2-isocyanatoethyl methacrylate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In accordance with Column 1 of REACH Annex IX the extended one-generation reproductive toxicity study does not need to be conducted as no adverse effects on reproductive organs or tissues were observed in the available 90-day inhalation toxicity study.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Effects on fertility: via oral route

No data are available.

 

Effects on fertility: via inhalation route

In the available subchronic repeated dose toxicity study (The Dow Chemical Company, 1980) the test material was investigated for repeated dose toxicity via inhalation. The study predates the appropriate OECD test guideline and GLP, but was conducted in compliance with standards used in this laboratory at that time. However, the study was conducted comparable to the OECD test guideline 413. 20 Fischer 344 rats per sex per dose were treated with vapour of the test item in a whole-body inhalation system for 6 h/day and 5 days/week for 13 consecutive weeks at doses of 25, 80, and 250 ppb (equivalent to 1.583, 0.507, and 0.158 mg/m³), whereas control animals were treated with the vehicle only (air). At the end of the exposure period 10 animals per sex per dose were sacrificed. In order to assess the reversibility of treatment-related effects and to identify potential latent effects of exposure, the remaining 10 animals per sex per dose were maintained for further 30 and 90 days of observation, respectively. At gross pathology, accessory sex glands, epididymides, mammary tissue, ovary, oviduct, testes, and uterus were investigated for treatment related effects, whereas epididymides, mammary tissue, ovary, oviduct, and seminal vesicles of control and high dose animals, as well as all low and mid dose animals with grossly described lesions, were submitted to histopathological examination. In addition, tested were weighed. No treatment related effects were observed in any of the animals at any dose. Additionally, animals of the recovery groups did not show any delayed effect on the reproductive organs or tissues. Based on these findings, the NOEL for effects on reproductive organs and tissues was set at 250 ppb (equivalent to 1.583 mg/m³).

In accordance with Column 1 of REACH Annex IX, the extended one-generation reproductive toxicity study (required in Section 8.7.3 of REACH Annex IX) does not need to be conducted as data from this inhalative 90-day study do not indicate adverse effects on reproductive organs or tissues of both males and females.

 

Effects on fertility: via dermal route

No data are available.

Effects on developmental toxicity

Description of key information

Developmental toxicity (OECD 414, rat, m/f):

NOAEL developmental toxicity ≥ 110 mg/kg bw/day

NOAEL maternal toxicity = 31 mg/kg bw/day

NOAEL local toxicity < 7 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 Sep 2021 - 01 Mar 2022

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

adopted in 2018

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hino Breeding Center, Charles River Laboratories Japan
- Age at study initiation: 11 weeks (males) and 10 and 11 weeks (females)
- Weight at study initiation: 346.4 - 413.7 g (males) and 203.1 - 253.6 (females; 203.1 - 230.6 g at 10 weeks of age, 215.9 - 253.6 g at 11 weeks of age)
- Housing: In hanging-type stainless wire mesh cages measuring 226 x 346 x 198 mm. Equipment for animal enrichment such as nesting materials, gnawing materials and rest boards were placed in each cage. During quarantine and acclimatisation, 2-3 animals of the same sex were housed in the same cage. During mating males and females were housed 1:1/cage, thereafter the animals were housed 1 female/cage or 1 male/cage.
- Diet: Pellet diet for experimental animals (CRF-1, Oriental Yeast Co., Ltd.), ad libitum
- Water: Well water, admixed with sodium hypochlorite (0.2 ppm), ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24.8
- Humidity (%): 42.3 - 69.6
- Air changes (per hr): 10 - 20
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: 21 Sep - 19 Oct 2021

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was accurately weighed in a beaker and the property of vehicle was added and stirred with a magnetic stirrre to dissolve. Confirming the dissolution, the total volume was transferred to a measuring cylinder. The vehicle was added and mixed by end-over-end rotation to make a prescribed concentration. After preparation, the dosing formulation was divided into brown glass vials and the vials were filled with nitrogen gas.
Dosing formulations were prepared once every 2 to 3 days.
Storage temperature: The dosing formulations after preparation were divided into glass vials for each dosing day, and stored in a cold place, shielded from light in a glass vial filled with nitrogen gas (actual temperature: 3.5°C to 6.2°C, permissible range: 1°C to 15°C, storage area: in a medical refrigerator.


VEHICLE
- Concentration in vehicle: 1.75, 7.75 and 27.5 mg/mL
- Amount of vehicle: 4 mL/kg bw

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Stability of the test item in the vehicle was demonstrated in a separate study for the concentration levels 1 and 250 mg/mL (Study no. P210104). The formulations at 1 mg/mL were confirmed to be stable for 3 days in a cold place, followed by the storage period of 4 hours at room temperature in nitrogen-filled brown glass vessels. The test article formulations at 250 mg/mL were confirmed to be stable for 8 days in a cold place, followed by the storage period of 4 hours at room temperature in nitrogen-filled brown glass vessels.

Details on mating procedure:

- Impregnation procedure: cohoused
- Mating was started at 12 weeks of age. Males and females were housed on a 1:1 base day and night.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear taken in the morning, referred to as Day 0 of gestation (GD 0).

Duration of treatment / exposure:

Gestation Days 6 - 19

Frequency of treatment:

daily, 7 days/week

Duration of test:

Day 20 of gestation

Dose / conc.:

7 mg/kg bw/day (actual dose received)

Dose / conc.:

31 mg/kg bw/day (actual dose received)

Dose / conc.:

110 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels were set based on the results of a preliminary dose range-finding study for prenatal developmental oral toxicity in rats which was conducted at the same testing facility. The animals were dosed at 0, 11, 110, 330 and 1000 mg/kg bw/day. Death and moribundity occurred at 330 mg/kg bw/day or more, and low body weight of the live male and female fetuses were noted at 330 mg/kg bw/day. At 110 mg/kg bw/day, low body weight and food consumption were noted in dams, while no effects on embryo/fetal development was noted. At necropsy, reddish patch in the mucosa of the forestomach was observed at 11 mg/kg bw/day and depressed patch in the mucosa of the forestomach was observed at 110 and 330 mg/kg bw/day, suggesting irritation of the test article to the stomach. Therefore, the high dose level of the present study was set at 110 mg/kg bw/day which was expected to develop some toxicity but not to occur death and severe suffering. The middle and low dose levels were set at 31 and 7 mg/kg bw/day, respectively, with a common ratio of about 4.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical signs and mortality were observed twice a day (before dosing and after dosing) during the dosing period and once a day during the other periods.
- Cage side observations included: mortality and clinical signs

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured on GDs 0, 3, 6, 9, 12, 15, 18, and 20.

FOOD CONSUMPTION: Yes
Food consumption was weighed on GDs 0 to 1, 2 to 3, 5 to 6, 8 to 9, 11 to 12, 14 to 15, 17 to 18, and 19 to 20.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Ovaries and uterus. To investigate the effects of the test substance on the stomach and intestinal tract in more detail, histopathological examination was also performed for nasal cavity, larynx, trachea, lungs, esophagus, stomach, duodenum,jejunum, ileum, cecum, colon, or rectum in dams.


OTHER:
Thyroid Hormone analysis:
- Time schedule for collection of blood: Blood samples were collected from the subclavian vein at scheduled necropsy on gestation Day 20.
- Anaesthetic used for blood collection: No
- How many animals: all pregnant animals in all groups
- Parameters examined: triiodothyronine (T3), thyroxin (T4) and thyroid stimulating hormone (TSH)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Blood sampling:

- Plasma: Yes
- Serum: No
- Volume collected : 1.5 mL

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
- Anogenital distance of all live rodent pups: Yes: all per litter

Statistics:

Details on statistics are listed in the field "Any other information on materials and methods incl. tables".

Indices:

Pre-implantation loss index: [(Number of corpora lutea - number of implantations) / number of corpora lutea] × 100

Post-implantation loss index: [(Number of implantations - number of live foetuses)/ number of implantations)] × 100

Early resorption index: (Number of early resorptions / number of implantations) × 100

Late resorption index: (Number of late resorptions / number of implantations) × 100

Dead foetus index: (Number of dead foetuses / number of implantations) × 100

Incidence of foetuses with external anomalies (by type of anomaly): [Number of foetuses with anomalies (by type of anomaly) / number of foetuses examined] × 100

Incidence of foetuses with placental anomalies (by type of anomaly): [Number of placentas with anomalies (by type of anomaly) / number of placentas examined] × 100

Incidence of foetuses with skeletal anomalies (by type of anomaly): [Number of foetuses with anomalies (by type of anomaly) / number of foetuses examined] × 100

Incidence of foetuses with skeletal variations (by type of anomaly): [Number of foetuses with variations (by type of variation) / number of foetuses examined] × 100

Incidence of foetuses with visceral anomalies (by type of anomaly): [Number of foetuses with anomalies (by type of anomaly) / number of foetuses examined] × 100

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 110 mg/kg bw/day, 16/20 dams showed loose stool from GD 7-19 and 15/20 dams showed salivation from GD 11-19. The findings were noted after dosing and salivation disappeared by the following day. There were no findings at lower dose levels. For details, please refer to Table 1 under "Attachments", PDF document on result tables.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No maternal death occurred at any dose level.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was a statistically significant decrease in body weight noted for the high dose group on GD 12-20 (-4, -5, -7 and -7% at GD 12, 15, 18 and 20). The finding was in line with a reduced food intake in these animals from GD 8-19.
For details, please refer to Table 2 under "Attachments", PDF document on result tables.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

There was a statistically significant decrease in food consumption noted for the high dose group on GD 8-19 (-14, -15, -11, -15 and -10% at GD 9, 11, 14, 17 and 19). The finding was in line with a reduced body weight gain in these animals from GD 12-20.
For details, please refer to Table 3 under "Attachments", PDF document on result tables.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not specified

Description (incidence and severity):

The following ED-related parameters were investigated in the study: T3, T4 and TSH level, anogenital distance, genital abnormalities, thyroid weight, gravid uterus weight, foetal development, litter size, litter/pup weight, number of implantations/ corpora lutea, number of embryonic or foetal deaths and viable foetuses, post-implantation losses, pre-implantation losses, presence of foetal anomalies (external, visceral and skeletal) and sex ratio.
For details, please refer to the respective result fields and the endpoint summary.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No statistically significant difference was observed in either absolute or relative thyroid weight between the control and any test article treatment group.
For details, please refer to Tables 4 and 5 under "Attachments", PDF document on result tables.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Depressed patch in the mucosa of the forestomach was noted in 3/20 dams at 31 mg/kg bw/day and in 17/20 dams at 110 mg/kg bw/day. The findings were in line with histopathological alterations and considered treatment-related.
For details, please refer to Table 6 under "Attachments", PDF document on result tables.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the stomach, hyperplasia of squamous cells and inflammatory cell infiltrate in the forestomach were observed at ≥ 7 mg/kg bw/day. Erosion/ulcer of the forestomach was observed at ≥ 31 mg/kg bw/day. Hypertrophy of mucous neck cells in the glandular stomach was observed in the 110 mg/kg bw/day group. The changes are indicative of a local direct irritancy of the test item and attributed to treatment.

In the larynx and trachea, erosion/ulcer, focal regeneration of mucosal epithelium, and inflammatory cell infiltrate in the mucosa were observed in the 110 mg/kg bw/day group. These changes were considered irritant changes due to direct exposure of the test article by gavage-related reflux.
For details, please refer to Table 7 under "Attachments", PDF document on result tables.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Thyroid hormone analysis revealed no treatment-related changes in any group. Although plasma TSH concentrations at 110 mg/kg bw/day were statistically significantly increased when compared to control animals (+14%), the values were comparable to the historical control values generated in the testing facility. In addition, no treatment-related changes were observed in the thyroid at histopathological examination.
For details, please refer to Tables 8 and 9 under "Attachments", PDF document on result tables.

Number of abortions:

no effects observed

Description (incidence and severity):

No abortion occurred during the study.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Total litter losses by resorption:

not specified

Early or late resorptions:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Dead fetuses:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

The number of pregnant animals in the control, 7, 31, and 110 mg/kg bw/day groups was 20, 20, 20, and 17, respectively.

Key result

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

31 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Dose descriptor:

LOAEL

Remarks:

maternal toxicity

Effect level:

110 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

Key result

Dose descriptor:

NOAEL

Remarks:

local toxicity

Effect level:

< 7 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Dose descriptor:

LOAEL

Remarks:

local toxicity

Effect level:

7 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

histopathology: non-neoplastic

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Anogenital distance of all rodent fetuses:

no effects observed

Description (incidence and severity):

No statistically significant difference was observed in AGD or AGI between the control and any test article treatment group.
For details on cesarean section data, please refer to Table 10 under "Attachments", PDF document on result tables.

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

No abnormalities were observed in any fetus. Also no placental abnormalies were observed.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No skeletal anomalies were observed at 110 mg/kg bw/day. In the control group, skeletal anomalies were observed in 1 fetus (0.6%). With regard to individual types of skeletal anomalies, hemicentric thoracic centrum was observed in 1 fetus (0.6%).

Skeletal variations were observed in 24 fetuses (17.2%) and 19 fetuses (14.3%) in the control and 110 mg/kg bw/day groups, respectively. With regard to individual types of skeletal variations, the following findings were observed in the control and 110 mg/kg bw/day groups: bipartite ossification of thoracic centrum in 2 fetuses (1.3%) and 1 fetus (0.7%), full supernumerary rib in 3 fetuses (2.5%) and 2 fetuses (1.4%), short supernumerary rib in 16 fetuses (11.9%) and 13 fetuses (9.7%), asymmetry of the sternebra in 2 fetuses (1.3%) and 3 fetuses (2.4%), and bipartite ossification of sternebra in 5 fetuses (3.4%) and 1 fetus (0.7%), respectively. However, no statistically significant differences were observed in their incidences between the control and 110 mg/kg bw/day groups. Additionally, all effects observed in the 110 mg/kg bw/day group were seen in the control group with a similar frequency. The findings of bipartite ossification of supraoccipital bone in 1 fetus (0.6%) and 7 lumbar vertebrae in 1 fetus (1.0%) were observed only in the control group.

In addition, no statistically significant differences were observed in the number of sacrocaudal vertebral bodies or sternebrae between the control and 110 mg/kg bw/day groups.
The findings on skeletal anomalies and variations were not attributed to treatment.

For details on litter data, please refer to Table 11 under "Attachments", PDF document on result tables.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Visceral anomalies were observed in 5 fetuses (4.0%) and 1 fetus (0.9%) in the control and 110 mg/kg bw/day groups, respectively. With regard to individual types of visceral anomalies, thymic remnant in the neck was observed in 1 fetus (0.9%) in the 110 mg/kg bw/day group. However, this change was also observed in the control group [4 fetuses (3.0%)]. The finding dilated renal pelvis and dilated ureter were observed in 1 fetus (1.0%) was observed only in the control group. The observations were not attributed to treatment.
For details on litter data, please refer to Table 12 under "Attachments", PDF document on result tables.

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

>= 110 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Remarks on result:

other: corresponding to the highest dose level tested

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

The test item had no effect on intrauterine development. The NOAEL for developmental toxicity was ≥ 110 mg/kg bw/day.
The NOAEL for maternal toxicity was 31 mg/kg bw/day, based on clinical signs of toxicity, reduced food consumption and impaired body weight development at 110 mg/kg bw/day.
The NOAEL for local toxicity was < 7 mg/kg bw/day, based on hyperplasia of squamous cells in the stomach and inflammatory cell infiltrate in the forestomach at ≥7 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

110 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study performed with the registered substance, and is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.6, of Regulation (EC) No. 1907/2006.

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

The test item was investigated for its teratogenic potential in a prenatal developmental toxicity study in rats according to OECD guideline 414 and in compliance with GLP (Showa Denko, 2022). The test substance was dissolved in corn oil and administered by oral gavage to groups of 20 pregnant rats from gestation Days (GD) 6 to 19. Based on the results of a preliminary toxicity study in pregnant rats of this strain, test item dose levels of 7, 31 and 110 mg/kg bw/day were chosen. A similar constituted group received the vehicle (corn oil) and served as control.

The animals were observed for mortality and clinical signs of toxicity and individual body weights, as well as food consumption were recorded at regular intervals during gestation. On Day 20 of pregnancy, all dams were sacrificed and maternal and fetal animals were examined. Blood was collected from all females prior to caesarean section for analysis of thyroid hormone levels. The uteri and ovaries were dissected and evaluated for gravid uterus weight, the number of corpora lutea, implantations, pre- and post implantation loss, early and late resportions and live and dead fetuses. In addition, fetuses were evaluated for sex ratio, body weight and anogenital distance and examined for external, placental, visceral and skeletal abnormalities.

Homogeneity and stability of the test item formulated in vehicle were confirmed by analytical methods. There was no mortality observed during the whole study period. Maternal toxicity became evident in clinical signs of toxicity, reduced body weight and reduced food consumption. At 110 mg/kg bw/day, loose stool and salivation were noted in the dams after dosing. Body weight of the high dose group animals was statistically significantly reduced (by up to -7%) on gestation Days 12-20. The observation was in line with a significant decrease in food consumption at 110 mg/kg bw/day from gestation Days 8-19 (up to -15%).

There were no findings in thyroid weight and no treatment-related changes on thyroid hormone levels. Gross necropsy revealed a depressed patch in the mucosa of the forestomach in animals of the 31 and 110 mg/kg bw/day dose groups. At histopathological examination, hyperplasia of squamous cells in the stomach and inflammatory cell infiltrate in the forestomach were observed at ≥ 7 mg/kg bw/day. Erosion/ulcer of the forestomach was observed at ≥ 31 mg/kg bw/day. Hypertrophy of mucous neck cells in the glandular stomach was observed in the 110 mg/kg bw/day group. The changes are indicative of a local direct irritancy of the test item and attributed to treatment. Further, in the larynx and trachea, erosion/ulcer, focal regeneration of mucosal epithelium, and inflammatory cell infiltrate in the mucosa were observed in the 110 mg/kg bw/day group. These changes were considered irritant changes due to direct exposure of the test article by gavage-related reflux.

No findings were observed in caesarean section data with respect to the number of corpora lutea, implantation sites, pre- and post-implantation loss, early and late resorptions and live and dead fetuses. In addition, sex ratio and anogenital distance were not affected by treatment and no treatment-related external, placental, visceral and skeletal abnormalities or variations were noted.

Based on these results and under the conditions of this study, a NOAEL for maternal toxicity was set to 31 mg/kg bw/day. The NOAEL for local effects was < 7 mg/kg bw/day. With regard to foetal developmental toxicity, the NOAEL was 110 mg/kg bw/day in Crl:CD(SD) rats, corresponding to the highest dose level tested.

Toxicity to reproduction: other studies

Additional information

No data are available.

Justification for classification or non-classification

The available data on developmental toxicity and the histopathological examination of reproductive organs in the 90-day inhalation toxicity study do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.

However, as no further information on fertility is available, the overall conclusion for classification of reproductive toxicity is data lacking.