Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A repeated dose study with screening for reproduction and developmental effects performed with a substance analogue according to OECD 422 is available.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The read-across rationale is attached in Section 13.
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Salivation was noted in 200 and 50 mg/kg bw/day group animals after administration. This was considered to be due to the irritancy of the substance and since no further neurological effects were found, not regarded as a systemic effect. During recovery no clinical signs in females and only one male with soiled perineal area was noted.
Mortality:
no mortality observed
Description (incidence):
No dead or moribund males or females were noted in any group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight was significantly lower in the males at 200 mg/kg bw/day throughout the administration period and in the females at the same dose level on Day 15 of administration, throughout pregnancy, and on Days 0 and 6 of lactation. Body weight was also lower in the males at 50 mg/kg/day on Days 29 and 36 of administration. However, these findings at 50 mg/kg bw/day are not considered attributable to the test substance, since (1) the differences from the control group were small, (2) these findings were transient changes, and (3) food consumption was not adversely affected by the test substance at this dose level. During the recovery period, body weight stayed lower in both sexes at 200 mg/kg bw/day but tended to revert to the normal body weight.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the measurement of food consumption, lower food consumption was noted in the males at 200 mg/kg bw/day at the beginning of the administration period, but no changes attributable to the test substance were noted in the females at this dose level. During the recovery period, food consumption was higher in the males at 200 mg/kg/day, but this finding is considered to be a recoverable change which occurred after termination of the administration period.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
In the measurement of water consumption, higher water consumption was noted in the males at 200 mg/kg bw/day at the end of the administration period, in the females at this dose level before the start of mating, and in the females at 200 and 50 mg/kg/day during the lactation period. However, these findings were not regarded as having been caused by the toxicity of the test substance, since all of them were transient changes. During the recovery period, water consumption was higher in the males at 200 mg/kg bw/day, but no changes attributable to the test substance were noted in the females at this dose level.
Haematological findings:
no effects observed
Description (incidence and severity):
No changes attributable to test substance were noted in either sex on termination of the administration period or recovery period.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No changes attributable to test substance were noted in either sex on termination of the administration period or recovery period.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No changes attributable to test substance were noted in either sex on termination of the administration period or recovery period.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
In the measurement of spontaneous motor activity in the females at 200 mg/kg bw/day, the ambulatory count and vertical count were lower 70 minutes after administration, and a lower total vertical count and a tendency for total ambulatory count to be lower were noted on termination of the administration period. In the males, no changes attributable to the test substance were noted in the spontaneous motor activity. Regarding FOB, sensory reactivity, and grip strength, no changes attributable to the test substance were noted in either sex at any dose level.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In the organ weight measurement on termination of the administration period, a higher relative spleen weight and a tendency for the absolute spleen weight to be higher were noted in the males at 200 mg/kg bw/day, and higher absolute and relative spleen weights were noted in the females at this dose level. On termination of the recovery period, no changes attributable to the test substance were noted in either sex at any dose level. However, the histopathological examinations on termination of the administration period (see below) shows that there were no changes attributable to the test substance in the spleen in either sex, and hematological examinations shows that the parameters related to the organ weight changes were not affected by the test substance. Therefore, the findings in the spleen weights at 200 mg/kg bw/day in the present study are considered to be minor changes.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test substance-like residuals were noted in the stomach of animals of both sexes at 200 mg/kg bw/day.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the histopathological examinations, the following findings were noted in the males:
slight or mild hyperplasia of squamous epithelium in the forestomach in all 6 males at 200 mg/kg bw/day and in 1 male at 50 mg/kg bw/day, slight or mild hyperkeratosis in the forestomach in all 6 males at 200 mg/kg bw/day, slight inflammatory cell infiltration in the forestomach in 1 male at 200 mg/kg bw/day, and cystic changes in the epithelial layer of the forestomach in 1 male at 200 mg/kg bw/day. In the females at 200 mg/kg bw/day, the following findings were noted: slight hyperplasia of squamous epithelium in the forestomach in 3 females, slight inflammatory cell infiltration in the forestomach in 1 female, and cystic changes in the epithelial layer of the forestomach in 1 female. From these findings in the stomach, it can be said that the above-mentioned higher water consumption in both sexes at 200 mg/kg bw/day was a change to alleviate the irritancy of m-xylylene diisocyanate given to the stomach; the higher water consumption noted in the present study is not judged to be a toxicological change. Since no histopathological changes in the stomach were noted in either sex on termination of the recovery period, higher water consumption occurring during administration will revert to normal water consumption after the discontinuation of administration.
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
In the examinations for reproductive/developmental toxicity in parent animals, no changes attributable to the test substance were noted in the number of estrous cases during the administration period (for 14 days) before the start of mating, copulation index, number of conceiving days, number of pregnant females, fertility index, length of gestation, gestation index, number of corpora lutea, number of implantation sites, implantation index, delivery conditions, or nursing conditions.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Decreased body weight in males and pregnant females.
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths, number of live pups born on Day 0 of lactation, delivery index, birth index, live birth index, sex ratio, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, clinical signs, body weight on Day 0 or 4 of lactation, appearance, or necropsy findings.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Based on the results of a repeated dose study with screening for reproductive and developmental effects, the reproductive/developmental NOAEL is sconcluded to exceed 200 mg/kg bw/day as no effects were noted in any parameter in either sex. At 200 mg/kg bw/day, a decreased body weight was found in males and pregnant females and thus the parental NOAEL is set at 50 mg/kg bw/day. This result is read across to NBDI.
Executive summary:

Rats were administered 0, 12.5, 50 or 200 mg/kg bw/d of test substance in a study performed according to OECD 422 (1996). Rats were dosed from 14 days before mating during mating and afterwards (total 42 days) for males and during mating period, pregnancy and up to lactation day 6 for females. No mortality occurred. Salivation was noted at 50 and 200 mg/kg bw/d in both sexes. Body weight was decreased in both sexes at 200 mg/kg bw/d. For food and water consumption only transient effects were noted which may be due to irritation of the stomach. No test substance-related effect was seen on haematological, clinical chemistry and urinalysis parameters or at gross pathology. Histopathology revealed an increased incidence of hyperplasia of squamous epithelium and hyperkeratosis in the forestomach in both sexes at 200 mg/kg bw/d. Inflammatory cell infiltration in the forestomach and mild cystic changes in the epithelial cell layer of the forestomach were noted in one male and one female at 200 mg/kg bw/d. In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths, number of live pups born on Day 0 of lactation, delivery index, birth index, live birth index, sex ratio, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, clinical signs, body weight on Day 0 or 4 of lactation, appearance, or necropsy findings. In addition, no effects on reproduction organs in parental animals were observed. This result is read across to NBDI.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was performed according to GLP and OECD test guideline (Klimisch score 1).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No study with the substance itself is available, but with analogue isocyanate XDI. In an OECD 422 study, rats were exposed orally to 0, 12.5, 50 and 200 mg/kg bw/day of XDI. In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths, number of live pups born on Day 0 of lactation, delivery index, birth index, live birth index, sex ratio, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, clinical signs, body weight on Day 0 or 4 of lactation, appearance, or necropsy findings. In addition, no effects on reproduction organs in parental animals were observed. The parental NOAEL is 50 mg/kg bw/d and the developmental/fertility NOAEL is >= 200 mg/kg bw/d.

Due to the skin corrosive and sensitizing effects and the local inhalatory effects, stringent personal protective equipment should and will be used as described in the CSR. This personal protection is required to prevent mainly local effects (and sensitization) which occur at much lower effect levels compared to the systemic effects.

The substance is only used as a monomer for the production of optical lenses (production of the substance itself is outside the EU). The potential worker exposure is extensively described in chapter 2 of the CSR. This shows that the industrial process is highly controlled, with a limited potential of exposure (only 2 main downstream users, limited activities, and high personal protection measures), with only very low inhalation and dermal exposure possible (see chapter 9 of the CSR). No exposure of consumers, also not via the environment as no emission of the substance takes place (see CSR chapter 9 for an extensive description), is possible.

Inhalation is a more relevant route of exposure, since only worker exposure is envisaged, no consumer exposure, thus no effects on gonads are seen, nor expected. Moreover, for the structurally related substance XDI showing a very much related toxicological profile, no such findings were observed in the oral repeated toxicity study. No other related isocyanate substance is known to give such an effect, and in addition, several publications of other isocyanates show that these substances are not reprotoxic or show developmental toxicity. Moreover, a predictive toxicity assessment of the two constituents of NBDI was performed using DEREK (see section 13 of IUCLID). None of the isomers was predicted to give reproduction/developmental toxicity.

Based on the toxicological profile, the limited use, with very limited exposure to the substance, and the personal protective equipment used, no hazard and no risk is considered present for reproductive toxicity as well as for developmental toxicity. Therefore, no such study is considered to be required.

Effects on developmental toxicity

Description of key information
In an oral OECD 422 study with rats, no effects on reproduction and development were observed up to 200 mg/kg bw/day XDI (an isocyanate substance analogue), while paternal toxic effects were seen at 200 mg/kg bw/day. The read-across rationale can be found in the category approach document attached in Section 13 of IUCLID.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 25-November 19, 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: Organisation of Economic Co-operation and Development (OECD) Guidelines for Testing of Chemicals, Guideline 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, March 1996
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CD (SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hino Breeding Center, Charles River Laboratories Japan, Inc.
- Age at study initiation: 10 weeks
- Weight at study initiation: males 355-394 g and females 240-285 g, females satellite groups 247-279 g
- Fasting period before study:
- Housing: During acclimatization animals were housed individually in stainless stgeel suspended ages. Animals were paired in males' cages. Dams were housed individually in plastic cages floored with an autoclaved substate of wood chips on Day 18 of pregnancy and thereafter. The dams were housed individually in stainless steel suspended cages on Day 4 of lactation and thereafter.
- Diet: ad libitum to feeders of solid diet (CRF-1, Oriental Yeast Co., Ltd.)
- Water: ad libitum tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.9-24.3
- Humidity (%): 44-63
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required amount of the test substance was measured out and dissolved in corn oil to a concentration of 40 mg/ml. Dosing preparations containing the test substance at concentrations of 10 and 2.5 mg/ml were prepared by serial dilution of the dosing preparation at 40 mg/ml with corn oil. Preparations were used within 4 hours and 54 minutes of preparation. Dosing volumes 5 ml/kg/day on the most recent body weight.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: same dosing volume.
- Lot/batch no.: V8F7016
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations of the substance in dosing preparations which were used for both sexes in the test groups on the first day of dosing and for the males in the test gorups on the last dosing day were measured by gas chromatography. Concentrations were between 92.9 and 95.1% of target concentration.
Details on mating procedure:
- M/F ratio per cage: 1/1 one female was cohabitated with one male of the same treatment group, avoiding sibling mating
- Length of cohabitation: A maximum of 14 days was allowed for mating.
- Proof of pregnancy: Detection of mating was confirmed by evidence of sperm in the vaginal smear, or or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 of preganancy. Once mating had occurred, the males and females were separated.
- After successful mating each pregnant female was caged individually and was allowed to deliver the litters spontaneously and observed for delivery conditions and completion of delivery daily from Day 21 of pregnancy to day 25 of pregnancy. The day when deliver was completed was defined as day 0 of lactation.
Duration of treatment / exposure:
Males treated for 14 days before mating and thereafter 28 days, total of 42 days. Half of the males per group were given a 14-day recovery period. Females treated for 14 days before mating, during the mating period (max 4 days), and during pregnancy up to Day 6 of lactaction, a total of 44 - 48 days. Females of satellite groups, treated for 42 days, were given a 14-day recovery period.
Pups were not treated directly, but were potentially exposed to the test substance in utero and through lactational transfer.
Frequency of treatment:
Once daily
Dose / conc.:
12.5 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 males including 6 with a recovery period.
12 females
6 females in satellite group with recovery period.
Control animals:
yes, concurrent vehicle
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: Animals were observed for mortality and clinical signs twice a day, once before and once after administration, once a day during the recovery period and once on the day of necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week and on the day of necropsy, with females during pregnancy on Days 0, 7, 14 and 21 and on Days 0, 4 and 6 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Time schedule: approx twice a week

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: approx twice a week

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After last dosing day and after temination of recovery period.
- Anaesthetic used for blood collection: Yes, by ip injection of sodium pentobarbital
- Parameters examined: according to OECD 422 (1996)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see haematology
- Parameters examined: according to OECD 422 (1996)

URINALYSIS: Yes
- Time schedule for collection of urine: Fresh urine and 24-hour urine was collected. For males on day 37 of administration and day 9 of recovery, for females on day 5 of lactation and day 9 of recovery.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: All animals were observed for FOB before start of administration and once a week during administration.
- Dose groups that were examined: all dose groups
- Battery of functions tested: FOB consisted of observations on: posture, palpebral closure, biting behavior and convulsions; ease of removal from cage, ease of handling, muscle tone, fur conditions, lacrimation, salivation, and respiration. In the open field, frequency of rearing and frequency of grooming for 2 minutes, gait, palpebral closure, consciousness, behavioral abnormalities, and righting reflex.
Sensory reactivity and grip strength in males before necropsy, in 6 females/group on Day 3 of lactation. Spontaneous Motor Activity in males on day 40 of administration and females on day 4 of lactation.

OTHER:
Mating: After 14 days of treatment, males and females were paired continuously for a maximum period of 14 days until copulation was confirmed.
Nursing conditions: Dams were observed for nursing conditions once a day from days 0 to 4 of lactation.

GROSS PATHOLOGY: Yes
Organ weights in males: brain, pituitary, salivary glands, thyroids, thymus, heart, liver, spleen, kidneys, adrenals, testes and epididymides.
Females: number of corpora lutea and number of implantation sites were counted. After necropsy organ weights: same as males + ovaries and uterus.
HISTOPATHOLOGY: Yes
Organs and tissues from males and females of the high dose and control group were examined. When abnormalities were found, e.g. stomach, lower doses were also examined. Organs and tissues examined: heart, lungs, trachea, liver, pancreas, salivary glands, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, thymus, spleen, lymph nodes, kidneys, urinary bladder, testes, epididymides, seminal vesicles, prostate, pituitary, adrenals, thyroids, parathyroid glands, brain, spinal cord, sciatic nerves, eyeballs, Harderian glands, bone marrow and bones, testes, ovaries, uterus, vagina, and mammary glands.
Ovaries and uterine content:
The ovaries, uterus, vagina and mammary glands were examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
- Number of stillbirths: Yes
Fetal examinations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: the number of pups born, their sexes, number of stillbirths, live pups born, and external abnormalities.
- Mortality: once a day
- Clinical signs: once a day
- Body weights: Live pups were weighed on Days 0 and 4 of lactation.
Statistics:
Data were tested by Bartlett's test for homogeneity of variance, when variances were homogeneous, Dunnett's test was performed to compare the control group with each of the groups treated with substance. When variance was heterogeneous, Steel's test was performed.
FOB and reproduction/developmental parameters data were tested by Steel's test. Copulation index, fertility index and gestation index were tested by Fisher's exact test.
Effects in stomach: Steel's test was performed. When significant differences were seen, dose-responsiveness was tested by Cochran-Armitage exact test.
Indices:
- Implantation index: number of implantation sites/number of corpora lutea x 100
- Delivery index: number of pups born/number of implantation sites x 100
- Birth index: Number of live pups born on Day 0 of lactation/Number of implantation sites x 100
- Live birth index: Number of live pups born on Day 0 of lactation/Number of pups born x 100
- Viability index: Number of live pups on Day 4 of lactation / Number of pups born alive x 100
- Incidence of external abnromalities: number of pups with external abnormalities/number of live pups born x 100
- Sex ratio: number of males/number of females
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Salivation was noted in 200 and 50 mg/kg bw/day group animals after administration. This was considered to be due to the irritancy of the substance and since no further neurological effects were found, not regarded as a systemic effect. During recovery no clinical signs in females and only one male with soiled perineal area was noted.
Mortality:
no mortality observed
Description (incidence):
No dead or moribund males/females were found in any group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight was significantly lower in the females at the high dose level on Day 15 of administration, throughout pregnancy, and on Days 0 and 6 of lactation. During the recovery period, body weight stayed lower at 200 mg/kg bw/day but tended to revert to the normal body weight.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects on food consumption were found in exposed females.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
In the measurement of water consumption, higher water consumption was noted in the females at this dose level before the start of mating, and in the females at 200 and 50 mg/kg bw/day during the lactation period. However, these findings were not regarded as having been caused by the toxicity of the test substance, since all of them were transient changes. During the recovery period, no changes attributable to the test substance were noted in the females at this dose level.
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Behaviour (functional findings):
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test substance-like residuals were noted in the stomach of animals at 200 mg/kg bw/day.
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the histopathological examinations, the following findings were noted in the females at 200 mg/kg/day, the following findings were noted: slight hyperplasia of squamous epithelium in the forestomach in 3 females, slight inflammatory cell infiltration in the forestomach in 1 female, and cystic changes in the epithelial layer of the forestomach in 1 female. From these findings in the stomach, it can be said that the above-mentioned higher water consumption in both sexes at 200 mg/kg/day was a change to alleviate the irritancy of m-xylylene diisocyanate given to the stomach; the higher water consumption noted in the present study is not judged to be a toxicological change. Since no histopathological changes in the stomach were noted in either sex on termination of the recovery period, higher water consumption occurring during administration will revert to normal water consumption after the discontinuation of administration.
Details on maternal toxic effects:
In the examinations for reproductive/developmental toxicity in parent animals, no changes attributable to the test substance were noted in the number of estrous cases during the administration period (for 14 days) before the start of mating, copulation index, number of conceiving days, number of pregnant females, fertility index, length of gestation, gestation index, number of corpora lutea, number of implantation sites, implantation index, delivery conditions, or nursing conditions.
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Based on decreased body weight of pregnant females.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths or number of live pups born on Day 0 of lactation
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
Only examined until PND 4.
External malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Only early postnatal pup development parameters were examined including body weight, post-natal loss, sex ratio, clinical signs, body weight and external macroscopy.

In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths, number of live pups born on Day 0 of lactation, delivery index, birth index, live birth index, sex ratio, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, clinical signs, body weight on Day 0 or 4 of lactation, appearance, or necropsy findings.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects seen up to and including the highest dose tested.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the results of a repeated dose study with screening for reproduction and developmental effects, the reproductive/developmental NOAEL is considered to exceed 200 mg/kg bw/day as no effects were noted in any parameter in either sex. At 200 mg/kg bw/day a decreased body weight was found in pregnant females and thus the parental NOAEL is set at 50 mg/kg bw/day.
Executive summary:

Rats were administered 0, 12.5, 50 or 200 mg/kg bw/d of test substance in a study performed according to OECD 422 (1996). Rats were dosed from 14 days before mating during mating and afterwards (total 42 days) for males and during mating period, pregnancy and up to lactation day 6 for females. No mortality occurred. Salivation was noted at 50 and 200 mg/kg bw/d in both sexes. Body weight was decreased in both sexes at 200 mg/kg bw/d. For food and water consumption only transient effects were noted which may be due to irritation of the stomach. No test substance-related effect was seen on haematological, clinical chemistry and urinalysis parameters or at gross pathology. Histopathology revealed an increased incidence of hyperplasia of squamous epithelium and hyperkeratosis in the forestomach in both sexes at 200 mg/kg bw/d. Inflammatory cell infiltration in the forestomach and mild cystic changes in the epithelial cell layer of the forestomach were noted in one male and one female at 200 mg/kg bw/d. In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths, number of live pups born on Day 0 of lactation, delivery index, birth index, live birth index, sex ratio, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, clinical signs, body weight on Day 0 or 4 of lactation, appearance, or necropsy findings. In addition, no effects on reproduction organs in parental animals were observed. The NOAEL for systemic parental effects is 50 mg/kg bw/d based on

decreased body weight and salivation and the NOAEL for developmental toxicity is >= 200 mg/kg bw/d.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was performed according to GLP and OECD test guideline. However, since the study was performed with a substance analogue and the data are read across, the Klimisch score is 2.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In an OECD 422 study, rats were exposed to XDI orally to 0, 12.5, 50 and 200 mg/kg bw/day.

In the pups (F1), no changes attributable to the test substance were noted in the number of pups born, number of stillbirths, number of live pups born on Day 0 of lactation, delivery index, birth index, live birth index, sex ratio, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, clinical signs, body weight on Day 0 or 4 of lactation, appearance, or necropsy findings. In addition, no effects on reproduction organs in parental animals were observed. The parental NOAEL is 50 mg/kg bw/d and the developmental/fertility NOAEL is >= 200 mg/kg bw/d.

No further studies have been performed.

Due to the skin corrosive and sensitizing effects and the local inhalatory effects, stringent personal protective equipment should and will be used as described in the CSR. This personal protection is required to prevent mainly local effects (and sensitization) which occur at much lower effect levels compared to the systemic effects.

The substance is only used as a monomer for the production of optical lenses (production of the substance itself is outside the EU). The potential worker exposure is extensively described in chapter 2 of the CSR. This shows that the industrial process is highly controlled, with a limited potential of exposure (only 2 main downstream users, limited activities, and high personal protection measures), with only very low inhalation and dermal exposure possible (see chapter 9 of the CSR). No exposure of consumers, also not via the environment as no emission of the substance takes place (see CSR chapter 9 for an extensive description), is possible.

Inhalation is a more relevant route of exposure, since only worker exposure is envisaged, no consumer exposure, thus no effects on gonads are seen, nor expected. Moreover, for the structurally related substance XDI showing a very much related toxicological profile, no such findings were observed in the oral repeated toxicity study. No other related isocyanate substance is known to give such an effect, and in addition, several publications of other isocyanates show that these substances are not reprotoxic or show developmental toxicity. Moreover, a predictive toxicity assessment of the two constituents of NBDI was performed using DEREK (see section 13 of IUCLID). None of the isomers was predicted to give reproduction/developmental toxicity.

Based on the toxicological profile, the limited use, with very limited exposure to the substance, and the personal protective equipment used, no hazard and no risk is considered present for reproductive toxicity as well as for developmental toxicity. Therefore, no such study is considered to be required.


Justification for selection of Effect on developmental toxicity: via oral route:
Only one study available

Justification for classification or non-classification

Based on the currently available data, NBDI is not classified for adverse effects on reproduction and development according to the CLP Regulation (EC) No. 1272/2008.