4-methoxybenzyl alcohol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

secondary literature

Remarks:

Experimental data from various test chemicals

Justification for type of information:

Weight of evidence approach based on the available information from various test chemicals.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on two reproductive toxicity studies via oral route on rats,
1.Repeated dose oral toxicity study with the reproduction / developmental toxicity screening test (OECD TG 422) of test material was conducted on rats for a period of 42 days.
2.Long term toxicity and carcinogenicity study of test material was performed in mice.

GLP compliance:

not specified

Limit test:

no

Species:

other: 1. rats 2.mice

Strain:

other: 1.Crj: CD(SD) ,2.B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

1.- Source: Charles River Japan Inc.
- Age at study initiation: 9 weeks
- Weight at study initiation: Range of average, 381.8-385.1g for males, 236.5-237.9g for females
- Fasting period before study: No
- Housing: One animal/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-25°C
- Humidity (%): 50-65%
- Air changes (per hr): 15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

2.- Source:Cumberland View Farms
- Age at study initiation: 7 dyas
- Weight at study initiation: 10-19 gms
Fasting period before study:
- Housing: Animals were 6 mice to a cage. 2160 mice couli be housed in each room.
- Diet (e.g. ad libitum): food , ad libitum
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): A dual duct high velocity system was used for heating, ventilation and air conditioning.Unidirectional air-flow minimized room to room contamination with absolute filtration of all incoming air to remove particulate matter of 0.3 micron diameter or greater.

Route of administration:

other: 1.oral: gavage ,2.oral administration by stomach tube and after dose is administer through diet.

Vehicle:

other: 1.corn oil 2. Diet(ground feed) and 0.5% gelatin

Details on exposure:

1.
PREPARATION OF DOSING SOLUTIONS: The test substance was dissolved with corn oil at concentration of 0.4-10%.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Solution
- Concentration in vehicle: 0.4-10%
- Amount of vehicle (if gavage): 5 ml/kg bw
2.
oral administration by stomach tube from day 7 to 28 and after dose is administer through diet for 18 months

Details on mating procedure:

Study 1
- M/F ratio per cage:1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:Vaginal plug/sperm in vaginal smear] referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how): One female/cage with bedding to nest
- Any other deviations from standard protocol:
Study 2
No data available

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Study 1
For males: Male rats were dosed for 42 days from 14 days before mating.
For females: Female rats were dosed from 14 days before mating to day 4 of lactation throughout the mating and pregnancy period.
Study 2
18 months

Frequency of treatment:

once a day

Details on study schedule:

Study 1
- F1 parental animals not mated until 2 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 4 days of age.
- Age at mating of the mated animals in the study:9 weeks

Remarks:

Study 1.
0, 20, 100, or 500 mg/kg bw/day
Study 2
0 and 215 mg/kg bw/day

No. of animals per sex per dose:

Study 1.
Total:104
0 mg/kg:13male and 13 female
20 mg/kg:13male and 13 female
100 mg/kg:13male and 13 female
500 mg/kg:13male and 13 female

Study 2
Total: 150
0 mg/kg bw :18 Females
0 mg/kg bw :18 Females
215 mg/kg bw :18 Females

Positive control
Ethyl carbamate: 24 Females
Amitrol: 18 Females
E:thylene imine: 18 Females
Aramite: 18 Females
Dihydrosafrole: 18 Females
Safrole: 18 Females

Control animals:

yes, concurrent vehicle

Details on study design:

Study 1
- Dose selection rationale: Based on a preliminary study, in which 9 weeks old male and female rats were given 4-methoxybenzaldehyde at a dose of 0, 250, 500 or 1000mg/kg for 14 days.
- Rationale for animal assignment (if not random): Random

Study 2
- Dose selection rationale: The basic concept of the dosage choice was the use of a maximum tolerated dose. The calculated dose was not adjusted to the changing body weight during the three weeks of stomach tubing but a single adjustment was made at the time of conversion from stomach tube to mixture in the feed.
- Rationale for animal assignment (if not random): Dosing of individual mice was based on the average weight within a single group and, in the case of repetitive administration, was based on starting weights and not adjusted as the study continued.( An exception to this was the recalculation in the definitive study, at the time of weaning when administration was converted from daily stomach tubing to incorporation in the diet.)

Positive control:

Study 1:No Data
Study 2:Ethyl carbamate, Amitrol, E:thylene imine, Aramite, Dihydrosafrole and Safrole were used as positive control.

Parental animals: Observations and examinations:

Study 1
Parental animals observation and examinations
AGE SIDE OBSERVATIONS: Yes
- Time schedule: Once a day

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined on days 1 (before dosing), 7, 14, 21, 28, 35, 42 and 43 (at autopsy) in males and on days 1 (before dosing), 7 and 14 in all females, on days 21 and 28 in some females, on days 0, 7, 14 and 20 of gestation in pregnant females, and on days 0, 4 and 5 (at autopsy) of lactation in females that delivered, and day 25(at autopsy) of gestation in females that had not delivered.

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: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
Food consumption was determined for days 1-2, 7-8, 13-14, 29-30, 35-36 and 41-42 of the administration period in males, for days 1-2 and 7-8 in all females, for days 0-1, 7-8, 14-15 and 20-21 of gestation in pregnant females, and for days 0-1 and 3-4 of lactation in females that delivered.

Study 2
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Daily
- Cage side observations checked in table [No.?] were included: Mortality and morbidity were observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: palpated weekly at time of weighing for enlargement of liv,~r and spleen, or any subcutaneous tumor.

BODY WEIGHT: Yes
- Time schedule for examinations: six animals in each cage were weighed once a week.

Oestrous cyclicity (parental animals):

Study 1:
Yes, Estrous cycle was observed from 14 days before mating to day of copulation

Sperm parameters (parental animals):

Study 1:Testes and epididymides weights were determined.

Litter observations:

Study 1:STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: No

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: For F1 offspring, number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain were observed.


GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.

Postmortem examinations (parental animals):

Study 1:
Postmortem examinations (SACRIFICE
Males and females were sacrificed at the end of the observation period; on day 43 of the administration period and on day 5 of the lactation period, respectively.

GROSS NECROPSY
Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

ORGAN WEIGHTS
Weights of organs such as brain, thymus, heart, liver, spleen, kidneys, adrenals, testes and epididymides in males, and brain, thymus, heart, liver, spleen, kidneys and adrenals in females were determined at necropsy.

HISTOPATHOLOGY
Histopathological examination of brain, pituitary, spinal cords, alimentary canal, liver, kidneys, adrenals, spleen, pancreas, heart, thymus, thyroid, trachea, lung, urinary bladder, mesentery lymph node, submandibular lymph node, sciatic nerve, femur bone marrow, seminal vesicle, prostate, vagina, ovaries, uterus, testes and epididymides were performed in 5 males and pregnant females in the 0 and 500 mg/kg bw/day groups. In addition, testes and epididymides in males and ovaries in females in the 20 and 100 mg/kg bw groups and liver and stomach in males and females and heart in males in the 20 and 100 mg/kg bw groups were histopathologically examined.

Study 2
Gross pathology and histopathology were examined.

Postmortem examinations (offspring):

Study 1:
SACRIFICE
- All dead pups (F1) were necropsied. All live pups(F1) were sacrificed under anesthesia to examine for viseceral anomalies on day 4 of the lactation period.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.


HISTOPATHOLOGY / ORGAN WEIGTHS: Not examined

Statistics:

Study 1:
Statistical analysis was conducted using the Dunnett's test, Bartlett's test, Mann-Whitney U- test and Fisher' direct test.
Study 2
Chi square test &Yates Correction were used

Reproductive indices:

Study 1:
Reproductive and developmental parameters:
No. of pairs mated, no. of pairs copulated, copulation index (no. of copulated pairs/no. of mated pairs x 100), no. of pregnant females, fertility index (no. of pregnant animals/no. of animals with successful copulation x 100), estrous cycle, frequency of vaginal estrus, no. of pregnant females with live pups, gestation index (no. of females with live pups/no. of pregnant females x 100), gestation length, no. of corpora lutea, implantation index (no. of implantation sites/no. of corpora lutea x 100), no. of pups born, deliver index (no. of pups born/no. of implantation sites x 100)

Offspring viability indices:

Study 1:
No. of live pups on day 0 of lactation, birth index (no. of live pups on day 0/no. of implantation sites x 100), live birth index (no. of live pups on day 0/no. of pups born x 100), pups weight on day 0 of lactation, sex ratio of pups on day 0 of lactation, no. of live pups on day 4 of lactation, viability of pups on day 4 of lactation, pups weight on day 4 of lactation, and sex ratio of pups on day 4 of lactation were determined. All pups born were examined for external anomalies at birth and all live pups were sacrificed under anesthesia to examine for visceral anomalies on day 4 after birth.

Clinical signs:

no effects observed

Description (incidence and severity):

Study 1:Temporary salivation after administration was observed in males and females in the 500 mg/kg bw group.

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

Study 1:No animal died in any group.
Study 2: No effect on survival of treated female mice were observed as compared to control.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1:Body weight tended to be increased in males and females in the 100 and 500 mg/kg bw groups.
Study 2:Body weight gain was observed with the increase in duration of treatment.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Study 1:Increase in food consumption was observed in males of the 500 mg/kg bw group and females in the 100 and 500 mg/kg bw groups

Food efficiency:

not specified

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

not specified

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Study 1:Hyperplasia of squamous epithelium was detected in males and females in the 100 and 500 mg/kg bw groups. In liver, centrilobular hypertrophy of hepatocytes was detected in males of the 500mg/kg bw group.

Histopathological findings: neoplastic:

not specified

Description (incidence and severity):

Study 2:No fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control.

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Study 1:The compound showed no adverse effects in terms of estrous cycle

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Study 1:In the 500 mg/kg bw group, the number of non-pregnant females was increased whereas all pairs copulated, and the fertility index was reduced.The delivery index was lower than in controls at 500 mg/kg bw/day.The compound showed no adverse effects number of corpora lutea and implant rate at any dose level.
Study 2:Not Disrupted sexual function

Dose descriptor:

NOAEL

Effect level:

> 100 - <= 215 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

reproductive performance

Remarks on result:

other: No toxic effects observed at given dose level

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Study 1:In the 500 mg/kg bw group, the number of pups, the delivery index and the number of live pups were lower than in the controls.(

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1:A decrease in body weight on day 0 of lactation was observed in the 500 mg/kg bw group.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

sexual maturation

clinical signs

mortality

body weight and weight gain

gross pathology

Remarks on result:

other: overall no developmental toxic effects observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Reproductive performance

 

Compound dose Mg/kg bw	0	20	100	500
Mean length of estrous cycle in days Mean SD	4.3 0.6	4.0 0.0	4.2 0.3	4.3 0.4
Number of mated pairs	13	13	13	13
Number of copulated pairs	13	13	13	13
Copulation index(%)	100	100	100	100
Number of pregnant animals	12	12	12	6
Fertility index	92.3	92.3	92.3	46.2*
Pairing days until copulation Mean SD	2.7 1.1	2.5 1.2	2.7 1.2	2.9 2.5
Frequency of vaginal estrous Mean SD	1.0 0.0	1.0 0.0	1.0 0.0	1.1 0.3

*:p<0.05 (by Fisher's direct test)

 

Summary of development of pups

 

Compound dose Mg/kg bw	0	20	100	500
Number of pregnant females	12	12	12	6
Number of pregnant females with pups alive	12	12	12	5
Gestation index (%)	100	100	100	83.3
Day 0 of lactation
Number of pups born Mean SD	14.0(12) 4.5	14.3(12) 1.4	11.8(12) 4.3	9.3(6)* 5.2
Delivery index(%) Mean SD	94.7(12) 5.4	92.2(12) 9.5	90.9(12) 8.0	66.5(6)** 33.9
Number of pups alive Mean SD	13.8(12) 4.8	14.2(12) 1.6	11.8(12) 4.3	10.6(6)* 2.5
Birth index (%) Mean SD	85.3(12) 27.9	91.6(12) 9.7	90.9(12) 8.0	76.0(6) 13.0
Live birth index (%) Mean SD	90.5(12) 28.8	99.3(12) 2.4	100.0(12) 0.0	95.4(6) 10.3
Pups weight (g)
Male Mean SD	7.0(11) 0.7	7.0(12) 0.6	7.4(12) 1.2	6.6(5) 0.7
Female Mean SD	6.5(11) 0.6	6.6(12) 0.4	7.0(12) 0.9	6.1(5) 0.6
Sex ratio (male/female) on day 0 (%) Mean SD	86(11) 54	116(12) 73	142(12) 110	110(5) 71
Day 4 of lactation
Number of pups alive Mean SD	14.8(11) 2.2	14.2(12) 1.6	11.8(12) 4.3	10.2(5)* 2.8
Viability index (%) Mean SD	98.7(11) 3.0	100.0(12) 0.0	100.0(12) 0.0	96.0(5)* 8.9
Pups weight (g)
Male Mean SD	11.3(11) 1.3	11.3(12) 1.4	12.7(12) 3.0	11.3(5) 1.3
Female Mean SD	10.8(11) 1.1	10.9(12) 1.1	12.3(12) 2.8	11.1(5) 0.9
Sex ratio (male/female) on day 4 (%) Mean SD	92(11) 69	116(12) 73	142(12) 110	102(5) 74

 

*:p<0.05; **:p<0.01

Conclusions:

The NOAEL for reproductive toxicity was considered to be in range of 100-215 mg/kg bw/day as No effects on reproductive parameters were observed .When male and female rats or mice were treated with test chemical orally.

Executive summary:

Study 1.

In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422), the male and femaleCrj:CD(SD)IGSrats were given test material by gavage at 0, 20, 100, or 500 mg/kg bw/day for 42 days beginning 14 days before mating in males, and from 14 days before mating to day 4 of lactation throughout the mating and pregnancy period in females.The test substance was dissolved with corn oil and adminstered in dose volume 5ml/kg bw once daily . 13 animals/sex/dose were used. Body weights were determined on days 1 (before dosing), 7, 14, 21, 28, 35, 42 and 43 (at autopsy) in males and on days 1 (before dosing), 7 and 14 in all females, on days 21 and 28 in some females, on days 0, 7, 14 and 20 of gestation in pregnant females, and on days 0, 4 and 5 (at autopsy) of lactation in females that delivered, and day 25(at autopsy) of gestation in females that had not delivered. Food consumption was determined for days 1-2, 7-8, 13-14, 29-30, 35-36 and 41-42 of the administration period in males, for days 1-2 and 7-8 in all females, for days 0-1, 7-8, 14-15 and 20-21 of gestation in pregnant females, and for days 0-1 and 3-4 of lactation in females that delivered. For F1 offspring, number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain were observed.Males and females were sacrificed at the end of the observation period; on day 43 of the administration period and on day 5 of the lactation period, respectively.

Histopathological examination of brain, pituitary, spinal cords, alimentary canal, liver, kidneys, adrenals, spleen, pancreas, heart, thymus, thyroid, trachea, lung, urinary bladder, mesentery lymph node, submandibular lymph node, sciatic nerve, femur bone marrow, seminal vesicle, prostate, vagina, ovaries, uterus, testes and epididymides were performed in 5 males and pregnant females in the 0 and 500 mg/kg bw/day groups. In addition, testes and epididymides in males and ovaries in females in the 20 and 100 mg/kg bw groups and liver and stomach in males and females and heart in males in the 20 and 100 mg/kg bw groups were histopathologically examined. All dead pups (F1) were necropsied. All live pups(F1) were sacrificed under anesthesia to examine for viseceral anomalies on day 4 of the lactation period.Estrous cycle was observed from 14 days before mating to day of copulation

No animal died in any group. Temporary salivation after administration was observed in males and females in the 500 mg/kg bw group. Body weight tended to be increased in males and females in the 100 and 500 mg/kg bw groups. Increase in food consumption was observed in males of the 500 mg/kg bw group and females in the 100 and 500 mg/kg bw groups. Hyperplasia of squamous epithelium was detected in males and females in the 100 and 500 mg/kg bw groups. In liver, centrilobular hypertrophy of hepatocytes was detected in males of the 500mg/kg bw group.

No effects on Estrous cycle was observed. In the 500 mg/kg bw group, the number of non-pregnant females was increased whereas all pairs copulated, and the fertility index was reduced. Epididymidal weight was decreased in males of the 500 mg/kg bw group. Dark spots in the mucosa of the stomach and nodes in the epididymis were observed by one animal each in the 500 mg/kg bw group. In the 500 mg/kg bw group, the number of pups, the delivery index and the number of live pups were lower than in the controls. A decrease in body weight on day 0 of lactation was observed in the 500 mg/kg bw group.No effects on sexual maturation and gross pathology. The No Observed Adverse Effect Level (NOAEL) for reproductive toxicity in rats was considered to be 100 mg/kg bw/day.

Study 2

In a reproductive toxicity study, B6C3F1 female mice were treated with test material in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using test material for 18 months.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from experimental study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 2.

In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422), the male and femaleCrj:CD(SD)IGSrats were given test material by gavage at 0, 20, 100, or 500 mg/kg bw/day for 42 days beginning 14 days before mating in males, and from 14 days before mating to day 4 of lactation throughout the mating and pregnancy period in females.The test substance was dissolved with corn oil and adminstered in dose volume 5ml/kg bw once daily . 13 animals/sex/dose were used. Body weights were determined on days 1 (before dosing), 7, 14, 21, 28, 35, 42 and 43 (at autopsy) in males and on days 1 (before dosing), 7 and 14 in all females, on days 21 and 28 in some females, on days 0, 7, 14 and 20 of gestation in pregnant females, and on days 0, 4 and 5 (at autopsy) of lactation in females that delivered, and day 25(at autopsy) of gestation in females that had not delivered. Food consumption was determined for days 1-2, 7-8, 13-14, 29-30, 35-36 and 41-42 of the administration period in males, for days 1-2 and 7-8 in all females, for days 0-1, 7-8, 14-15 and 20-21 of gestation in pregnant females, and for days 0-1 and 3-4 of lactation in females that delivered. For F1 offspring, number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain were observed.Males and females were sacrificed at the end of the observation period; on day 43 of the administration period and on day 5 of the lactation period, respectively.

Histopathological examination of brain, pituitary, spinal cords, alimentary canal, liver, kidneys, adrenals, spleen, pancreas, heart, thymus, thyroid, trachea, lung, urinary bladder, mesentery lymph node, submandibular lymph node, sciatic nerve, femur bone marrow, seminal vesicle, prostate, vagina, ovaries, uterus, testes and epididymides were performed in 5 males and pregnant females in the 0 and 500 mg/kg bw/day groups. In addition, testes and epididymides in males and ovaries in females in the 20 and 100 mg/kg bw groups and liver and stomach in males and females and heart in males in the 20 and 100 mg/kg bw groups were histopathologically examined. All dead pups (F1) were necropsied. All live pups(F1) were sacrificed under anesthesia to examine for viseceral anomalies on day 4 of the lactation period.Estrous cycle was observed from 14 days before mating to day of copulation

No animal died in any group. Temporary salivation after administration was observed in males and females in the 500 mg/kg bw group. Body weight tended to be increased in males and females in the 100 and 500 mg/kg bw groups. Increase in food consumption was observed in males of the 500 mg/kg bw group and females in the 100 and 500 mg/kg bw groups. Hyperplasia of squamous epithelium was detected in males and females in the 100 and 500 mg/kg bw groups. In liver, centrilobular hypertrophy of hepatocytes was detected in males of the 500mg/kg bw group.

No effects on Estrous cycle was observed. In the 500 mg/kg bw group, the number of non-pregnant females was increased whereas all pairs copulated, and the fertility index was reduced. Epididymidal weight was decreased in males of the 500 mg/kg bw group. Dark spots in the mucosa of the stomach and nodes in the epididymis were observed by one animal each in the 500 mg/kg bw group. In the 500 mg/kg bw group, the number of pups, the delivery index and the number of live pups were lower than in the controls. A decrease in body weight on day 0 of lactation was observed in the 500 mg/kg bw group.No effects on sexual maturation and gross pathology. The No Observed Adverse Effect Level (NOAEL) for reproductive toxicity in rats was considered to be 100 mg/kg bw/day.

Study 3

In a reproductive toxicity study, B6C3F1 female mice were treated with test material in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using test material for 18 months.

Based on the data available from different studies, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

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

Thus, comparing this value with the criteria of CLP regulation test chemical is not likely to classify as reproductive toxicant.