2,3-dihydro-2,2,6-trimethylbenzaldehyde

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Oral: NOAEL (rat – general toxicity and reproductive/developmental toxicity): 125 mg/kg bw/day ; male/female, OECD TG 422, 2010

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From March 5, 2020 to September 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was weighed and olive oil was added to prepare the 2.50 w/v% formulation. A part of the 2.50 w/v% formulation was diluted with olive oil to prepare the 0.400 and 1.00 w/v% formulations.
The formulations and vehicle were subdivided into plastic containers, and stored at the cold place (target range: 1 to 10ºC). On each dosing day formulations and vehicle were taken out from the storage place and dosed to the animals. The formulations were used within 16 days after preparation.

DIET PREPARATION
- Rate of preparation of diet (frequency): Not applicable
- Mixing appropriate amounts with (Type of food): Not applicable
- Storage temperature of food: Not applicable

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item dissolved in olive oil at concentration of 20.0 w/v% (non-GLP). This vehicle is used for a general toxicity study and we have historical control data of this vehicle.
- Concentration in vehicle: Concentrations of the test item formulations were confirmed with HPLC in the first preparation (CERI study no. X02-0325). Actual concentrations of the 2.50, 1.00 and 0.400 w/v% formulations were 2.48, 0.980 and 0.400 w/v%, respectively. The formulations were within a permissible range of CERI Hita.
- Amount of vehicle (if gavage): Treatment volume was 5 mL/kg for control (negative, untreated group) and all treatment groups with applicable test item concentrations per group.
- Lot/batch no. (if required): lot no. 801029 and 810022, Japanese Pharmacopeia, TAISEI Pharmaceutical Industories

Details on mating procedure:

In the mating period each female was housed in a male’s cage in each dose group. Copulated females were housed in polycarbonate cages (PC cage, 265 W×426 D×150 H mm, TOKIWA) with wooden bedding (Sunflake, lot no. 200327, Charles River Laboratories Japan), enrichments of autoclaved gnawing wood (Woodbite, lot no. 190702, Charles River Laboratories Japan) and hemp mats from gestation day 14. Pups were housed with a dam after delivery.

Duration of treatment / exposure:

Males and females were administrated for 14 days before mating. Thereafter, males were treated for 29 days including the mating period. Females were administrated until day 13 of nursing period throughout the mating and gestation periods. Non-mating females were treated for 29 days.

Frequency of treatment:

Once daily

Details on study schedule:

Forty four males and sixty six females were obtained at 7 weeks old. The animals were 9 weeks old at the start of dosing.
Initiation of Dosing March 26, 2020
Initiation of Mating April 9, 2020
Initiation of Delivery May 2, 2020
Completion of Study September , 2020

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Recovery control group

Dose / conc.:

20 mg/kg bw/day (nominal)

Remarks:

Low - Group

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

Intermediate - Group

Dose / conc.:

125 mg/kg bw/day (nominal)

Remarks:

High - Group

Dose / conc.:

125 mg/kg bw/day (nominal)

Remarks:

Recovery High - Group

No. of animals per sex per dose:

10 per sex per dose (10 male / 10 female) for mating groups; 5 animal per sex for control and high dose groups for recovery. For Each five animals of the first half are the main group, later five animals are the recovery group.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels were based on the results of a previously conducted 14-days sighting study (Report number from CERI, no. C21-0049).
- Rationale for animal assignment (if not random): Randomly assigned

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
All animals were observed for clinical signs twice a day, i.e. before and after dosing including observation of mortality during the dosing period. Females were observed delivery and nursing conditions. In the recovery period the animals were observed once a day.

BODY WEIGHT: Yes
Time schedule for examinations:
Body weights were measured using an electric balance (SARTORIUS) on the following days:
- males on day 1, 3, 7, 14, 21, 28 of dosing and day 1, 7, 14 of recovery
- non-mating females on day 1, 3, 7, 14, 21, 28 of dosing and day 1, 7, 14 of recovery
- females on day 1, 3, 7, 14 of dosing, on gestation day 0, 7, 14, 20 and on postnatal day 0, 4, 8, 13, and day 21, 35, 42 and 49 of dosing for non-copulated female (animal no. 143)
- in addition, all animals were weighed on the necropsy days.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not applicable.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable.

FOOD EFFICIENCY: No

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
Blood was collected from the abdominal aorta under isoflurane anesthesia from the following animals: five males and five dams for the same animals of the sensorimotor function examinations, non-mating five females, males and females of the recovery group, two pups per litter on day 4 after birth and two pups per litter at termination on day 13 after birth.
- Anaesthetic used for blood collection: Yes (isoflurane anesthesia)
- Animals fasted: Not specified
- How many animals:
39
- Parameters checked: Red blood cell count (RBC), Hemoglobin conc. (Hb), Hematocrit value (Ht), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin conc. (MCHC), Platelet count (Platelet), Reticulocyte count ratio (Reticulo), White blood cell count (WBC), Differentiation of leukocytes, Prothrombin time (PT) and Activated partial thromboplastin time (APTT).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
Blood was collected from the abdominal aorta under isoflurane anesthesia from the following animals: five males and five dams for the same animals of the sensorimotor function examinations, non-mating five females, males and females of the recovery group, two pups per litter on day 4 after birth and two pups per litter at termination on day 13 after birth.
- Animals fasted: Not specified
- How many animals: 39
- Parameters checked: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), γ-Glutamyl transpeptidase (γ-GTP), Total cholesterol (T-Cho), Triglyceride (TG), Blood urea nitrogen (BUN), Creatinine, Total protein (T-Protein), Albumin, A/G ratio, Glucose, Total bilirubin (T-Bil), Total bile acids (TBA), Inorganic phosphorus (IP), Calcium (Ca), Sodium (Na), Potassium (K), Chloride (Cl) and Thyroid hormone (T4)

URINALYSIS: Yes
- Time schedule for collection of urine:
Five males of the main group (same animals of sensorimotor function examinations), non-mating females, and males and females of the recovery group were housed in a metabolic cages in the afternoon of the each last observation day with free drinking and no feed until next morning for 15-17 h. Collected urines were examined for the following parameters. Urine sediments were examined in males and non-mating females in the control and high dose groups, and the recovery group.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: urine volume, color, turbidity, specific gravity, pH, protein, glucose, occult blood and urinary sediment.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
last dosing week
- Dose groups that were examined:
The animals were examined for the parameters of the following table in five males of each dose group, five non-mating females of the control and high dose groups, and selected five parental females of each dose group in each last dosing week.
- Battery of functions tested: reflex tests / grip strength / motor activity

IMMUNOLOGY: No

Oestrous cyclicity (parental animals):

Vaginal smears of all females in the mating group were collected from day 1 to 14 of dosing. The stages of estrous cycle were determined with a light microscope after giemsa staining. The days from estrous to the next estrous were regarded as an estrous cycle length and the mean estrous cycle length was calculated. When the estrous was successive the first day was regarded as an estrous.

Sperm parameters (parental animals):

Parameters examined in male parental generations: Testes, epididymides, prostate (ventral and dorsolateral lobes), seminal vesicles (including coagulating gland)

Litter observations:

After finishing of delivery (postnatal day 0), number of males and females including stillborns, number of live pups and their total number were counted. Clinical observations including the external surface were carried out once a day until postnatal day 13. Males and females were counted for the number of live pups and the total number on postnatal day 4 and 13, and their body weights were measured on postnatal day 0, 4 and 13.
Anogenital distance (AGD) of each pup was measured on postnatal day 4. Each AGD was collected with the cube root of the body weight on the same day. The number of nipples/areolae in male pups was counted on postnatal day 13.
Thyroid was collected from pups on postnatal day 13 and fixed with 10% neutralized buffered formalin.
From these results, the value of each litter, the mean values and standard deviations of each dosing group were calculated as follows:
- Birth index: (Number of live pups at birth / Number of implantation sites) × 100
- Viability index at birth: (Number of live pups at birth / Number of pups at birth) × 100
- Sex ratio of pups at birth: Number of live males at birth / Number of live pups at birth
- Viability index on day 4 after birth: (Number of live pups on day 4 / Number of live pups at birth) × 100
- Sex ratio of pups on day 4 after birth: Number of live males on day 4 / Number of live pups on day 4.

Statistics:

Data regarding body weights of parental animals, food consumption, grip strength, locomotor activity count, parameters of hematology and blood chemistry, urine volume, urine specific gravity, organ weights, body weights on necropsy, mean estrous cycle length, pairing days until copulation, gestation length, number of implantation sites, number of pups born, number of live pups, body weights of pups, AGD and number of nipples/areolae were analyzed by the Bartlett’s test for homogeneity of variance. If significant difference (p<0.05) was not noted, the values of the control group and each test item group were analyzed by the Dunnet’s test. If significant difference (p<0.05) was noted in the Bartlett test, the values of the control group and each test item group were analyzed by the nonparametric Dunnet’s test.
Abnormal estrous cyclicity, copulation index, conception index and delivery dam index were analyzed by the Fisher’s exact test between the control group and each test item group.
Indexes of delivery, birth, viability and sex ratio were examined by the Bartlett’s test. If significant difference (p<0.05) was not noted, the values of the control group and each test item group were analyzed by the Dunnet’s test. If significant difference (p<0.05) was noted, the values of the control group and each test item group were analyzed by the nonparametric Dunnet’s test.
Data regarding body weights and food consumption during the recovery period, and parameters of hematology and blood chemistry, urine volume, urine specific gravity, organ weights and body weights at necropsy day for the recovery group were analyzed by the F-test for variance ratio. If there were no significant differences at a significance level of 5%, the Student t-test was performed. If there were significant differences at a significance level of 5%, the Aspin-Welch t-test was performed. The frequencies of defecation and urination during the recovery period were analyzed by the Mann-Whitney U-test.

Reproductive indices:

Each female was cohabited in the cage of a male in the same dose level, as a pair of male and female at night on the dosing day 15, and the females were returned to the original cage next morning. Cohabitation was continued until showing evidence of copulation or maximum of 14 days. When a vaginal plug or sperms in vaginal smear were confirmed it was considered to be an evidence of mating (day 0 of pregnancy).
When the dams delivered spontaneously, built a nest or milked their pups by 10:00, those were regarded as an evidence of delivery and the day was designated as delivery day (postnatal day 0). If the delivery finished after 10:00, the delivery day was regarded as a next day.
Delivered dams with implantation site of the uterus was regarded as a pregnant female.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

In males, salivation was observed just after dosing in all test item groups, and some animals salivated just before dosing in the 125 mg/kg group. One animal showed loosening and loss of right upper incisor in the 125 mg/kg group from day 27.
In females, salivation was observed in all test item groups, and some animals salivated just before dosing in the 50 and 125 mg/kg groups. Restlessness was observed just after dosing in almost animals of the 125 mg/kg group.

Salivation was observed in all test item groups. This change was considered related to the taste or smell of the test item since the animals transiently salivated just after or just before dosing, and was considered to be no toxicologically relevance. Restlessness was considered to be related to the salivation since the restlessness was observed as the same time as the salivation.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One animal (animal no. 123) in the 20 mg/kg group died during delivery (administration day 39).
One animal (animal no. 126) in the 20 mg/kg group showed much food on tray, decreased spontaneous locomotion, incomplete eyelids opening, staining around the anus, emaciation and reddish tear from postpartum day 4 (administration day 42), and this animal was sacrificed on postpartum day 8 (administration day 46) as a moribund animal.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Food consumption were increased in females of the 125 mg/kg group, this change was considered to be secondary effect of the salivation and no toxicologically significant.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No toxicologically relevant changes were noted in hematology or clinical biochemistry parameters.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

No toxicologically relevant changes were noted in hematology or clinical biochemistry parameters.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

No treatment-related changes were noted in urinalysis except for renal tubular epithelial cells in males, which change was considered to be related to the histopathological lesions of the kidney.

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In histopathological examinations, accumulation of hyaline droplets in the proximal tubules of the kidney was observed in males of the 20, 50 and 125 mg/kg groups. This change was considered to be male rats specific and no toxicologically significant since relationship to α2u-globulin was confirmed. At the end of the recovery period, regeneration of the tubules of the kidney was observed in males of the 125 mg/kg group.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Reproductive function: oestrous cycle:

effects observed, non-treatment-related

Description (incidence and severity):

Estrous stage of each dosing group was as follows: metestrus in 1/9, diestrus in 8/9 of the control group; diestrus in 7/7 of the 20 mg/kg group; metestrus in 1/6, diestrus in 5/6 of the 50 mg/kg group; metestrus in 2/8, diestrus in 6/8 of the 125 mg/kg group.
Non-delivered females showed following stage: proestrus (animal no. 109) in the control group; estrus (animal no. 122) in the 20 mg/kg group; proestrus (animal no. 139) and not-determined (animal no. 136) in the 50 mg/kg group; metestrus (animal no. 141) in the 125 mg/kg group.
Moribund female (animal no. 126) in the 20 mg/kg group showed metestrus.
Dams (animal no. 131 and 137) which all pups died in the 50 mg/kg group showed metestrus or diestrus.
Non-copulated female (animal no. 143) in the 125 mg/kg group showed diestrus.
Non-mating females had following estrous stage: proestrus in 2/5, metestrus in 2/5, diestrus in 1/5 of the control group; proestrus in 2/5, estrus in 1/5, diestrus in 2/5 of the 125 mg/kg group.

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Slight shortage of group mean gestation length (22 days vs 22.7 days in the control group), was noted in the 125 mg/kg group, although it was statistically significant, this change was within historical control rage, and comparable to the individual dam in the control and other treated groups. Thus this finding was considered to be not toxicologically significant.
Estrous cycle during the dosing period, copulation index, conception index, delivery index or delivery dam index were not affected in any females of the test item groups.

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no test substance related adverse effect findings

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

Deaths were observed in 1/119, 10/114, 19/96 and 3/122 of the control, 20, 50 and 125 mg/kg groups, respectively. These signs were not dose-related.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The relative higher body weights in the control group was noted due to the litter no. 104 (four pups alive), and driven the higher mean body weights of the control group from PND 0 till PND 13 (details seen table below). Body weights in the 125 mg/kg group were decreased in males at birth, females on postnatal day 4, males and females on postnatal day 13. The decreases in all treatment group including the control group were within our control ranges. Body weight gains of the 125 mg/kg group were relative lower than concurrent control values during the postnatal period, however given the relative higher litter size in the high dose group verse to control, the findings were considered not to be adverse. Although body weights were decreased in the 50 mg/kg group at birth, there were no dose-relationship and this change was considered to be a single occurrence.

Pups weight Sex 0 mg/kg (Without 104) 0 mg/kg (With 104) 20 mg/kg 50 mg/kg 125mg/kg
PND 0 Male 7.18 ± 0.44 7.57 ± 1.22 6.72 ± 0.66 6.37 ± 0.60 6.58 ± 0.45
Female 6.84 ± 0.49 7.12 ± 0.97 6.33 ± 0.64 6.04 ± 0.79 6.34 ± 0.42
PND 13 Male 30.12 ± 1.66 32.71 ± 7.90 30.26 ± 3.96 28.48 ± 2.04 26.05 ± 1.98
Female 29.18 ± 2.28 31.23 ± 6.51 28.72 ± 3.98 27.86 ± 2.54 25.28 ± 1.52

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not specified

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no test substance related adverse effect findings

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Remarks on result:

not measured/tested

Remarks:

Not yet available

Reproductive effects observed:

no

Treatment related:

no

Conclusions:

Based on results, the following No Observed Effect Levels (NOEL) and No Observed Adverse Effect Levels (NOAEL) were derived:
The NOEL was 50 mg/kg/day and NOAEL was 125 mg/kg/day for reproduction and developmental toxicity based on decreased body weights of pups under the conditions tested.

Executive summary:

“Acombined repeated dose toxicity study with the reproduction/developmental toxicity screening test” was performed to assessthe repeated-dose,reproductive and developmental toxicities ofSafranal Pin accordance with OECD Guideline for the Testing of Chemicals No. 422.

Male and female Crl:CD(SD) rats at 9 weeks of age were treated with the test item for 14 days and set on mating period for maximum of 14 days. Males and females were administrated until day 29 of dosing and 13 days after delivery, respectively. The dosage levels were set at 20, 50 and 125 mg/kg/day. Control animals were similarly dosed with olive oil.Recovery groups were set for the vehicle control and high dose groups.

The animals transiently salivated just after dosing or just before dosing in all test item groups. Restlessness was observed in females of the 125 mg/kg group.One female died in the 20 mg/kg group during delivery and other female showed moribund state after delivery, and these were considered to be no treatment-related.

In urinalysis, renal tubular epithelial cells were observed in male of the 50 and 125 mg/kg groups.

There were no abnormal changes in detailed clinical observations, sensorimotor function examinations, body weights, food consumption, hematology or blood chemistry.

In organ weights, relative weights of the kidneys were increased in males of the 125 mg/kg group.

In macroscopic examinations, bilateral apparent spotty pattern of the surface of the kidneys was observed in males of the 50 and 125 mg/kg groups

In histopathological examinations, accumulation of hyaline droplets in the proximal tubules of the kidney was observed in males of the 20, 50 and 125 mg/kg groups.This change was considered to be male rats specific and no toxicologically significant since relationship to α_2u-globulin was confirmed.At the end of the recovery period, regeneration of the tubules of the kidney was observed in males of the 125 mg/kg group.

Body weights of pups were decreased in the 125 mg/kg group.The body weight gains were slightly decreased during the postnatal period but the changes were within our historical control ranges.

No adverse effects of the test item were noted in number of pups, the viability index, AGD or number of nipples/areolae of pups.

In conclusion, the No-Observed-Adverse-Effect Level (NOAEL) ofSafranal Punder the conditions tested was considered to be 125 mg/kg/day for repeated-dose toxicity, and the NOEL was 50 mg/kg/day and NOAEL was 125 mg/kg/day for reproduction and developmental toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

125 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP compliant and of a high quality (Klimisch 1); The available information as a whole meets the tonnage driven information requirements of REACH.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Based on results, the following No Observed Effect Levels (NOEL) and No Observed Adverse Effect Levels (NOAEL) were derived:

The NOEL was 50 mg/kg/day and NOAEL was 125 mg/kg/day for reproduction and developmental toxicity based on decreased body weights of pups under the conditions tested.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Self-classification:

Based on the available information, no additional self-classification is proposed regarding the specific target organ toxicity after oral dose-repeated exposure according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

No information is available regarding the dermal and inhalation route.