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REACH

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, isocyanurate type

EC number: 931-312-3 | CAS number: 53880-05-0

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No studies have been performed to explicitly address the question of reproductive effects in animals caused by the test item. However, in the prenatal developmental toxicity study according to OECD 414 the reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item (see below; LPT, 2017).

Read across, according to REACH Annex XI, 1.5., from the available data on reproductive toxicity/fertility, obtained from similar substances, gives no indications for a reproductive toxic potential/fertility. Furthermore, in accordance to REACH Annex XI, 1.2., the available data on MoA and repeated dose toxicity give sufficient weight of evidence to conclude that the substance is not a reproductive/fertility toxicant. The available data are considered adequate and sufficient for the purpose of classification and labelling and risk assessment, and thereforea data waiver is claimed for a definite reproductive / fertility toxicity study.

Link to relevant study records

Referenceopen all close all

Reference 1

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

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

other: Grouping and read-across according to Reg (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Reg (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates

Remarks:

see also "Justification for type of information"

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to ECHA Practical Guide 6 the maximum score for read across is rel. 2

Justification for type of information:

Remark regarding read across approach IPDI oligomers, isocyanurate type:
3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate oligomers, isocyanurate type, CAS 53880-05-0, is a prepolymerised aliphatic polyisocyanate compound, used in manufacture of polyurethanes. The idealised structure is built of 3 units of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (= Isophorondiisocyanat, IPDI), but actually the product contains a range of oligomeric structures with also 5, 7, 9, and > 11 IPDI units and an average molecular weight of MW = 930 g/mol (Mn 790).

The only reactive functional group in the molecule, the isocyanate group (NCO-group; N=C=O; common functional group), is responsible for the toxicological mode of action (MoA) of the substances.No toxic effect is anticipated from the aliphatic backbone of the molecules or the species that is yield from the NCO-conversion. The MoA is characterised by the local irritant effect at the first site of contact/port-of-entry (e.g. respiratory tract, skin, eyes) and is, moreover, the common MoA for other aliphatic monomeric and homopolymeric isocyanates. This defines the applicability domain of substances that should belong to the group: aliphatic monomeric and homopolymeric isocyanates without any other functional groups. Examples are hexamethylene 1,6-diisocyanate (HDI)-based or 4,4'-methylenedicyclohexyl diisocyanate (H12MDI)-based polyisocyanates. A comprehensive database is available for some of these substances pointing to that common primary toxicological profile, dominated by the irritation potential at the first site of contact/port-of-entry.
A full and detailed text "Justification for grouping and read-across according to Regulation (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Regulation (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates" is attached to chapter 13 of IUCLID. Based on this comparative evaluation the conclusion is drawn that in this case grouping and read-across of toxicological data according to Regulation (EC) No. 1907/2006 (REACH), Annex XI, 1.5 is justified.

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

(1995)

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Wistar Hsd Cpb:WU (SPF)
- Source: Harlan-Winkelmann GmbH, Borchen, Germany
- Age at study initiation: 13 weeks
- Weight at study initiation: males 365 (344-388) g, females 218 (198-233) g
- Housing: singly in Makrolon Type IIIh cages except during their overnight co-housing during the matings
- Diet and Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): approx. 50
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure (if applicable):

nose only

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Mode of exposure: Animals were nose-only exposed to the aerosolized test article in restrainers made of Plexiglas. The type of exposure is comparable with a directed-flow exposure design (Moss and Asgharian, Respiratory Drug Delivery IV, 1994, 197-201).
- Exposure apparatus: Chambers used are commercially available (TSE, Bad Homburg, Germany) and the performance as well as their validation has been published (e.g. Pauluhn, Journal of Applied Toxicology, 14, 55-62, 1994). Each segment of the aluminum inhalation chamber has the following dimensions: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm (internal volume = about 3.8 I).
- Generation of aerosol: In order to increase the efficiency of the generation of respirable particles and to prevent larger particles from entering the chamber a preseparator/baffle system was used. Under dynamic conditions the various concentrations of the test substance were nebulized into the baffle (pre-separator) which entrained the substance into the intake of the cylindrical inhalation chamber. For nebulization a binary nozzle (maintained at a temperature of 30°C) and conditioned compressed air (15 L/min and 10 µL/min test substance; dispersion pressure approximately 600 kPa). The test substance was fed into the nozzle by a digital pump (Hamilton Microlab M). This atmosphere was diluted further with 45 L/min prior to entering the inhalation chamber. The targeted concentrations were achieved by using air extraction/substitution dilution cascades.
- Inhalation chamber equilibrium concentration: The test atmosphere generation conditions provide an adequate number of air exchanges per hour (> 200 x, continuos generation of test atmosphere). Under such test conditions used chamber equilibrium is attained in less than one minute of exposure (t99% = 4.6 x chamber volume/chamber airflow). The ratio between the air supplied and exhausted was chosen so that approximately 90% of the supplied air is removed via the exhaust system.
- Conditioning the compressed air: Compressed air was supplied by Boge compressors and was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer. Adequate control devices were employed to control supply pressure.
- Exhaust air treatment: The exhaust air was purified via cotton woll and HEPA filters.
- Temperature and humidity measurements were performed by the computerized Data Acquisition and Control System using FTF11-Sensoren (Fa. Elka Electronic, Lüdenscheid, Germany).

TEST ATMOSPHERE
- The integrity end stability of the aerosol generation and exposure system was monitored using a RAM-1 (MIE, Bedford, MA, USA) and FhG (Fraunhofer Institute, Hannover, Germany) real-time aerosol photometer.
- Samples taken from breathing zone: yes
- Brief description of analytical method used: gravimetric analysis of filter samples (filter: Glass-Fibre-Filter, Sartorius, Göttingen, Germany; digital balance).
- Particle size distribution: The particle-size distribution was analyzed using a BERNER-Type Aeras low-pressure critical orifice cascade impactor. > 92 % of the particle mass had an aerodynamic diameter - MMAD (Mass median aerodynamic diameter): The respirability of the aerosol was adequate, i.e. the mass median aerodynamic diameter (MMAD) was 1.1 µm at 1 mg/m³, 1.1 µm at 6 mg/m³ and 1.0 µm at 36 mg/m³ (geometric standard deviation (GSD) approx. 2).

Details on mating procedure:

MATING PROCEDURES: During the following mating period the first F0 male was cohoused with the first female F0 animal within the group and so on over night at a maximum of 12 times during the two-week mating period. As a rule inseminated females were not further co-housed. Insemination was established by investigating vaginal smears prepared in the morning.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Actual target concentrations were measured in each chamber up to 3 times per day per gravimetric analysis. Chamber samples were taken in the viscinity of the breathing zone.

Duration of treatment / exposure:

The test substance was administered to parental (F0) animals two weeks prior to and during their mating, during the resultant pregnancy up day
19 p.c. Males were dosed 28 days at a minimum. For technical reasons (to avoid withdrawal from their pups) females were not treated during lactation.

Frequency of treatment:

6 hours/day, 7 days/week, for 2 weeks

Details on study schedule:

After a gestation period of about 22 days litters were born and the dams were allowed to rear them up to day 4-6 p.p. Then dams and their pups were killed.

Remarks:

Doses / Concentrations:
1, 6, 36 mg/m³
Basis:
other: target concentration

Remarks:

Doses / Concentrations:
1.06, 5.95, 34.04 mg/m³
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
5, 20, 119 mg/m³
Basis:
nominal conc.

No. of animals per sex per dose:

12 test animals / 12 controls

Control animals:

other: conditioned air

Details on study design:

- Dose selection rationale: An orientating aerosol inhalation pilot study with 5 male and 5 female rats exposed nose-only for 1 week to target concentrations of 1, 6 and 36 mg/m³ establishes a NOAEL of 6 mg/m³ and serves for dose selection rationale

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes, all F0 parental animals
- Time schedule: Twice daily (once daily on weekends and public holidays); Any findings such as course of birth e.g. prolonged parturition, morbidity and mortality as well as lactation behavior noticed during this cage side observation were recorded. Furthermore, all rats were clinically observed before and after inhalation exposure especially for symptoms concerning nose and breathing.

DETAILED CLINICAL OBSERVATIONS: Yes, all F0 parental animals
- Time schedule: Prior to the study and at least once weekly as routine at their cage change. This investigation includes the evaluation of the general state of health, behavior, condition of the fur, and the orifices as well as excretory products. During gestation periods females were clinically examined on day 0, 7, 14,20, and during lactation on day 0 and 4 in the same way.

BODY WEIGHT: Yes, all F0 parental animals
- Time schedule for examinations: at study-start (first day of dosing), then weekly for male animals up to necropsy and for female animals up to established insemination. After that female animals were weighed on postcoital days 0, 7, 14 and 20; and on days 0 and 4 after birth of their pups. F0 animals were weighed at the day of necropsy to permit calculations of the relative organ weights.

FOOD CONSUMPTION: Yes, all F0 parental animals
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

Oestrous cyclicity (parental animals):

At necropsy also the number of corpora lutea in the right and left ovary was determined.

Sperm parameters (parental animals):

Parameters examined in male parental generation:
- Organ weight of left epididymis and testes were done during the scheduled necropsy
- Examination on Sperms and Spermatids: Determination of spermatozoa motility and viability, determination of spermatozoa morphology, determination of spermatozoa in epididymis (spermatozoa density per mg epididymis), determination of homogenization resistant spermatid heads in the testis (number of spermatid heads per mg testis)

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring shortly after birth and on day 4 p.p.:
- number of live and dead pups
- sex of the pups
- body weights
- clinical signs
- apparent malformations were determined

Postmortem examinations (parental animals):

SACRIFICE
- Unscheduled Necropsies: Parental animals that died or were killed in moribund condition (under diethyl ether narcosis) during the study were necropsied and macroscopically examined.
- Scheduled Necropsies: When pups were 4 to 6 days old dams were anesthetized with carbon dioxide and killed by exsanguination (at carotid artery) and examined for gross pathology. F0 males were killed as scheduled under carbon dioxide narcosis when they were administered 28 days to a minimum.

GROSS NECROPSY
In F0 females implantation sites were counted and documented. Implantation sites were stained with 10% ammoniumsulfide. At necropsy also the number of corpora lutea in the right and left ovary was determined.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Organ weight determinations of the lungs (with trachea), left epididymis and testes were done during the scheduled necropsy.
- Fixed organs/organ specimen of the F0 parental animals(in 10 % neutral buffered formalin solution): lungs (instilled) with trachea, head, one testis, ovaries with oviducts, one epididymis, seminal vesicles, coagulation glands, prostate, tattooed ears and all organs/organ specimen exhibiting macroscopic changes.
- Histopathological evaluation of testes, epididymides and ovaries of control and high dose rats.

Postmortem examinations (offspring):

GROSS NECROPSY
- Unscheduled Necropsies: Pups that were found dead at birth, that died during lactation as well as those killed (with carbon dioxide) in moribund condition were macroscopically inspected after opening the body cavities, with particular attention on the organs of reproduction except for cases of autolysis or cannibalism. This includes also visible skeletal abnormalities as far as possible. A lung flotation in water was performed during the necropsy of pups found dead on the day of the first litter inspection to determine whether pups had breathed at birth or not. Macroscopically changed organs were fixed in 10% formalin.
- Scheduled Necropsies
When they were 4 to 6 days old pups were killed under carbon dioxide anesthesia and were examined for macroscopical alterations as described above.

Statistics:

Dunnett-Test with a variance analysis; Fisher’s exact CHI-SQUARE (positive ANOVA probability test with a significance levels of alpha = 5%).

Reproductive indices:

- Indices: insemination, fertility, gestation

Offspring viability indices:

- Indices: live birth, viability

Details on results (parental animals)
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
At 36 mg/m³ changes in breathing behavior and/or serous nasal discharge (nostrils with red encrustation) were noted in the majority of F0 rats. At 36 mg/m³ in single animals also signs of poor general conditions occurred and slightly increased (2 of 24 rats) mortality was observed. One male of the high dose group was found dead during the premating period and one female of the high dose group has to be killed in moribund condition. At 6 mg/m³ only serous nasal discharge and red encrusted nostrils were noted in F0 rats.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No toxic effect was seen on body weights of F0 rats up to 6 mg/m³. At 36 mg/m³ reduced body weight gain was noted at some time points in both sexes (males: week 5-6: 2.8g vs. 9.8g in controls, week 4-5: 10.2g vs. -1.2g in controls; females: week 1-2: -11.2g vs -4.7g in controls). The food intake of 36 mg/m³ F0 males was transiently reduced. The absolute (14%) and relative (18%) weights of the lungs were increased in 36 mg/m3 F0 male rats.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Results of sperm analysis were excluded from the study evaluation, because mechanical stress on the epididymides and testes caused by the narrowness of exposure restrainers had induced untypical and test-compound independent low sperm motility (below 30%) and increase in sperm abnormalities (higher than 50%) in all groups which corroborate with testicular and epididymal changes seen histologically.
Dose mg/m³: 0 / 1 / 6 / 36
Sperm motility, (first min) %: 21 / 7 / 26 / 16
Sperm motility (fifth min) %: 18 / 6 / 25 / 15
Abnormal sperms %: 59.4 / 87.4 / 60.9 / 66.4
Mean number of spermatids per mg testis: 52773 / 41767 / 41989 / 49707
Mean number of sperms per mg epididymis: 490037 / 138194 / 347913 / 323042

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
At 36 mg/m³ a slightly reduced fertility index was noted. No other reproduction parameter was affected.
Dose mg/m³: 0/ 1/ 6/ 36
Insemination index %: 100.0/ 91.7/ 100.0/ 100.0
Fertility index %: 91.7/ 81.8/ 83.8/ 66.7 (p > 0.05)
Gestation index %: 90.9/ 100.0/ 100.0/ 100.0
Gestation length Days: 22.11/ 22.25/ 22.22/ 22.00
Co-housed females n: 12/ 12/ 12/ 12
Number of implantation sites (per litter): 10.8 / 10.56 / 11.50 / 9.88
Litters alive n: 10/ 9/ 10/ 8
Live birth index %: 98.57 / 99.07 / 97.22 / 96.36
Viability index %: 99.00 / 100.0 / 92.17 / 98.96

HISTOPATHOLOGY (PARENTAL ANIMALS)
No test compound-related effects were seen in the testes and epididymides of F0 rats. In the testes of both groups evaluated (control and high dose) tubular degeneration (mainly multi/focal) was seen in the majority of animals:
dose mg/m³: 0 ; 36
Focal tubular degeneration: 5/12 ; 8/12
Dif. tubular degeneration: 2/12 ; 0/12
In the epididymides, spermatic debris and oligospermia occurred in almost all rats.

dose mg/m³: 0 ; 36
Spermatic debris: 12/12 ; 11/12
Oligospermia: 11/12 ; 10/12
The morphology of the ovaries of F0 females was not affected.

Dose descriptor:

NOAEL

Effect level:

1 mg/m³ air

Sex:

male/female

Basis for effect level:

other: General toxicity: signs of respiratory irritation (breathing behaviour, nose discharge) at higher dose group (6 and 36 mg/m3)

Dose descriptor:

NOAEL

Effect level:

6 mg/m³ air

Sex:

male/female

Basis for effect level:

other: Reproduction Toxicity: slightly reduced fertility index at next higher dose group (36 mg/m3)

VIABILITY (OFFSPRING)
dose mg/m³: 0 / 1 / 6 / 36
- Live birth index %: 98.57 / 99.07 / 97.22 / 96.36
- Viability index %: 99.00 / 100.0 / 92.17 / 98.96
- Males %: 54.31 / 50.56 / 49.23 /53.90

CLINICAL SIGNS (OFFSPRING)
No remarkable clinical signs were observed during the four day lactation period up to 36 mg/m³.

GROSS PATHOLOGY (OFFSPRING)
No effect on body weights and no macroscopical alterations were noted at pup necropsies up to 36 mg/m³.

Key result

Dose descriptor:

NOAEL

Generation:

Effect level:

>= 36 mg/m³ air (nominal)

Sex:

male/female

Basis for effect level:

other: no adverse effects were observed up to 36 mg/m3

Reproductive effects observed:

not specified

Remark regarding read across approach IPDI oligomers, isocyanurate type:

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate oligomers, isocyanurate type, CAS 53880-05-0, is a prepolymerised aliphatic polyisocyanate compound, used in manufacture of polyurethanes. The idealised structure is built of 3 units of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (= Isophorondiisocyanat, IPDI), but actually the product contains a range of oligomeric structures with also 5, 7, 9, and > 11 IPDI units and an average molecular weight of MW = 930 g/mol (Mn 790).

The only reactive functional group in the molecule, the isocyanate group (NCO-group; N=C=O; common functional group), is responsible for the toxicological mode of action (MoA) of the substances.No toxic effect is anticipated from the aliphatic backbone of the molecules or the species that is yield from the NCO-conversion. The MoA is characterised by the local irritant effect at the first site of contact/port-of-entry (e.g. respiratory tract, skin, eyes) and is, moreover, the common MoA for other aliphatic monomeric and homopolymeric isocyanates. This defines the applicability domain of substances that should belong to the group: aliphatic monomeric and homopolymeric isocyanates without any other functional groups. Examples are hexamethylene 1,6-diisocyanate (HDI)-based or 4,4'-methylenedicyclohexyl diisocyanate (H12MDI)-based polyisocyanates. A comprehensive database is available for some of these substances (see list below) pointing to that common primary toxicological profile, dominated by the irritation potential at the first site of contact/port-of-entry.

A full and detailed text "Justification for grouping and read-acrossaccording to Regulation (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Regulation (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates" is attached to chapter 13 of IUCLID. Based on this comparative evaluation the conclusion is drawn that in this case grouping and read-across of toxicological data according to Regulation (EC) No. 1907/2006 (REACH), Annex XI, 1.5 is justified.

Short name	Name used for registration	CAS no	EC /ECHA list no
IPDI	3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate	4098-71-9	223-861-6
IPDI oligomers, isocyanurate type	3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, isocyanurate type	53880-05-0	931-312-3
HDI	Hexamethylene diisocyanate	822-06-0	212-485-8
HDI oligomers, isocyanurate type	HDI oligomers, isocyanurate	28182-81-0	931-274-8
HDI oligomers, iminooxadiazindione type	HDI oligomers, iminooxadiazindione	28182-81-0	931-297-3
HDI oligomers, biuret type	HDI oligomers, biuret	28182-81-0	939-340-8
HDI oligomers, uretdione type	HDI oligomers, uretdione	28182-81-0	931-288-4
H12MDI	4,4'-Methylenedicyclohexyl diisocyanate	5124-30-1	225-863-2

Executive summary:

4,4´-Methylenedicyclohexyl diisocyanate has already been assessed in the OECD HPV programme.

Cited from SIAR for SIAM20 (Paris, April 19 -22, 2005): "In a reproduction/developmental toxicity screening test according to OECD TG 421 (...) Wistar rats (12 animals/sex/dose) were exposed to 4,4´-methylenedicyclohexyl diisocyanate aerosol. The rats were exposed nose-only daily for 6 hours/day to concentrations of 0, 1, 6 and 36 mg/m³ (= target concentrations). F0male and female rats were exposed for 2 weeks (premating exposure period), which was continued during the approximately 2 week mating period. Males were exposed for at least 28 days (prior to necropsy) whereas the exposure of the F0females continued during the pregnancy up to day 19 post coitum (p.c.). Exposure of the F0females was suspended up to the day of necropsy on day 4 - 6 p.p. (post partum), i.e., the time points at which F1pups were sacrificed. In all exposure groups, the aerosol was highly respirable to rats, i.e., the average mass median aerodynamic diameter (MMAD) was ≈ 1 μm, the geometric standard deviation (GSD) was ≈ 2. Clinical signs as changes in breathing behavior and/or serous nasal discharge were documented for F0animals of the 6 and 36 mg/m³ groups. One male of the high dose group was found dead during the premating period and one female of the high dose group had to be killed in moribund condition. No effect on body weights gain, food consumption and necropsy findings, were observed at ≤ 6 mg/m3. Significant increases of absolute and relative weights of the lungs were detected at 36 mg/m³ in male rats. No effects of 4,4´-methylenedicyclohexyl diisocyanate on reproductive parameters such as insemination index, gestation index and length and the number of implantation sites were described. At 36 mg/m³ a slightly reduced fertility index was noted (0, 1, 6, 36 mg/m³: fertility index: 91.7, 81.8, 83.8, 66.7* % (*= p > 0.05)). No remarkable clinical signs were seen in any F1pubs during the 4 day lactation period and body weight gain was comparable to the control animals. In the testes of both groups evaluated (control and high concentration F0animals) tubular degeneration (mainly multi/focal) was seen in the majority of animals. In the epididymides, spermatic debris and oligospermia occurred in almost all rats. These histopathological findings are concordant with the results of the spermatological evaluation of all animals (no or very low sperm motility and high percentage of abnormal sperms in control rats and in all concentration groups). Nevertheless the findings seen in the testes are not substance-related because they were found also in the control animals and they are dose independent. Mechanical stress on the epididymides and testes caused by the narrowness of exposure restrainers seems to be responsible for the effects seen in all 4,4´-methylenedicyclohexyl diisocyanate and air exposed animals.

Based on these findings, the NOAELs were considered to be 1 mg/m³ in males and females for general toxicity. Due to a slightly reduced fertility index at 36 mg/m³, 6 mg/m³ is the NOAEL for reproductive toxicity in rats."

Reference 3

Endpoint:: one-generation reproductive toxicity
Type of information:: other: Grouping and read-across according to Reg (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Reg (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates
Remarks:: see also "Justification for type of information"
Adequacy of study:: weight of evidence
Study period:: 1999
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: other: According to ECHA Practical Guide 6 the maximum score for read across is rel. 2
Justification for type of information:: Remark regarding read across approach for IPDI oligomers, isocyanurate type:
3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate oligomers, isocyanurate type, CAS 53880-05-0, is a prepolymerised aliphatic polyisocyanate compound, used in manufacture of polyurethanes. The idealised structure is built of 3 units of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (= Isophorondiisocyanat, IPDI), but actually the product contains a range of oligomeric structures with also 5, 7, 9, and >11 IPDI units and an average molecular weight of MW = 930 g/mol (Mn 790).

The only reactive functional group in the molecule, the isocyanate group (NCO-group; N=C=O; common functional group), is responsible for the toxicological mode of action (MoA) of the substances. No toxic effect is anticipated from the aliphatic backbone of the molecules or the species that is yield from the NCO-conversion. The MoA is characterised by the local irritant effect at the first site of contact/port-of-entry (e.g. respiratory tract, skin, eyes) and is, moreover, the common MoA for other aliphatic monomeric and homopolymeric isocyanates. This defines the applicability domain of substances that should belong to the group: aliphatic monomeric and homopolymeric isocyanates without any other functional groups. Examples are hexamethylene 1,6-diisocyanate (HDI)-based or 4,4'-methylenedicyclohexyl diisocyanate (H12MDI)-based polyisocyanates. A comprehensive database is available for some of these substances pointing to that common primary toxicological profile, dominated by the irritation potential at the first site of contact/port-of-entry.

A full and detailed text "Justification for grouping and read-across according to Regulation (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Regulation (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates" is attached to chapter 13 of IUCLID. Based on this comparative evaluation the conclusion is drawn that in this case grouping and read-across of toxicological data according to Regulation (EC) No. 1907/2006 (REACH), Annex XI, 1.5 is justified.
Qualifier:: according to guideline
Guideline:: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:: no
GLP compliance:: yes
Species:: rat
Strain:: Sprague-Dawley
Sex:: male/female
Details on test animals or test system 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
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 eaeh 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 inereases in RH due to chamber handling and animal care. The increase to 70% RH is in accordanee 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, 0.005, 0.050, 0.300 ppm
Basis:
nominal conc.
Remarks:: Doses / Concentrations:
0, 0.005, 0.053, 0.299 ppm
Basis:
analytical conc.
No. of animals per sex per dose:: 15
Control animals:: yes, sham-exposed
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-Oawley 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 histopathologie 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 histopathologie 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 produee 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
: Key result
Dose descriptor:: NOEL
Remarks:: parental toxicity
Effect level:: 0.005 ppm (nominal)
Sex:: male/female
Basis for effect level:: other: Microscopic alterations in the nasal cavity at next higher concentration
: Key result
Dose descriptor:: NOEL
Remarks:: fertility
Effect level:: 0.3 ppm (nominal)
Sex:: male/female
Basis for effect level:: other: No effect on fertility up to the highest dose tested
: Key result
Dose descriptor:: NOEL
Remarks:: pub toxicity
Generation:: F1
Effect level:: 0.3 ppm (nominal)
Sex:: male/female
Basis for effect level:: other: The no-observed-effect-level (NOEL) for reproduction (including neonatal development) as well as for hematology, clinical chemistry, and neurotoxicity was 0.300 ppm (2.03 mg/m3)
Reproductive effects observed:: not specified
Conclusions:: Under the conditions of this OECD 422 study, the no-observed-effect-level (NOEL) for reproduction (including neonatal development) as well as for hematology, clinical chemistry, and neurotoxicity was 0.300 ppm (2.03 mg/m3) and the overall NOEL was 0.005 ppm (0.034 mg/m3).
Executive summary:: In a combined reproductive/developmental/neurotoxicity study (OECD TG 422) with 1,6-hexamethylene diisocyanate (HDI) rats were exposed, via whole-body exposure, to HDI vapour concentrations of 0, 0.005, 0.050, or 0.300 ppm for 6 hours/day during a 14-day premating phase, up to a 14-day mating phase, and a 21-day gestation phase. Analytically confirmed overall (for the entire study) mean HDI vapour concentrations were 0.005, 0.053 and 0.299 ppm. 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 0.050 and 0.300 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 0.300 ppm (2.03 mg/m3) and the overall NOEL was 0.005 ppm (0.034 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

Studies in Animals

No studies have been performed to explicitly address the question of reproductive toxicity in animals caused by the test item. However, in the prenatal developmental toxicity study according to OECD 414 the reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item (see below; LPT, 2017).

Furthermore, histopathological results of a subchronic 13 week inhalation study with the test item in female and male Wistar rats according to OECD Guideline 413 (Ma-Hock et al., BASF, 2009) showed no substance induced effects on the examined reproductive organs (testes, ovaries, epididymides, oviducts, uterus, vagina) up to the highest test concentration (75 mg/m3).

For further detaills on general toxicity see chapter 7.5.2 of IUCLID.

Based on read across further reliable data are used to assess the endpoint reproductive toxicity/fertility for the substance. A full and detailed text "Justification for grouping and read-across according to Regulation (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Regulation (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates" is attached to chapter 13 of IUCLID. Based on this comparative evaluation the conclusion is drawn that in this case grouping and read-across of toxicological data according to Regulation (EC) No 1907/2006 (REACH), Annex XI, 1.5 is justified. Furthermore, in accordance to REACH Annex XI, 1.2., the available data on MoA and repeated dose toxicity give sufficient weight of evidence to conclude that the substance is not a reproductive/fertility toxicant.

However, since no definite study is available for reproductive toxicity/fertility a data waiver is claimed.

Discussion

No explicit study for effects on Reproductive Toxicity/Fertility is available for any of the similar aliphatic isocyanates that were considered to belong to a group. The only available studies regarding reproductive /fertility toxicity are one Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422; Astroff et al., 2000a) and one Reproduction/Developmental Toxicity Screening Test (OECD 421; Eiben & Rosenbruch, 2004), both with inhalation exposure, for HDI and H12MDI, respectively. The data of these monomeric building blocks reflect a worst-case szenario for the polyisocyanates, since the inhalation toxicity of the monomers is anticipated to induce the higher inhalation toxicity (i.e. respiratory irritant) compared to the polyisocyanates, due to their higher reactivity.

The monomeric HDI, which was administered as vapour in the above outlined screening study, serves as representative of the more volatile and more toxic aliphatic isocyanates. H12MDI, on the other hand, can serve as an example for the less toxic/less volatile aliphatic isocyanates, which are administered as aerosols. Accordingly, reproductive toxicity data exists for an example of the most severe as well as for an example of the less toxic aliphatic isocyanates, thus allowing a reliable estimation of the other members of the group. Regarding the MoA and the threshold of effects both studies are in accordance with the results of the corresponding repeated dose studies. Besides a slightly reduced fertility index observed in the study with H12MDI at a dose 2-fold above the threshold for general toxicity, no effect on fertility or fetal development was observed in neither of the reproductive screening studies.

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,Mangelsdorf et al. 2003, Ulbrich & Palmer 1995, Janer et al. 2007, Dent 2007, Sanbuissho et al. 2009; for details of references see attached document). 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 sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

For the purpose of assessing reproductive toxicity/fertility, the available repeated dose studies were evaluated for effects on reproductive organs. In a first step it was investigated if any/which reproductive organs were examined in the respective study. It could be seen that all of the studies, whether if chronic, subchronic or subacute, included at least the determination of organ weights and histopathological examination of ovaries and testes. Regarding the chronic (2 year) and subchronic (90-day) studies at least ovaries, prostate, seminal vesicle, testes and uterus were examined histopathologically. The result is that none of the repeated dose studies revealed effects on any of the reproductive organs examined. Moreover, as already outlined in the previous chapter, no adverse systemic effects at all were observed in the entire repeated dose database for the respective aliphatic isocyanates.

Therefore, the conclusion can be drawn that data uniformly show that toxicity for aliphatic isocyanates is limited to the port-of-entry; any other manifestations of toxicity in reproductive toxicity studies occur only as secondary effect, e.g. secondary effects on the development. 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 studies no potential for reproductive toxicity was seen for the substance. It is not expected that full studies on reproductive toxicity/fertility would reveal new insights for the hazard and risk assessment and therefore they should be omitted in case of IPDI oligomers, isocyanurate type. This takes also into account animal welfare considerations and the aim to balance the value of additional information gained with the need to avoid animal testing whenever possible.

Nevertheless, if additional studies on reproductive toxicity/fertility are judged to be necessary such new studies on reproductive toxicity should take into account the relevant route of exposure. This is for the specific substance the inhalation route, since inhalation exposure might occur during handling and use. In contrast, oral exposure is not expected to occur. In addition, the toxicological profile of the substance is dominated by the local reactivity at the respiratory tract. Systemic availability after oral exposure was not observed in the one recently conducted developmental toxicity study with oral exposure (LPT, 2017). Under such circumstances route to route extrapolation is scientifically questionable and therefore the oral route should be avoided. Also dose finding for any additional study will benefit from the already available database on repeated dose toxicity, which is by the inhalation route.

Summarizing, although studies on fertility, respectively multi-generation studies were not available for the aliphatic isocyanates further testing should be omitted. Read across, according to REACH Annex XI, 1.5., from the available data on reproductive toxicity/fertility, obtained from relevant representatives of the group, gives no indications for a reproductive toxic potential/fertility. Furthermore, in accordance to REACH Annex XI, 1.2., the available data on MoA and repeated dose toxicity give sufficient weight of evidence to conclude that the substance is not a reproductive/fertility toxicant.

Studies in Humans

There are no data available.

Justification for selection of Effect on fertility via oral route:
Data regarding effects on fertility are not available. A data waiver is claimed.

Justification for selection of Effect on fertility via inhalation route:
The relevant route of exposure during use is by inhalation. Data regarding effects on fertility are not available. A data waiver is claimed.

Justification for selection of Effect on fertility via dermal route:
Data regarding effects on fertility are not available. A data waiver is claimed.

Effects on developmental toxicity

Description of key information

In a gavage study performed in accordance with OECD 414, the test item showed no adverse effects on the development of rats up to and including the highest tested dose level of 1000 mg/kg bw/day (LPT, 2017). Under the present test conditions, the no-observed-adverse-effect level (NOAEL) for the fetal organism was 1000 mg test item/kg bw/day. The reproductive parameters (number of implantation sites, number of resorbtions and number of fetuses) were also not influenced by the test item.

Additionally, three fully reliable inhalation developmental toxicity studies on rats according to OECD 414 are available based on read across for comparable aliphatic isocyanates and give no indication for any specific developmental toxicity for the aliphatic isocyanates. Fetal development is affected only at levels that causes clear maternal toxicity and thus considered as secondary effect (Klaus, 2004; Astroff, 2000b; Langewische, 2004; for details see "Justification for grouping and read-across according to Regulation (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Regulation (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates", attached to chapter 13 of IUCLID).

Link to relevant study records

Referenceopen all close all

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2017-04-11 to 2017-05-09

Reliability:

1 (reliable without restriction)

Justification for type of information:

This study is used as DRF for the OECD 414 study (LPT, 2017).

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

adopted January 22, 2001

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Version / remarks:

May 30, 2008

GLP compliance:

Remarks:

The study was performed based on 'Good Laboratory Practice' Regulations of the EC enacted in Germany in the 'Chemikaliengesetz' [Chemicals Act], current edition; 'OECD Principles of Good Laboratory Practice' Document Nos. 1, 8 and 13 ENV/MC/CHEM (98) 17,

Limit test:

Species:

rat

Strain:

other: CD /Crl:CD(SD)

Details on test animals or test system and environmental conditions:

TEST ORGANISMS:
- Species: Rat
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Strain: CD / Crl: CD(SD)
- Age: 60 days
- body weight: 211.3 - 229.8 g
- Diet: ad libitum, Commercial diet ssniff® R/Z V1324 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water: ad libitum
- Acclimatisation period: 5 days
-Housing: Except during the mating period, the dams were kept singly in MAKROLON cages
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C +/- 3° C
- Humidity (%): 55% +/- 15 %
- Illumination: 12 hours artifical fluorescent light and 12 hours dark
- Ventilation rate: between fifteen to twenty air changes per hour.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

ADMINISTRATION:
- Frequency: once daily, day 6 to 20 of gestation
- Dose volume: 3 ml/kg b.w.
- Dose: 0, 100, 300, 1000 mg/kg/bw
- Animals: 3 female rats/dose
- DOSAGE PREPARATION:
The test item formulations were freshly prepared every day.
The test item was suspended in the vehicle to the appropriate concentration and was administered orally at a constant volume once daily from the
6th to the 20th day of gestation.
The amount of the test item was daily adjusted to the current body weight of the animal. The control animals received the vehicle at the same
administration volume daily in the same way.
The male rats for mating remained untreated.

Analytical verification of doses or concentrations:

Remarks:

For each test or reference item that is mixed with a vehicle, tests by appropriate analytical methods will be carried out for the main study to determine the concentration, homogeneity and, if needed, stability of the test item in the formulations.

Details on mating procedure:

Sexually mature ('proved') male rats of the same breed served as partners. The female breeding partners were randomly chosen.

Mating was monogamous: 1 male and 1 female animal were placed together in one cage during the dark period. Each morning a vaginal smear was taken to check for the pres-ence of sperm. If findings were negative, mating was repeated with the same partner. The day on which sperm was found was considered as the day of conception (day 0 of pregnancy). This procedure was repeated until enough pregnant dams were available for all groups. Rats which did not become pregnant were excluded from the analysis of the results and replaced by other animals. A post-mortem negative staining according to SALEWSKI was carried out in the replaced animals in order to confirm the non-pregnancy status.

Duration of treatment / exposure:

From gestation day 6 until gestation day 20, 15 administration days.

Frequency of treatment:

Once daily

Duration of test:

On gestation day 21, the rats were laparotomised.

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

vehicle control

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

low dosw

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

intermediate dose

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

high dose

No. of animals per sex per dose:

3 female rats/dose , orally dosed with 0, 100, 300 or 1000 mg test item/kg b.w.
Evaluated litters: 2 litters per group

Control animals:

yes, concurrent vehicle

Details on study design:

Selection of species: The rat is a commonly used rodent species for such embryotoxicity studies.

Dose selection rationale:
The dose levels were selected in agreement with the Sponsor/Monitor based on available toxicological data (LD50 cut-off for the rat,
oral: > 14000 mg/kg b.w.).

Selection of route of administration: According to OECD guideline 414

Maternal examinations:

Dated and signed records of all activities relating to the day to day running and maintenance of the study within the animal units, as well as to the
group observations and examinations outlined in the Study Plan, were recorded in the appropriate documentation. In addition, observations relating
to the individual animals made throughout the study were recorded.

The following observations were made during the course of the study:
Clinical signs
Individual animals were observed daily for behavioural changes, reaction to treatment, or illness.
Immediately after administration, any signs of illness or reaction to treatment were recorded. In case of changes, the animals were observed until the symptoms disappeared. In addition, animals were checked regularly throughout the working day from 7.00 a.m. to 3.45 p.m.
On Saturdays and Sundays, the animals were checked regularly starting from 7.00 a.m. to 11.00 a.m. with a final check performed at approximately
3.30 p.m.
Dated and signed records of appearance, change and disappearance of clinical signs were maintained on clinical history sheets for individual animals.

Viability
Further checks were made early in the morning and again in the afternoon of each working day to look for dead or moribund animals. This would have allowed post mortem examinations to be carried out during the working period of that day. On Saturdays and Sundays, a similar procedure was followed except that the final check was carried out at approximately midday.
Animals showing signs of abortion or premature delivery would have been sacrificed on the same day. Fetuses obtained this way were examined for abnormal development, whenever possible. No abortion occurred in the study.

Body weight
The weight of each rat was recorded on day 0 of gestation (the day of detection of a positive mating sign), followed by daily weighing - always at the
same time of the day.
The body weight gain was calculated in intervals (i.e. day 0-3, 3 6, 6-9, 9-12, 12 15, 15-18 and 18-21), for the whole study (gestation day 0 - 21) and
for the period after the start of dosing (gestation day 6 to gestation day 21). Furthermore the carcass weight and the net weight gain from day 6 are
given.
These values are stated in the report.
These measurements were also used for calculating the daily amount of test item to be administered.

Food and drinking water consumption
The quantity of food consumed by each rat was recorded daily. Food intake per rat (g/rat/day) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment day.
The relative food consumption (g/kg b.w./day) was calculated using the following formula:

Daily food consumption [g/kg b.w./day]= Total food intake in g / Body weight in kg

Daily monitoring by visual appraisal of the drinking water bottles was maintained throughout the study. Dehydration of the dams was avoided.

EXAMINATIONS (NECROPSY), Examination of the dams
Dissection technique and evaluation of the animals:
On gestation day 21, the rats were laparotomised under ether narcosis. The ovaries and the uteri of the dams were removed; the gravid uteri (in toto) were weighed. In order to check for possible drug effects, a dissection with macroscopic examination of the internal organs and placentae of the dams was carried out on the day of sacrifice or on the day on which the animals were found dead. In case of macroscopical findings, the affected maternal tissues were preserved in 7% buffered formalin for possible future histopathological examinations.

Ovaries and uterine content:

Corpora lutea
- number per dam
- absolute number per group
- mean per group

Implantations
- number per dam
- distributions in the uterine horns
- absolute number per group
- mean per group

Resorptions
- number per dam
- distributions in the uterine horns
- absolute number per group
- mean per group
- early resorptions < 2 mm
- Late resorptions > 2 mm

Weight of placentae
- individual data per fetus
- mean per litter
- mean per group
- mean per sex and group

Weight of fetuses
- individual data per fetus (alive and dead)
- mean per litter
- mean per group
- mean per sex and group

Fetuses
- number per dam (alive)
- number per dam (dead)
- number of fetuses (alive and dead) per sex and dam
- distribution in the uterine horns
- absolute number of fetuses alive per group
- mean number of fetuses alive per group
- mean % of fetuses alive per group
- male/female ratio (alive and dead)

Runts
- number per dam
- mean per group

Malformed fetuses
- type of malformation
- individual data per fetus
- number and incidence (%) per group and litter

Total malformation rate [%] = malformed fetuses per group / fetuses per group x 100

Fetuses with variations
- type of variation
- individual data per fetus
- number and incidence (%) per group and litter

Total variation rate [%] = fetuses per group with variations / fetuses per group x 100

Indices of pre-implantation loss and post-implantation loss:

Calculation of group indices
Pre implantation
loss [%] = Corpora lutea (per group) - Implantations (per group) / Corpora lutea (per group) x 100

Post implantation
loss [%] = Implantations (per group) - living fetuses (per group) / Implantations (per group) x 100

Calculation of mean indices per litter
Pre implantation
loss [%] = sum of pre-implantation losses per litter in a group [%] / number of litters in a group

Post implantation
loss [%] = sum of post-implantation losses per litter in a group [%] / number of litters in a group

Fetal examinations:

Statistics:

No statistical analysis was conducted as only 2 animals per group were evaluated. The data of the spare animal of each group was not included.

Indices:

DRF, Fertility Index, Viability Index, Resorption Index, Pre-Implantation Loss Index, Post-Implantation Loss Index, Runts Index, Variation Index,
Number of litters having abnormalities, Number of abnormalities per litter

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related changes in behaviour, the external appearance or the faeces were noted in any of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
At 300 mg test item/kg b.w./day, a haemorrhagic nose/snout was noted for dam 5 on GD 15. As only one dam was affected on one day, this observation was considered to be incidental.

Mortality:

no mortality observed

Description (incidence):

No premature deaths were noted in the control group and in the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Body weight
No test item-related differences in body weight were noted between the dams of the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Throughout the study, the animals of the dose groups were noted with a slightly higher body weight (at maximum 14.3% above the control group for the low dose group on GD 21). This difference was considered to be within the range of spontaneous variability and not test item-related.

Body weight gain
No test item-related difference for the body weight gain compared to the control group was noted for the animals treated with 100, 300 or 1000 mg test item/kg b.w./day.
Like the body weight, also the body weight gain of the treatment groups was slightly higher as compared to the control group. This was considered to be not test item-related as noThe gravid uterus weight had a minor influence on the body weight gain as, in comparison to the control group, a slightly higher gravid uterus weight was noted for the treatment groups dose-response relationship was present.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test item-related differences were noted between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Food efficiency:

not examined

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

no effects observed

Description (incidence and severity):

No test item-related changes in drinking water consumption were noted between the dams of the control group and the dams of the treatment groups by visual appraisal.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Gravid uterus and carcass weight
No test item-related differences were noted between the gravid uterus weight and car-cass weight of the control dams and the dams of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
As already stated in section 'Body weight and body weight gain', the treatment groups were noted with slightly higher gravid uterus weights (at maximum 39.1% above the value of the control group in the low dose group). However, due to the absence of a dose-response relationship, this difference was considered to be not test item-related.

Body weight gain from gestation day 6
No test item-related differences for the absolute body weight gain and the net body weight gain between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day) were noted between gestation day 6 and gestation day 21.
For the net body weight gain, slightly higher values were noted for the treatment groups compared to the control group (at maximum 70.4% above the value of the control group in the intermediate dose groups). Combined with the higher weights of the gravid uterus, this led to higher values for the absolute body weight gain between 27.6% above the values of the control group for the high dose group and 42.2% above the value of the control group for the low dose group.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No observations were noted for the dams of the control group and the dams of the treat-ment groups (100, 300 or 1000 mg test item/kg b.w./day) during the macroscopic inspection of the organs and tissues.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

Description (incidence and severity):

No test item-related influence on the reproductive parameters (number of implantation sites, fetuses, resorptions and the indices of pre- and post-implantation) were noted between the dams of the control group and the dams of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Early or late resorptions:

no effects observed

Description (incidence and severity):

Dead fetuses:

no effects observed

Description (incidence and severity):

Changes in pregnancy duration:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Details on maternal toxic effects:

Maternal toxic effects:no effects

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The placental and fetal weights showed no test item-related differences between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Slightly higher values for the placental weights compared to the control group were noted for the male and female fetuses of the dams treated with 300 or 1000 mg test item/kg b.w./day (at maximum 27.0% above the value of the control group for the placentae of the male fetuses of the intermediate dose group). As no dose-response relationship was present, these differences were considered to be not test item-related.

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): see above

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

No dead fetus was noted in the control group and in the test item treated groups (100, 300 or 1000 mg test item/kg b.w./day).

Changes in sex ratio:

no effects observed

Description (incidence and severity):

No test item-related differences between the ratio of male and female fetuses (range: 0.50 - 1.33) were noted between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day). The wide range of the sex distribution was due to the low number of the evaluated litters.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Weight of placentae
The placental weights showed no test item-related differences between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

External macroscopic inspection of the fetuses at laparotomy
No macroscopically visible external alterations (malformations or variations) were noted for the fetuses of the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day) during the macroscopic inspection at laparotomy.

Skeletal malformations:

no effects observed

Description (incidence and severity):

Internal macroscopic inspection of the fetuses at laparotomy
No macroscopically visible internal alterations (malformations or variations) were noted for the fetuses of the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day) during the macroscopic inspection at laparotomy.

Visceral malformations:

no effects observed

Description (incidence and severity):

Other effects:

no effects observed

Description (incidence and severity):

Number of runts
No runt was noted in the control group and in the test item-treated groups (100, 300 or 1000 mg test item/kg b.w./day)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: prenatal developmental toxicity; highest dose tested

Developmental effects observed:

Conclusions:

Under the conditions of the study, test item did not show any teratogenic potential.
Based on the data obtained in this dose-range-finding study, the following dose levels are suggested for Prenatal developmental toxicity study in rats:
Group 1: Control, Group 2: 100 mg test item/kg b.w./day, p.o, Group 3: 300 mg test item/kg b.w./day, p.o, Group 4: 1000 mg test item/kg b.w./day, p.o

Executive summary:

The aim of this dose-range-finding study was to determine the dose levels for a prenatal developmental toxicity study of the test item in pregnant rat when administered orally during the critical period of organogenesis and the fetal development (6th to 20th day of gestation).

In this dose-range-finding study for a prenatal developmental toxicity study, the test item was administered orally to female rats at dose levels of 100, 300 or 1000 mg/kg b.w./day from the 6th to 20th day of pregnancy.

Findings


Examination of the dams:
Mortality	No premature deaths were noted in the control group and in the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Clinical signs	No test item-related signs of toxicity were noted.
Body weight and body weight gain	No test item-related differences were noted.
Food consumption and drinking water consumption	No test item-related differences were noted.
Necropsy findings	No test item-related changes were noted during the macroscopic inspection of the dams at necropsy.
Uterus and carcass weights	No test item-related differences were noted.
Reproduction data	No test item-related influence was noted on the reproductive parameter (number of implantation sites, resorptions and fetuses).

Examination of the fetus:
Mortality	No dead fetuses were noted in any of the test groups.

Body weight of the fetuses and the placentae	No test item-related differences were noted between the control group and the treatment groups.

Fetal alterations
Malformations	No malformations were noted during the external and internal macroscopic examinations at laparotomy.

Variations	The external and internal macroscopic examinations at laparotomy revealed no test item-related variations.

Under the present test conditions, the no-observed-adverse-effect level (NOAEL) was above 1000 mg test item/kg b.w./day for the dams.

No prematurely deceased dams were noted during the study.

No test item-related change in body weight, body weight gain, food and water consumption was noted in any treatment group.

No changes were noted in the macroscopic examination during laparotomy.

The no-observed-adverse-effect level (NOAEL) for the fetal organism was also above 1000 mg test item/kg b.w./day.

The reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item.

No dead fetuses, no malformations and no test item-related variations or retardations were noted.

Under the conditions of the study, test item did not show any teratogenic potential.

Based on the data obtained in this dose-range-finding study, the following dose levels are suggested for Prenatal developmental toxicity study in rats.

Group 1: Control

Group 2: 100 mgtest item

Group 3: 300 mgtest item

Group 4: 1000 mg test item

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017-06-19 to 2017-07-20

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 January 22, 2001

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Version / remarks:

May 30, 2008

GLP compliance:

yes (incl. QA statement)

Limit test:

Specific details on test material used for the study:

The test item was suspended in corn oil to the appropriate concentrations and was administered orally at a constant volume once daily from the 6th to the 20th day of gestation.

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ORGANISMS:
- Species: Rat
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Strain: CD / Crl: CD(SD)
- Age: 61 days
- body weight: 197.7 - 261.9 g
- Diet: ad libitum, Commercial diet ssniff® R/Z V1324 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water: ad libitum
- Acclimatisation period: 5 days
-Housing: Except during the mating period, the dams were kept singly in MAKROLON cages
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C +/- 3° C
- Humidity (%): 55% +/- 15 %
- Illumination: 12 hours artifical fluorescent light and 12 hours dark
- Ventilation rate: between fifteen to twenty air changes per hour.
ENVIROMENTAL ENRICHMENT
- The animals received one piece of wood (certified for animal use) to gnaw on once weekly at change of the cages.
- Octagon-shaped red-tinted huts (polycarbonate) were placed in the cages to offer the animals a resting and hiding place.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

ADMINISTRATION:
- Frequency: once daily, day 6 to 20 of gestation
- Dose volume: 3 ml/kg b.w.
- Dose: 0, 100, 300, 1000 mg/kg/bw
- Animals: 25 female rats/group
DOSAGE PREPARATION:
- The test item formulations were freshly prepared every day.
- The test item was suspended in the vehicle to the appropriate concentrations and was administered orally at a constant volume once daily from the 6th to the 20th day of gestation.
- The amount of the test item was daily adjusted to the current body weight of the animal.
- The control animals received the vehicle at the same administration volume daily in the same way.
- The male rats for mating remained untreated.

Analytical verification of doses or concentrations:

yes

Remarks:

The analysis was performed at LPT using a validated method. The following parameters were determined: Linearity, Accuracy, Precision, Sensitivity, Specificity, Stability

Details on analytical verification of doses or concentrations:

For the analysis of the test item-vehicle formulations, samples of approximately 2 mL were taken at the following times and stored at -20°C or colder until analysis at LPT:
At start of dosing
- Analysis of stability and concentration: Immediately after preparation of the formulations as well as after 8 and 24 hours storage of formulations at room temperature. (3 samples/test item group), Number of samples: 3 x 3 = 9,
- Homogeneity: At the start of dosing, during (middle) administration and before dosing to the last animal of the test item group. (3 samples/test item group), Number of samples: 3 x 3 = 9

At the end of the dosing period (at a time when the majority of animals was dosed):
- Analysis of concentration: During treatment with the test item always before administration to the last animal of the dose level group. (1 sample/test item group),
Number of samples: 1 x 3 = 3

Sum of all samples: 21

Details on mating procedure:

- Sexually mature ('proved') male rats of the same breed served as partners.
- The female breeding partners were randomly chosen.
- Mating was monogamous: 1 male and 1 female animal were placed together in one cage during the dark period.
- Each morning a vaginal smear was taken to check for the pres-ence of sperm. If findings were negative, mating was repeated with the same partner.
- The day on which sperm was found was considered as the day of conception (day 0 of pregnancy).
- This procedure was repeated until 25 mated dams were available for all groups.
- Those rats that did not litter were laparotomised on gestation day 24.
- The non-pregnant animals were excluded from the analysis of the results and replaced by other animals.
- A post-mortem negative staining according to SALEWSKI was carried out in the replaced animals in order to confirm the non-pregnancy status.

Duration of treatment / exposure:

From gestation day 6 until gestation day 20

Frequency of treatment:

Once daily

Duration of test:

On gestation day 21, all rats were euthanized by carbon dioxide (CO2) inhalation and laparotomised.

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Vehicle control

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Low dose

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Intermediate dose

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

HIgh dose

No. of animals per sex per dose:

25 female rats/dose , orally dosed with 0, 100, 300 or 1000 mg test item/kg b.w.
Evaluated litters: 20 litters per group

Control animals:

yes, concurrent vehicle

Details on study design:

The dose levels were selected in agreement with the Sponsor based on the results of a dose-range-finding study for a prenatal developmental toxicity (LPT study no. 34637).
In this dose-range finding study, test item was administered to pregnant female rats at dose levels of 100, 300 or 1000 mg/kg b.w./day orally, by gavage, once daily from gestation day 6 to 20.
No premature deaths and no signs of toxicity were noted for the dams.
No embryotoxic properties (no dead fetuses, no malformations and no test item-related variations) were noted at any of the tested dose levels.
Therefore, for the present embryotoxicity study (LPT Report No. 34638), dose levels of 100, 300 or 1000 mg test item/kg b.w./day, administered orally, by gavage once daily (at a contact volume of 3 mL/kg b.w./day) from 6th to the 20th day of pregnancy, were selected.

Maternal examinations:

Dated and signed records of all activities relating to the day to day running and maintenance of the study within the animal units, as well as to the
group observations and examinations outlined in the Study Plan, were recorded in the appropriate documentation. In addition, observations relating
to the individual animals made throughout the study were recorded.

The following observations were made during the course of the study:
Clinical signs
Individual animals were observed daily for any signs of behavioural changes, reaction to treatment, or illness.
Immediately after administration, any signs of illness or reaction to treatment were rec-orded. In case of changes, the animals were observed until thesymptoms disappeared. In addition, animals were checked regularly throughout the working day from 7.00 a.m. to 3.45 p.m.
On Saturdays and Sundays, the animals were checked regularly starting from 7.00 a.m. to 11.00 a.m. with a final check performed at approximately
3.30 p.m.
Dated and signed records of appearance, change and disappearance of clinical signs were maintained on clinical history sheets for individual animals.

Viability
Further checks were made early in the morning and again in the afternoon of each working day to look for dead or moribund animals. This allowed
post mortem examinations to be carried out during the working period of that day. On Saturdays and Sundays, a similar procedure was followed
except that the final check was carried out at approximately midday.
Animals showing signs of abortion or premature delivery would have been sacrificed on the same day. Fetuses obtained this way were examined for
abnormal development, whenever possible. No abortion occurred in the study.

Body weight
The weight of each rat was recorded on day 0 of gestation (the day of detection of a positive mating sign), followed by daily weighing - always at the same time of the day.
The body weight gain was calculated in intervals (i.e. day 0-3, 3 6, 6-9, 9-12, 12-15, 15-18 and 18-21), for the whole study (gestation day 0 - 21) and for the period after the start of dosing (gestation day 6 to gestation day 21). Furthermore the carcass weight and the net weight gain from day 6 is given.
These values are stated in the report.
These measurements were also used for calculating the daily amount of test item to be administered.

Food and drinking water consumption
The quantity of food consumed by each rat was recorded daily. Food intake per rat (g/rat/day) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment day.

The relative food consumption (g/kg b.w./day) was calculated using the following formula:
Daily food consumption [g/kg b.w./day]= Total food intake in g / Body weight in g x 1000

Daily monitoring by visual appraisal of the drinking water bottles was maintained throughout the study. Dehydration of the dams was avoided.

EXAMINATIONS (NECROPSY), Examination of the dams
Dissection technique and evaluation of the animals:
On gestation day 21, the rats were laparotomised under ether narcosis. The ovaries and the uteri of the dams were removed; the gravid uteri (in toto) were weighed. In order to check for possible test item effects, a dissection with macroscopic examination of the internal organs and placentae of the dams was carried out on the day of sacrifice or on the day on which the animals were found dead. In case of macroscopical findings, the affected maternal tissues were preserved in 7% buffered formalin for possible future histopathological examinations.

Ovaries and uterine content:

Corpora lutea
- number per dam
- absolute number per group
- mean per group

Implantations
- number per dam
- distributions in the uterine horns
- absolute number per group
- mean per group

Resorptions
- number per dam
- distributions in the uterine horns
- absolute number per group
- mean per group
- early resorptions < 2 mm
- Late resorptions > 2 mm

Weight of placentae
- individual data per fetus
- mean per litter
- mean per group
- mean per sex and group

Weight of fetuses
- individual data per fetus (alive and dead)
- mean per litter
- mean per group
- litter mean per sex and group

Fetuses
- number per dam (alive)
- number per dam (dead)
- number of fetuses (alive and dead) per sex and dam
- distribution in the uterine horns
- absolute number of fetuses alive per group
- mean number of fetuses alive per group
- mean % of fetuses alive per group
- male/female ratio (alive and dead)

Runts
- number per dam
- mean per group

Malformed fetuses
- individual data per fetus
- type of malformation
- number and incidence (%) per group and litter

Total malformation rate [%] = malformed fetuses per group / fetuses per group x 100

Fetuses with variations
- type of variation
- individual data per fetus
- number and incidence (%) per group and litter

Total variation rate [%] = fetuses per group with variations / fetuses per group x 100

Fetuses with retardations
- type of retardation
- individual data per fetus
- number and incidence (%) per group and litter

Indices of pre-implantation loss and post-implantation loss:

Calculation of group indices
Pre implantation
loss [%] = [Corpora lutea (per group) - Implantations (per group)] / Corpora lutea (per group) x 100

Post implantation
loss [%] = [Implantations (per group) - living fetuses (per group)] / Implantations (per group) x 100

Calculation of mean indices per litter
Pre implantation
loss [%] = sum of pre-implantation losses per litter in a group [%] / number of litters in a group

Post implantation
loss [%] = sum of post-implantation losses per litter in a group [%] / number of litters in a group

Fetal examinations:

The fetuses were removed and the following examinations performed:
(a) Macroscopic inspection (gross evaluation) of the placentae for example for focal indurations or abnormal appearance (e.g. size, colour, shape).
(b) The number of fetuses (alive and dead) and placentae (location in the uterus and the assignment of the fetuses) was determined.
(c) Sex and viability of fetuses were determined. Animals are said to be viable when they are found alive (spontaneous breathing, spontaneous movement).
(d) Number and size of resorptions were determined.
(e) Corpora lutea in the ovaries, implantations and location of fetuses in the uterus were determined.
(f) Weights of fetuses and weights of the placentae were determined (fetuses were considered as runts if their weight was less than 70% of the mean litter weight).
(g) All fetuses (dead and alive) were inspected externally for damages, especially for malformations .
(h) The fetuses were sacrificed by an ether atmosphere.
(i) Examination of fetuses and determination of number and kind of retardations, variations or malformations:
1) 50% of the number of fetuses in each litter were examined for skeletal anomalies. The thorax and peritoneal cavity (without damage to ribs and sternum) were opened and the location, size and condition of the internal organs were determined.
Then the skeleton was double-stained with Alcian blue for the examination of cartilage and with Alizarin red to reveal ossifications (according to DAWSON). The skeletal system was examined (determination of the number and type of retardations, variations as well as malformations).
2) The remaining 50% of the number of fetuses in each litter were examined for soft tissue anomalies. Body sections were made and examined according to WILSON.
The fetuses were allocated to the evaluation of DAWSON or WILSON on an alternating basis.

Statistics:

Parametrical data:
The statistical evaluation of the parametrical values was done by Provantis using the following settings:
Homogeneity of variances and normality of distribution were tested using the BARTLETT’s and SHAPIRO-WILKS test. In case of heterogeneity and/or non-normality of distribution, stepwise transformation of the values into logarithmic or rank values was performed prior to ANOVA. If the ANOVA yielded a significant effect (p ≤ 0.05), inter-group comparisons with the control group were made by the DUNNETT’s test (p ≤ 0.01 and p ≤ 0.05).

Non-parametrical data
The statistical evaluation of non-parametrical values was done using the FISHER or Chi2 test:
FISHERs exact test, n < 100; (p ≤ 0.05 and p ≤ 0.01)
or
Chi2 test, n ≤ 0.01 (p ≤ 0.05 and p ≤ 0.01)

The respective calculations for the FISHER and Chi2 test were performed using Provantis (maternal macroscopic findings at necropsy or findings during the external macro-scopic examination of the fetuses). or an internal computer program (e.g. findings during the fetal skeletal or soft tissue examination).
Note:
The statistical evaluation of the pre- and post-implantation index (per group) using the number of corpora lutea, implantation sites and/ or fetuses per group (see table 7-1 Re-production Data - Summary - Values per Group) was done using StatXact 4.0.1 software, as such a calculation is not possible in Provantis.

Significantly different data are indicated in the summary tables of the result sections of the report.

Indices:

Fertility Index, Viability Index, Resorption Index, Pre-Implantation Loss Index, Post-Implantation Loss Index, Runts Index, Variation Index,
Number of litters having abnormalities, Number of abnormalities per litter

Historical control data:

LPT Background Data, see Appendix 4
Summarized results of the 59 last embryotoxicity studies in Sprague-Dawley rats (Charles River Deutschland GmbH performed at LPT in the years 2000 to July 2016

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related changes in behaviour, the external appearance or the faeces that were considered to be of toxicological relevance were noted in any of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Changes in behaviour and external appearance that were noted in the intermediate and high dose group (300 or 1000 mg test item/kg b.w./day) and not considered to be test item-related are listed in the tables below.
At 300 mg test item/kg b.w./day, slight salivation was noted for dam no. 57 on GD 7. As only one dam was affected on one day, salivation was considered to be incidental and not adverse.
At 1000 mg test item/kg b.w./day, slight to moderate salivation (2 of 20 animals) and haemorrhagic canthus (1 of 20) were noted. As only 1 or 2 of 20 animals were noted for hemorrhagic canthus or salivation, these observations were considered to be incidental and not test item-related.

Start and duration of salivation
All observations of salivation for the intermediate and high dose groups (300 or 1000 mg test item/kg b.w./day) started immediately to 5 minutes post administration and disappeared within 20 to 60 minutes after administration.

Mortality:

no mortality observed

Description (incidence):

No premature deaths were noted in the control group and in the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight
No test item-related differences in body weight were noted between the dams of the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Body weight gain from GD 0 to 21
No test item-related difference for the body weight gain from GD 0 to 21 compared to the control group was noted for the animals treated with 100, 300 or 1000 mg test item/kg b.w./day.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related differences were noted between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Statistically significant changes in food consumption that were considered to be spontaneous and not test item-related

Food efficiency:

no effects observed

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

no effects observed

Description (incidence and severity):

No test item-related changes in drinking water consumption were noted between the dams of the control group and the dams of the treatment groups by visual appraisal.

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Gravid uterus weight and Carcass weight
No test item-related differences were noted between the gravid uterus weight and the carcass weight of the control dams and the dams of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related observations were noted for the dams of the control group and the dams of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day) during the macroscopic inspection of the organs and tissues.
The following findings were considered to be spontaneous and not test item-related as these findings were only single occurrences.
In the control, a change was noted for dam no. 4 in form of a dilated left uterine horn that was additionally filled with yellow liquid.
At 100 mg test item/kg b.w./day, dam no. 26 was noted with a mildly thickened and watery discolored uterus. In addition, dam no. 43 was noted with a cyst at the right kidney.
In the intermediate dose group (300 mg test item/kg b.w./day), dam no. 66 was noted with a yellow focus at the right kidney.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Details on results:

no findings

Number of abortions:

no effects observed

Description (incidence and severity):

No test item-related influence on the reproductive parameters (number of implantation sites, fetuses, resorptions and the index of pre- and post-implantation) were noted be-tween the dams of the control group and the dams of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day). See table below.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Early or late resorptions:

no effects observed

Description (incidence and severity):

Dead fetuses:

no effects observed

Description (incidence and severity):

Changes in pregnancy duration:

not examined

Description (incidence and severity):

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Details on maternal toxic effects:

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The placental and fetal weights showed no test item-related differences between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
The slight but statistically significantly increased fetal weights that were noted at the high dose level were considered to be spontaneous as an increase in the fetal body weight is not an adverse.

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, non-treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): The placental and fetal weights showed no test item-related differences between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
The slight but statistically significantly increased fetal weights that were noted at the high dose level were considered to be spontaneous as an increase in the fetal body weight is not an adverse.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

No dead fetus was noted in the control group and in the test item treated groups (100, 300 or 1000 mg test item/kg b.w./day).

Changes in sex ratio:

no effects observed

Description (incidence and severity):

No test item-related differences between the ratio of male and female fetuses (range: 0.88 - 1.06) were noted between the control group and the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

External inspection at laparotomy
No macroscopically visible external alterations (malformations or variations) were noted for the fetuses of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day) during the macroscopic inspection at laparotomy.
In the control group, one fetus (no. 4-1) was noted with a variation in form of a domed head and a malformation in form of a misshapen snout. These findings were within the normal range of spontaneous events.
Gross inspection of the organs and tissues at laparotomy
The macroscopic inspection of the organs and tissues for gross alterations at laparotomy revealed no malformations or variations for the fetuses of the control group and the fetuses of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).

Skeletal malformations:

no effects observed

Description (incidence and severity):

Skeletal malformations
No skeletal malformations were noted for the fetuses of the control group and the test item-treated groups (100, 300 or 1000 mg test item/kg b.w./day) during the skeletal examination according to DAWSON.
Skeletal variations
Skeletal variations were noted for the ribs (less than 13 ribs ossified, short or wavy) and the sternebrae (bipartite or misaligned to a slight degree).
No test item-related increase in the incidence of the observed skeletal variations in comparison to the control group was noted for the fetuses of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day).
Skeletal retardations
Retardations (delayed ossifications) were related to the skull (incomplete ossification of frontal, parietal, interparietal and/or supraoccipital areas), the hyoid (unossified), the sternum (sternebra(e) incompletely ossified, reduced in size or unossified), the thoracic vertebral bodies (bipartite, dumbbell-shaped or reduced in size), the caudal vertebral bodies (only one body ossified), the lumbar vertebral bodies (bipartite) the os pubis (in-completely ossified) and the metacarpalia and metatarsalia (absence of ossification in metacarpalia 2 to 5 and metatarsalia 2 to 5). see table below
No test item-related increase in the incidence of skeletal retardations at 100, 300 or 1000 mg test item/kg b.w./day was noted during skeletal examination according to DAWSON.

Visceral malformations:

no effects observed

Description (incidence and severity):

Malformations
No malformations were noted for the fetuses of the control group and the fetuses of the treatment groups (100, 300 or 1000 mg test item/kg b.w./day) during the soft tissue examination according to WILSON.
Variations
During the examination of the organs and tissues according to WILSON variations were noted for the kidneys (uni- or bilateral dilatation of the renal pelvis, hemorrhagic kidney or hemorrhagic adrenal), the liver (haemorrhagic focus/foci) or brain (dilatation of the cere-bral ventricle).
No test item-related differences and no statistically significant differences in the inci-dences of the observed variations were noted between the control group and the test item-treated groups (100, 300 or 1000 mg test item/kg b.w./day).
Unclassified observations
A thoracic cavity filled with blood was noted for one fetus (no. 46-11) of the low dose group (100 mg test item/kg b.w./day). This observation is a preparation induced artefact and not considered as test item-related.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

One runt (2-06) was noted in the control group and one runt (43-14) was noted in the low dose group (300 mg test item/kg b.w./day). The single occurrence of one runt was with-in the normal range of variation and therefore considered to be not test item-related.

Details on embryotoxic / teratogenic effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: prenatal developmental toxicity; highest dose tested

Key result

Developmental effects observed:

Examination of the dams

test item	Group 1 Control	Group 2 100 mg/kg	Group 3 300 mg/kg	Group 4 1000 mg/kg
Treated dams	25	25	25	25
Not pregnant dams	1	2	5	1
Dams without viable fetuses	0	0	0	0
Dams with early delivery	0	0	0	0
Prematurely deceased animals	0	0	0	0
Not examined dams (spare animals)	4	3	0	4
Evaluated litters	20	20	20	20

test item	Group 1 Control	Group 2 100 mg/kg	Group 3 300 mg/kg	Group 4 1000 mg/kg
Animal nos. of mated rats	1 - 25	26 - 50	51 - 75	76 - 100
Animal nos. with evaluable litters at laparotomy	1-18, 20, 21	27-38, 40‑47	51, 52, 54‑61, 63, 65-68, 71‑75	76-78, 80‑96
Dams not pregnant (animal nos.)	19	26, 39	53, 62, 64, 69, 70	79
Dams with total implantation loss (animal nos.)	none	none	none	none
Prematurely deceased animals (animal nos.)	none	none	none	none
Reserve animals (animal nos.)	22-25	48-50	none	97-100

Reproduction data of the dams

Parameter

Group 1

Control

(n=20)

Group 2

100

mg/kg

(n=20)

Group 3

300 mg/kg

(n=20)

Group 4

1000 mg/kg

(n=20)

Corpora lutea

total

mean per dam

275

13.8

289

14.5

280

14.0

268

13.4

Implantation sites

total

mean per dam

270

13.5

284

14.2

266

13.3

258

12.9

Resorptions

total

mean per dam

0.5

0.4

0.5

0.6

Early resorptions

total

mean per dam

0.3

0.4

0.5

0.6

Late resorptions

total

mean per dam

0.2

0.0

0.1

Live fetuses

total

mean per dam

261

13.1

277

13.9

256

12.8

246

12.3

Dead fetuses

total

Pre-implantation loss [%]

per group #¹

mean per dam

1.8

4.4

1.7

5.0

5.2

3.7

5.7

Post-implantation loss [%]

per group #²

mean per dam

3.3

2.5

2.7

3.8

3.3

4.7

6.3

Statistical analyses were performed for the mean values per dam using an ANOVA/DUNNETT test.

#¹

The statistical comparison of the pre-implantation loss per group was done by comparing the values of implantation sites/corpora lutea of the test group with the ratio of implantation sites/corpora lutea of the control group using the Chi²test (*/**: p ≤ 0.05/p ≤ 0.01).

#²

The statistical comparison of the post-implantation loss per group was done by comparing the values of live fetuses/implantation sites of the test group with the ratio of fetuses/implantation sites of the control group using the Chi²test (*/**: p ≤ 0.05/p ≤ 0.01).

Analysis of test item formulations

The results of the test item-formulation analyses for the investigated parameters are listed in the table below:

Parameter	Sampling / dealing	Range of % nominal concentration
Concentration	immediately after preparation	93.2% - 95.8%
Concentration	before administration to the last animal on test day 21	95.0% - 105.8%
Stability	8h after preparation	90.3% - 92.2%
Stability	24h after preparation	91.7% - 93.2%
Homogeneity	before administration to the first animal	92.9% - 94.3%
	during administration to the animals	90.9% - 94.4%
	before administration to the last animal	96.2% - 96.7%

The measured actual concentrations of the test item in the test item vehicle-mixtures were between 90.3% and 105.8% of the nominal concentrations, indicating correctly prepared, stable and homogenous formulations.

Conclusions:

Under the conditions of the study, test item did not show any teratogenic potential.

Executive summary:

The aim of this prenatal developmental toxicity study (OECD 414, oral) was the examination of the influence of the test item administered orally during the critical period of organogenesis and the fetal development (6th to 20th day of gestation) on the pregnant rat and the fetus.

Findings


Examination of the dams:
Mortality	No premature deaths were noted.

Clinical signs	No test item-related signs of toxicity were noted.

Body weight and body weight gain	No test item-related differences between the control group and the treatment groups were noted.

Food consumption	No test item-related differences were noted for the food consumption.

Drinking water consumption	No differences were noted.

Necropsy findings	No test item-related changes were noted during the macroscopic inspection of the dams at necropsy.

Uterus and carcass weights	No test item-related differences were noted.
Reproduction data	No test item-related influence was noted on the reproductive parameter (number of implantation sites, resorptions and fetuses).

Examination of the fetus:
Mortality	No dead fetuses were noted in any of the test groups.

Body weight of the fetuses and the placentae	No test item-related differences were noted between the control group and the treatment groups.

Fetal alterations
Malformations	No malformations were noted during the macroscopic examinations at laparotomy (external inspection and inspection of the organs and tissues for gross lesions), the skeletal examination according to DAWSON and the soft tissue examination according to WILSON in the treatment groups.

Variations	The macroscopic examinations at laparotomy, the skeletal examination according to DAWSON and the soft tissue examination according to WILSON revealed no test item-related variations in the treatment groups.

Unclassified observations	No test item-related unclassified observations were noted.

Retardations	No test item-related retardations (delays in ossification) were noted.

Analysis of test item formulations	The measured actual concentrations of the test item in the test item vehicle mixtures were between 90.3% and 105.8% of the nominal concentrations, indicating correctly prepared, stable and homogenous formulations.

Conclusion

In this prenatal developmental toxicity study, the test item was administered orally to female rats at dose levels of 100, 300, and 1000 mg/kg b.w./day from the 6th to 20th day of pregnancy.

Under the present test conditions, the no-observed-adverse-effect level (NOAEL) was above 1000 mg test item/kg b.w./day for the dams.

No prematurely deceased dams were noted during the study.

No test item-related changes in behaviour, external appearance or faeces were noted.

No test item-related change in food consumption, body weight or body weight gain was noted in any treatment group.

No changes were noted at the macroscopic examination during laparotomy.

The no-observed-adverse-effect level (NOAEL) for the fetal organism was also above 1000 mg test item/kg b.w./day.

The reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item.

No test item-related differences for the placental and fetal weights were noted in the treatment groups.

No dead fetuses, no malformations and no test item-related variations or retardations were noted in the treatment groups.

Therefore, under the conditions of the study test item did not show any teratogenic potential.

Effect on developmental toxicity: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 1 000 mg/kg bw/day
Species:: rat
Quality of whole database:: Klimisch 1 (reliable without restrictions)

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

Studies in Animals

In a gavage study performed in accordance with OECD 414, the test item showed no adverse effects on the development of rats up to and including the highest tested dose level of 1000 mg/kg bw/day (LPT, 2017). In this prenatal developmental toxicity study, the test item was administered orally to female rats at dose levels of 100, 300, and 1000 mg/kg b.w./day from the 6th to 20th day of pregnancy.

Under the present test conditions, the no-observed-adverse-effect level (NOAEL) was above 1000 mg test item/kg b.w./day for the dams.

No prematurely deceased dams were noted during the study.

No test item-related changes in behaviour, external appearance or faeces were noted.

No test item-related change in food consumption, body weight or body weight gain was noted in any treatment group.

No changes were noted at the macroscopic examination during laparotomy.

The no-observed-adverse-effect level (NOAEL) for the fetal organism was also above 1000 mg test item/kg b.w./day.

The reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item.

No test item-related differences for the placental and fetal weights were noted in the treatment groups.

No dead fetuses, no malformations and no test item-related variations or retardations were noted in the treatment groups.

Therefore, under the conditions of the study the test item did not show a teratogenic or developmental toxicant potential.

Discussion

Additionally, three fully reliable developmental toxicity studies on rats according to OECD 414 are available based on read across. A full and detailed text "Justification for grouping and read-across according to Regulation (EC) No 1907/2006, Annex XI, 1.5 and for weight of evidence according to Regulation (EC) No 1907/2006, Annex XI, 1.2 with respect to reproductive toxicity for aliphatic diisocyanate monomers and their polyisocyanates" is attached to chapter 13 of IUCLID. Based on this comparative evaluation the conclusion is drawn that in this case grouping and read-across of toxicological data according to Regulation (EC) No. 1907/2006 (REACH), Annex XI, 1.5 is justified, and that the substance is not a developmental toxicant.

Studies in Humans

There are no data available.

Toxicity to reproduction: other studies

Additional information

no further studies available

Justification for classification or non-classification

Regarding toxicity to reproduction the test item is not classified according to the criteria of EC Directive 67/548/EEC and EC Regulation 1272/2008.

Additional information

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Registration Dossier

Registration Dossier

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Diss Factsheets

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, isocyanurate type

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Link to relevant study records

Referenceopen allclose all

Reference 1

Reference 2

Reference 3

Effect on fertility: via oral route

Effect on fertility: via inhalation route

Effect on fertility: via dermal route

Additional information

Effects on developmental toxicity

Description of key information

Link to relevant study records

Referenceopen allclose all

Reference 1

Findings

Reference 2

Examination of the dams

Analysis of test item formulations

Effect on developmental toxicity: via oral route

Effect on developmental toxicity: via inhalation route

Effect on developmental toxicity: via dermal route

Additional information

Toxicity to reproduction: other studies

Additional information

Justification for classification or non-classification

Additional information

Referenceopen all close all

Referenceopen all close all