure regimen of the females: some of the females were exposed through gestation day 19, others were exposed through gestation day 18 only, and others were exposed through gestation day 18 and again on gestation day 20. In order to assess the impact of the deviation on the study the tissues from the respiratory tract of all females were examined microscopically. The results of these examinations did not indicate any differences between the females differentially exposed.
Remarks:
Doses / Concentrations: 0, 0.035, 0.35, and 2.1 mg/m³ (0, 0.005, 0.050, and 0.300 ppm)
Basis: target conc.
Remarks:
Doses / Concentrations: 0, 0.035, 0.37, and 2.1 mg/m³ (0, 0.005, 0.053, and 0.3 ppm)
Basis: analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
DOSE SELECTION RATIONALE:
The concentrations of HDl used in this study were based on a 21-day inhalation toxicity study, a 90day inhalation toxicity study, a chronic inhalation toxicity/oncogenicity study, and a sensory irritation study. In the 21-day study, Sprague-Dawley rats were exposed to either 0, 0.005, 0.0175,
0.15, or 0.3 ppm HDl for 5 hours/day, 5 days/week for 3 weeks. Compound-related ocular and nasal irritation were observed in animals exposed to 0.0175, 0.15, and 0.3 ppm on days of exposure only. These findings were not observed during non-exposure days. There were no compound-related effects on body weight, feed consumption, clinical chemistry, hematology, urinalysis, or gross pathology. At 0.3 ppm, liver and kidney weights were decreased in females. The major findings for both sexes were histopathologic lesions of the nasal mucosa and minor changes in the larynx and trachea. This study demonstrated that the target site following HDl exposure was the nasal cavity. In the 90-day study, Fischer 344 rats were exposed to HDl concentrations of 0, 0.01, 0.04 and 0.14 ppm for 6 hours/day, 5days/week for approximately 13 weeks. The only compound-related findings were ocular irritation and histopathologic lesions of the anterior nasal cavity. Both findings were observed at all three concentrations, therefore, a clear NOEL was not established in this study. In the chronic/oncogenicity study, Fischer 344 rats were exposed to HDl concentrations of 0, 0.005, 0.025 and 0.175 ppm for 6 hours/day, 5 days/week for up to 2 years. Animals were evaluated following both one and two years of exposure. A maximum tolerated dose was achieved at the highest concentration based on decreased body weight and slight anemia in the females, and histopathologic lesions of the nasal cavity in both sexes. The lowest concentration (0.005 ppm) was shown to be a NOEL after one year of exposure. However, after two years of exposure 0.005 ppm was considered to be a NOAEL based on the observation of reversible lesions, indicative of responses to non-specific irritation. In the sensory irritation study, female Sprague-Dawley rats were exposed using the head-only technique, to 0, 0.10, 0.21, 0.79, and 4.42 ppm Mondur HX (100% HDl) for three hours. Following exposure the animals were held for a seven-day recovery period. A concentration dependent increase in the respiratory response (sensory irritation) was observed. The severity of the response culminated in the death of two rats at the 4.42 ppm dose level. The RD50 (concentration which was estimated to produce a 50% depression in respiratory frequency) for the last hour of a three-hour exposure was 1.69 ppm. The NOEL for this study was 0.1 ppm. Based on these results, and the projected exposure of the animals for approximately six weeks during the current study, the proposed concentrations were 0, 0.005, 0.05, and 0.3 ppm HDI.
Positive control:
none
Dose descriptor:
NOAEL
Effect level:
0.035 other: mg/m³ (eq. to 0.005 ppm)
Sex:
male/female
Basis for effect level:
other: microscopic alterations in the nasal cavity
Dose descriptor:
NOEL
Remarks:
fertility
Effect level:
2.1 other: mg/m³ (eq. to 0.3 ppm)
Sex:
male/female
Basis for effect level:
other: No indications for toxicity on fertility up to the highest concentration tested (2.1 mg/m³).
Dose descriptor:
NOEL
Remarks:
pup toxicity
Generation:
F1
Effect level:
2.1 other: mg/m³ (eq. to 0.3 ppm)
Sex:
male/female
Basis for effect level:
other: no effect on pub growth/pub development were observed at any exposure level up to the highest concentration tested (2.1 mg/m³)
Key result
Reproductive effects observed:
no

Evidence of toxicity was demonstrated in the 0.300 ppm and to a lesser extent in the 0.050 ppm dose group. In the 0.300 ppm dose group a statistically significant decrease in body weight was observed in the females on day 4 of the study. No effects on body weight were observed in the females of the 0.05 or 0.005 ppm dose groups, or the males of any dose group. Also observed at the 0.300 ppm dose level, in both males and females, were microscopic alterations in the nasal cavity, primarily epithelial hyperplasia, squamous metaplasia, chronic-active inflammation, and more seriously, degeneration of the olfactory epithelium. Similar microscopic effects were also observed, albeit to a lesser extent, in the males and females of the 0.05 ppm dose level. No histopathological effects were observed in the 0.005 ppm dose level. There were no statistically significant effects on the mating, fertility, or gestation

indices. There were no effects observed on the days to insemination, gestation length, or total number of implantation sites. The NOEL for effects on

reproductive parameters was 0.300 ppm. There were no statistically significant  effects on litter size, total number of pups born, sex distribution, mean weight

of viable pups, mean number of viable pups or number of stillborn pups. No

statistically significant effects were observed on the live birth, viability,

lactation, or birth indices. The NOEL for effects on litter parameters was

0.300 ppm.

1,6-Hexamethylene diisocyanate demonstrated toxicity at vapor concentrations of 0.05 and 0.300 ppm. No effects were observed in the 0.005 ppm group, and no effects on hematology, clinical chemistry, reproduction (including neonatal development), or neurologic parameters were observed with any concentration. Therefore, the no-observed-effect-level (NOEL) for hematology, clinical chemistry, reproduction, and neurotoxicity for this study was 0.300 ppm and the overall NOEL was 0.005 ppm.

Executive summary:

In a combined reproductive/developmental/neurotoxicity study according to OECD TG 422 with 1,6-hexamethylene diisocyanate (HDI, CAS 822 -06 -0) rats were whole-body exposed to vapour concentrations of 0, 0.005, 0.053, or 0.3 ppm (0.035, 0.37, or 2.1 mg/m³) for 6 hours/day during a 14-day premating phase, up to a 14-day mating phase, and a 21-day gestation phase. Following the gestation phase the dams were transferred to nesting cages and permitted to deliver. The dams and their litters were maintained for a 4-day lactation phase during which exposure to HDI was discontinued. HDI demonstrated toxicity at vapour concentrations of 0.053 and 0.3 ppm resulting in microscopic alterations in the nasal cavity (primarily epithelial hyperplasia, squamous metaplasia, chronic-active inflammation, and more seriously, degeneration of the olfactory epithelium). No effects were observed in the 0.005 ppm group, and no effects on hematology, clinical chemistry, or neurologic parameters were observed with any concentration. There were no statistically significant effects on the mating, fertility, or gestation indices. There were no effects observed on the days to insemination, gestation length, or total number of implantation sites. 

There were no statistically significant effects on litter size, total number of pups born, sex distribution, mean weight of viable pups, mean number of viable pups or number of stillborn pups. No statistically significant effects were observed on the live birth, viability, lactation, or birth indices.

Therefore, the no-observed-effect-level (NOEL) for reproduction (including neonatal development) as well as for hematology, clinical chemistry, and neurotoxicity was 0.3 ppm (2.1 mg/m³) and the overall NOAEL was 0.005 ppm (0.035 mg/m³).

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No study on reproductive toxicity is available for the substance. Instead, read across is applied to the structural similar 1,6- diisocyanatohexane (HDI, CAS 822 -06 -0). The read across is justified in a separate document attached to the dossier.

For HDI a combined reproductive/developmental/neurotoxicity study according to OECD TG 422 is available. In that study rats were whole-body exposed to HDI vapour concentrations of 0, 0.005, 0.053, and 0.3 ppm (eq. to 0, 0.035, 0.37, and 2.1 mg/m³) for 6 hours/day during a 14-day premating phase, up to a 14-day mating phase, and a 21-day gestation phase. Following the gestation phase the dams were transferred to nesting cages and permitted to deliver. The dams and their litters were maintained for a 4-day lactation phase during which exposure to HDI was discontinued.

HDI demonstrated toxicity at vapour concentrations of 0.053 and 0.3 ppm resulting in microscopic alterations in the nasal cavity (primarily epithelial hyperplasia, squamous metaplasia, chronic-active inflammation, and more seriously, degeneration of the olfactory epithelium). No effects were observed in the 0.005 ppm group, and no effects on hematology, clinical chemistry, or neurologic parameters were observed at any concentration. There were no statistically significant effects on the mating, fertility, or gestation indices. There were no effects observed on the days to insemination, gestation length, or total number of implantation sites. There were no statistically significant effects on litter size, total number of pups born, sex distribution, mean weight of viable pups, mean number of viable pups or number of stillborn pups. No statistically significant effects were observed on the live birth, viability, lactation, or birth indices.

Therefore, the NOEL for reproduction (including neonatal development) as well as for hematology, clinical chemistry, and neurotoxicity was 0.3 ppm (2.1 mg/m³) and the overall NOAEL was 0.005 ppm (0.035 mg/m³).

Moreover, histopathological examinations of reproductive tissues in repeated dose rodent-studies are of high value and high sensitivity for the evaluation of reproductive toxicity, as confirmed by literature (BAuA Forschungsbericht 984, 2003, ISBN: 3-89701-967-1; Mangelsdorf et al., Reg. Tox. Pharm. 37, 356-369, 2003; Ulbrich & Palmer, J Am. College of Toxicology 14, 293-327, 1995; Janer et al., Reproductive Toxicology 24, 103-113, 2007; Dent, Regulatory Toxicology and Pharmacology 48, 241-258, 2007; Sanbuissho et al., J Tox. Sci. 34, 2009, Special Issue SP1-SP22). Histopathological changes on the reproductive organs in repeated dose studies are indicative of effects on fertility, whereas the absence of such effects gives evidence that a substance does not influence fertility. With this respect repeated dose toxicity studies should be considered as sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered. This is especially true for substances with a portal of entry irritant mode of action with lack of systemic toxicity. For PDI and HDI none of the repeated dose studies reveal effects on any of the reproductive organs examined. Moreover, no extrapulmonary findings and no indications for systemic toxicity at all were observed in the repeated dose studies of PDI and HDI.

Therefore, the conclusion can be drawn that the data uniformly show that inhalation toxicity for HDI and also for PDI is limited to the port-of-entry; no other toxic effect occurs in reproductive toxicity studies. Since the port of entry effect is a local effect, and is therefore independent of the basal metabolic rate, it should be noted that this conclusion is valid independent of animal species. Taking into account the principle mode of action and the entire available database of repeated dose toxicity and reproductive toxicity no potential for reproductive toxicity/fertility after inhalation exposure can be concluded for PDI and HDI.

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study According to ECHA Practical Guide 6 the maximum score for read across is rel. 2
Justification for type of information:
ANALOGUE APPROACH JUSTIFICATION
See document attached to this endpoint study record
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(1981)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Labs, Raleigh, NC
- Age at study initiation: 12-15 wks
- Weight at study initiation: Females: 237-325 g
- Housing: individual
- Diet: ad libitum (except during the exposure period)
- Water: ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 30 - 70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Remarks:
air
Details on exposure:
TEST SUBSTANCE GENERATION:
HDI was generated as a vapor by passing filtered, dry air through liquid HDI in a grass bubbler. During vapor generation the bubbler containing HDl was immersed in a constant temperature water bath. The vaporized material was entrained with chamber intake air flow for mixing at the chamber head. Both bubbler temperature and air flow may have been adjusted to maintain desired chamber HDl concentrations and these parameters were monitored continuously with recordings at half-hour intervals (minimum) during each six-hour exposure period.

EXPOSURE SYSTEM:
Chambers: The chambers used in this study were Hazleton H-2000 inhalation exposure chambers which are constructed of stainless steel with clear glass windows. Each chamber has an approximate volume of two cubic meters. The chambers are equipped with stainless steel, wire mesh cage-packs. Each cage-pack is fitted with removable feed troughs and an automatic watering system. The air supplied to the chamber passes through an activated charcoal trap and a HEPA filter before being conditioned to the desired temperature and relative humidity. These chambers have been used
previously for exposure of animals to HDI.

NOMINAL CHAMBER PARAMETERS (During Exposure):
Temperature: 22 ± 2°C; Relative Humidity: 50 ± 10%; Exhaust Flow: 650 ± 50 Lpm; Static Pressure: -0.25 to -1.0 inches of water relative to atmospheric.
To the extent possible these nominal values were maintained during each exposure period. During non-exposure periods (nights) nominal values for each chamber parameter were set to be maintained as Iisted above, with the exception that the range for RH shall be relaxed to be 40 - 70%. This was to accommodate expected increases in RH due to chamber handling and animal care. The increase to 70% RH is in accordance with AALAC guidelines governing care of rats.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber samples were collected near the animal's breathing zone using two midget impingers connected in series. Samples were collected at a frequency that ensured that the average daily value was representative of the required concentration. At a minimum, three samples (one for the control
chamber) were collected per chamber per day. An acetonitrile solution (at least 10 mL per impinger) containing N-4-nitrobenzyl-N-n-propylamine (nitro reagent) was used to trap and derivatize HDl to a UV-absorbing compound. All midget impinger samples were assayed by an established high performance liquid chromatography method. The homogeneous distribution of HDI within the inhalation chambers has been confirmed in previous studies, under the conditions utilized in the present study.
Details on mating procedure:
Rats were co-housed with a maximum of two females per male. Following cohabitation, morning vaginal smears were taken and examined for the presence of sperm. Females found to be sperm-positive were randomized into groups and the sire number was documented. The day on which sperm was observed in the vaginal smear was designated day 0 of gestation for that female.
Duration of treatment / exposure:
days 0 - 19 of gestation
Frequency of treatment:
once daily for 6 hours
Duration of test:
cesarean section and sacrifice at day 20 of gestation
No. of animals per sex per dose:
30 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
DOSE SELECTION RATIONALE:
The concentrations of HDl used in this study were based on a 21-day inhalation toxicity study, a 90day inhalation toxicity study, a chronic inhalation toxicity/oncogenicity study, and a sensory irritation study. In the 21-day study, Sprague-Dawley rats were exposed to either 0, 0.005, 0.0175,
0.15, or 0.3 ppm HDl for 5 hours/day, 5 days/week for 3 weeks. Compound-related ocular and nasal irritation were observed in animals exposed to 0.0175, 0.15, and 0.3 ppm on days of exposure only. These findings were not observed during non-exposure days. There were no compound-related effects on body weight, feed consumption, clinical chemistry, hematology, urinalysis, or gross pathology. At 0.3 ppm, liver and kidney weights were decreased in females. The major findings for both sexes were histopathologic lesions of the nasal mucosa and minor changes in the larynx and trachea. This study demonstrated that the target site following HDl exposure was the nasal cavity. In the 90-day study, Fischer 344 rats were exposed to HDl concentrations of 0, 0.01, 0.04 and 0.14 ppm for 6 hours/day, 5days/week for approximately 13 weeks. The only compound-related findings were ocular irritation and histopathologic lesions of the anterior nasal cavity. Both findings were observed at all three concentrations, therefore, a clear NOEL was not established in this study. In the chronic/oncogenicity study, Fischer 344 rats were exposed to HDl concentrations of 0, 0.005, 0.025 and 0.175 ppm for 6 hours/day, 5 days/week for up to 2 years. Animals were evaluated following both one and two years of exposure. A maximum tolerated dose was achieved at the highest concentration based on decreased body weight and slight anemia in the females, and histopathologic lesions of the nasal cavity in both sexes. The lowest concentration (0.005 ppm) was shown to be a NOEL after one year of exposure. However, after two years of exposure 0.005 ppm was considered to be a NOAEL based on the observation of reversible lesions, indicative of responses to non-specific irritation. In the sensory irritation study, female Sprague-Dawley rats were exposed using the head-only technique, to 0, 0.10, 0.21, 0.79, and 4.42 ppm Mondur HX (100% HDl) for three hours. Following exposure the animals were held for a seven-day recovery period. A concentration dependent increase in the respiratory response (sensory irritation) was observed. The severity of the response culminated in the death of two rats at the 4.42 ppm dose level. The RD50 (concentration which was estimated to produce a 50% depression in respiratory frequency) for the last hour of a three-hour exposure was 1.69 ppm. The NOEL for this study was 0.1 ppm. Based on these results, and the projected exposure of the animals for approximately three weeks during the current study, the proposed concentrations were 0, 0.005, 0.05, and 0.3 ppm HDI.
Statistics:
The data were analyzed with the litter as the primary experimental unit using applications provided by TASC. Parametric data (including dam body weights) were analyzed using an Analysis of Variance (ANOVA), and if significant differences were observed, a Dunnett's Test was performed. Fetal and
placental weights were specifically analyzed via the Healy's Test if significance was observed in the ANOVA. Nonparametric data (e.g. Iitter size and number of corpora lutea) were first analyzed by the Kruskal-Wallis test and then subjected to Dunn's Test if significant differences were identified. Nonparametric dichotomous data (e.g. number normal/abnormal) were initially analyzed by the Chi-Square Test and if significance was observed between groups then by the Fisher's Exact Test with the Bonferroni adjustment. A p-value less than or equal to 0.05 was considered statistically significant.
Historical control data:
yes
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
0.300 ppm:
No mortality; no clinical signs; no test compound related effects on maternal body weight, uterine weight, and net body weight; microscopic changes within the nasal cavity.
0.050 ppm:
No mortality; no clinical signs; no test compound related effects on maternal body weight, uterine weight, and net body weight; microscopic changes within the nasal cavity (to a lesser extent compared to the 0.300 ppm exposure group).
0.005 ppm:
No mortality; no clinical signs; no test compound related effects on maternal body weight, uterine weight, and net body weight; no microscopic changes.

Dose descriptor:
NOAEL
Effect level:
0.035 other: mg/m³ (eq. to 0.005 ppm)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
2.1 other: mg/m³ (eq. to 0.3 ppm)
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
All dose groups:
No effects on reproductive parameters; no embryotoxicity; no litter effects; no fetal external, visceral, and skeletal malformations.
Dose descriptor:
NOEL
Effect level:
2.1 other: mg/m³ (eq. to 0.3 ppm)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Key result
Developmental effects observed:
no

Maternal toxicity was demonstrated in the 0.300 and to a lesser extent in the 0.05 ppm exposure groups. No maternal effects were noted in the 0.005 ppm dose group. Test compound-related maternal effects were restricted to histopathological findings, and included acanthosis, hyperkeratosis, inflammation of the nasal turbinates, and more seriously, degeneration of the olfactory epithelium. No pathological alterations were noted in the larynx, trachea, or lungs in any dose group. No test compound-related effects were observed on any reproductive parameters, or any embryonic endpoints, including pre/post-implantation loss and resorptions. There were no effects on litter size or the number of fetuses per implantation site and no effects on fetal or placental weights were observed. No test compound-related fetal external, visceral, or skeletal findings were observed. No effect on the fetal or litter incidence of total malformations or variations was observed and there was no difference in the incidence of malformations between males and females.

1,6-Hexamethylene diisocyanate (HDI), administered as described in this study, produced maternal effects (nasal turbinate histopathology) at concentrations of 0.05 and 0.300 ppm. No developmental toxicity was observed at any concentration level. Therefore, the maternal no-observed-effect-level (NOEL) was 0.005 ppm HDI and the developmental NOEL was 0.300 ppm HDI.

Executive summary:

In a developmental toxicity study according to OECD TG 414 with 1,6-hexamethylene diisocyanate (HDI) rats were exposed, via whole-body exposure, to HDI vapour concentrations of 0, 0.005, 0.052, or 0.3 ppm (0.035, 0.36, or 2.1 mg/m³) for 6 hours/day on days 0 through 19 of gestation. Maternal toxicity was demonstrated in the 0.3 and to a lesser extent in the 0.05 ppm exposure groups. No maternal effects were noted in the 0.005 ppm dose group. Test compound-related maternal effects were restricted to histopathological findings, and included acanthosis, hyperkeratosis, inflammation of the nasal turbinates, and more seriously, degeneration of the olfactory epithelium. No pathological alterations were noted in the larynx, trachea, or lungs in any dose group. No test compound-related effects were observed on any reproductive parameters, or any embryonic endpoints, including pre/post-implantation loss and resorptions. There were no effects on litter size or the number of fetuses per implantation site and no effects on fetal or placental weights were observed. No test compound-related fetal external, visceral, or skeletal findings were observed. No effect on the fetal or litter incidence of total malformations or variations was observed and there was no difference in the incidence of malformations between males and females.

In summary, HDI produced maternal effects (nasal turbinate histopathology) at concentrations of 0.05 and 0.3 ppm. No developmental toxicity was observed at any concentration level. Therefore, the maternal NOAEL was 0.005 ppm and the developmental NOEL was 0.3 ppm.

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
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No study on developmental toxicity is available for the substance. Instead read across is applied to the structural similar substance 1,6 -hexamethylene diisocyanate (HDI, CAS 822 -06 -0). The read across is justified in a separate document attached to the dossier.

In a developmental toxicity study (OECD TG 414) with HDI rats were exposed, via whole body exposure, to vapour concentrations of 0, 0.005, 0.052, or 0.3 ppm (0, 0.035, 036, or 2.1 mg/m³) for 6 hours/day on days 0 through 19 of gestation.

Maternal toxicity was demonstrated in the 0.3 and to a lesser extent in the 0.05 ppm exposure groups. No maternal effects were noted in the 0.005 ppm dose group. Test compound-related maternal effects were restricted to histopathological findings, and included acanthosis, hyperkeratosis, inflammation of the nasal turbinates, and more seriously, degeneration of the olfactory epithelium. No pathological alterations were noted in the larynx, trachea, or lungs in any dose group. No test compound-related effects were observed on any reproductive parameters, or any embryonic endpoints, including pre/post-implantation loss and resorptions. There were no effects on litter size or the number of fetuses per implantation site and no effects on fetal or placental weights were observed. No test compound-related fetal external, visceral, or skeletal findings were observed. No effect on the fetal or litter incidence of total malformations or variations was observed and there was no difference in the incidence of malformations between males and females.

In summary, HDI produced maternal effects (nasal turbinate histopathology) at concentrations of 0.05 and 0.3 ppm. No developmental toxicity was observed at any concentration level. Therefore, the maternal NOAEL was 0.005 ppm (0.035 mg/m³) and the developmental NOEL was 0.3 ppm (2.1 mg/m³).

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex I, no classification is warranted for reproductive toxicity.