1,3-Benzenedimethanamine, N-(2-phenylethyl) derivs.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2012-07-14 to 2012-xx-xx

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study according to OECD guideline 421

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories, BV, Kreuzelweg 53, 5961 NM Horst / Netherlands
- Age at study initiation: (P) x 10 wks
- Weight at study initiation: (P) Males: 339-385 g; Females: 203-236 g; (F1)
- Fasting period before study: no
- Housing: Individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding (‘Lignocel’ J.Rettenmaier & Söhne GmbH & CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba SA, 4303 Kaiseraugst / Switzerland; batch/lot no. 02105120301) with paper enrichment (Envirodri from Lillico, Biotechnology, Surrey / UK), batch/lot no. 100099). During the pre-pairing period, cages with males were interspersed amongst those
holding females to promote the development of regular estrus cycles.
- Diet (e.g. ad libitum): Pelleted standard Harlan Teklad 2914C (batch no. 73/11) rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst / Switzerland) was available ad libitum.
- Water (e.g. ad libitum): Community tap-water from Itingen was available ad libitum in water bottles.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): for stability of the test item
- Concentration in vehicle: o, 1.25, 3.75 and 10.0 mg/mL/day
- Amount of vehicle (if gavage): 4 mL/kg bw
- Lot/batch no. (if required): Charge 260156161

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 14 days maximum
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): no data
:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The dose formulations were analyzed by an HPLC method adapted at Harlan Laboratories. The samples (approximately 2 g each) were delivered to the analytical laboratory.

Duration of treatment / exposure:

males: 4 weeks, females: 7 to 9 weeks

Frequency of treatment:

once daily

Details on study schedule:

- Age at mating of the mated animals in the study: 13 weeks

Remarks:

Doses / Concentrations:
5 mg/kg/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
15 mg/kg/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
40 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

11

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The highest dose level was chosen with the aim of inducing toxic effects but not death or severe suffering. A descending sequence of dose levels was selected with a view to demonstrating any dose related response. 2.67 to 3 fold intervals were chosen for the descending dose levels.

Positive control:

no

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Males: Recorded on the first day of dosing, once weekly thereafter and at termination. Females: Recorded on the first day of dosing, once weekly thereafter and on days 0, 7, 14 and 20 post coitum, on days 0, 1 and 4 post partum.

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

Parameters examined in P male parental generations: testis weight, epididymis weight, sperm staging

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, physical abnormalities

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

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals were sacrificed after they had been treated for at least 28 days
- Maternal animals: All surviving animals were sacrificed on day 4 post partum. If birth did not occur on the expected date (day 21 post coitum), the dam was sacrificed on day 25 post coitum.

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

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed, respectively: in males (testes and epididymides, prostate, seminal vesicles with coagulating gland, liver); in females (ovaries) that did not give birth and liver of all animals. In addition, microscopic examination of the reproductive organs of all infertile males was made.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: for any structural changes

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGTHS
no data

Statistics:

The following statistical methods were used to analyze food consumption, body weights and reproduction data:
• Means and standard deviations of various data were calculated.
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test was applied if the variables could be dichotomized without loss of information.

Reproductive indices:

Percentage mating = ( Females mated / Females paired) * 100
Fertility index = ( Females achieving a pregnancy / Females paired) * 100
Conception rate = ( Females achieving a pregnancy / Females mated) * 100
Gestation index = ( Number of females with living pups / Females pregnant) * 100

Offspring viability indices:

Viability index = (pups alive before culling on day 4 p.p. / pups born alive) * 100

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

abnormal posture or gait, body weight loss and lower food consuption at 40 mg/kg/day

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In males, the mean daily food consumption values at 40 mg/kg/day were significantly lower than the control males during pre-pairing period and in females, slightly lower during pre-pairing period and significantly lower during the gestation and lactation.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In males, the mean daily food consumption values at 40 mg/kg/day were significantly lower than the control males during pre-pairing period and in females, slightly lower during pre-pairing period and significantly lower during the gestation and lactation.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

An incerase in hepatocellular glycogen deposits was observed in the livers with gross lesions in six high dose animals.

Other effects:

not examined

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

An increased incidence in the mean post-implantation loss, postnatal loss, and lower viability index were observed at the high dose level.

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Clinical signs of abnormal posture or gait were observed in males and females from the pairing period in males and from the gestation period in the females. Body weight loss and lower food consumption of males and females were observed at 40 mg/kg/day.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
In males, the mean body weights at 40 mg/kg/day were significantly lower (generally p<0.01) than the control males from day 12 of the pre-pairing and pairing periods. Body weight gain was significantly lower (p<0.01) than the control males from day 2 of the pre-pairing period and from day 4 of the pairing period. In females, the mean body weights at 40 mg/kg/day were generally significantly lower (p<0.05) than the control females from day 12 of the pre-pairing period and during the pairing period. During the gestation period female mean body weights at 40 mg/kg/day were significantly lower (p<0.01) than the control females. Body weight gain was significantly lower (p<0.05 or p<0.01) than the control females from day 11 during the pre-pairing period and significantly lower (generally p<0.01) than the control females during the gestation and lactation periods.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
not examinated - gavage

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
no data

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
no effects

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
An increased incidence in the mean post-implantation loss, postnatal loss, and lower viability index were observed at the high dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS)
no effects

GROSS PATHOLOGY (PARENTAL ANIMALS)
At 40 mg/kg/day, three males had clay-colored livers and three females had clay or tan-colored livers.

HISTOPATHOLOGY (PARENTAL ANIMALS)
An incerase in hepatocellular glycogen deposits was observed in the livers with gross lesions in six high dose animals.

Dose descriptor:

NOAEL

Remarks:

for reproductive toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Higest dose tested. No adverse effects observed

Dose descriptor:

NOEL

Remarks:

for reproductive toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Dose descriptor:

NOAEL

Remarks:

and NOEL for systemic toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

body weight and weight gain

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

Dose descriptor:

LOAEL

Remarks:

for systemic toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: abnormal posture or gait, body weight loss and lower food consumption, clay- or tan-coloured livers

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Pup data at high dose group showed a high pup death in one litter (9 pups) or missing pups in other litter (12 missing and 2 dead pups).

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

lower viability index were observed at the high dose level.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The body weights of the remaining pups (out of 9 death in this litter) were lower on day 4 of lactation when compared with day 1.

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

One pup from the low dose and two pups from the mid dose had sores on the tail tip.

Histopathological findings:

not specified

VIABILITY (OFFSPRING)
Lower viability index were observed at the high dose level.

CLINICAL SIGNS (OFFSPRING)
Pup data at high dose group showed a high pup death in one litter (9 pups) or dead and missing pups in other litter (12 missing and 2 dead pups).

BODY WEIGHT (OFFSPRING)
The body weights of the remaining pups (out of 9 death in this litter) were lower on day 4 of lactation when compared with day 1.

SEXUAL MATURATION (OFFSPRING)
not examinated

ORGAN WEIGHTS (OFFSPRING)
no data

GROSS PATHOLOGY (OFFSPRING)
generally no effects, but one pup from the low dose and two pups from the mid dose had sores on the tail tip.

HISTOPATHOLOGY (OFFSPRING)
no data

Remarks on result:

other: Not determined

Reproductive effects observed:

not specified

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be at 40 mg/kg body weight/day since no histological evidence of a direct toxicological property in the reproductive organs was detected. The No Observed Effect Level (NOEL) for reproductive toxicity was established at 15 mg/kg body weight/day. The NOAEL and NOEL for systemic toxicity were established at 15 mg/kg body weight/day. The findings at 40 mg/kg/day including the clinical signs, moribundity, lower food consumption and decrease in body weight as well as the liver gross lesions correlating to an increase in glycogen contents.

Executive summary:

The purpose of this study was to generate preliminary information on the possible health hazards likely to arise from repeated exposure over a relatively limited period of time. In addition it will provide information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

This study should provide information to assess the need to conduct further investigations and may provide guidance in the design of subsequent studies. Eighty eight rats were assigned to 4 groups each containing 11 males and 11 females. The control, low, intermediate, and high dose group animals (groups 1 to 4) were treated with 0, 5, 15 or 40 mg/kg bw/day, respectively. At the end of the study period, all surviving parent males were sacrificed on study day 29, except high dose male no. 38 which was sacrificed on day 35. All surviving parent females were sacrificed on day 4 post partum (study days 40 to 46). All animals were necropsied and examined post mortem. Histological examinations were performed in all parent males and females of groups 1 and 4 as well as in parent male nos. 13, 14, 21, and 33 (groups 2 and 3) and parent female nos. 57, 58, 65, and 77 (groups 2 and 3) because no pregnancy or delivery occurred after mating. Under the conditions of this experiment, the test item “Gaskamine” did induce the following direct or indirect test item-related findings:

• One high dose male and two high dose females were sacrificed in moribund conditions. Only in one female the remaining fetuses in the uterus horns without delivery could be considered as cause of moribundity. In the male and the other female, the causes of death

were not evident from the organs examined.

• In three high dose males and three females, the livers were recorded as clay-colored or with a tan discoloration. All other gross lesions were considered to be background findindings.

• Possibly test item-related microscopical findings such as increased hepatocellular glycogen deposits were observed in the six livers with gross lesions although the body weights were decreased in high dose animals.

• No test item-related microscopical findings were noted in testes and epididymides; the minimally to slightly reduced secretory activity in prostate, coagulating glands, and/or seminal vesicles in some high dose males was considered to be consequent to the lower

body weights and not to be a direct effect of the test item. No histological evidence of a direct toxicological property in the reproductive organs was detected. Therefore the No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was

considered to be at 40 mg/kg bw/day. The No Observed Effect Level (NOEL) for reproductive toxicity was established at 15 mg/kg bw/day.

The NOAEL for systemic toxicity in liver has to be based on the gross lesions that were recorded only in a few high dose animals. A correlating increase in glycogen contents was noted in these few males and females although the body weights were decreased in high dose animals. Therefore, a relation to an effect of the test item cannot be excluded definitely at 40 mg/kg bw/day and the NOAEL was established at 15 mg/kg bw/day based on the livers with gross lesions.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP study, Klimisch 1

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A valid OECD 421 reproduction/development toxicity screening study has been conducted with the substance. The substance proved to be not reprotoxic up to a dose level of 40 mg/kg bw/day.

Short description of key information:
The substance is not reprotoxic up to a dose level of 40 mg/kg bw/day.

Justification for selection of Effect on fertility via oral route:
The selected study was performed under GLP and in accordance with OECD TG 421. No other studies are available.

Effects on developmental toxicity

Description of key information

The substance is not reprotoxic up to a dose level of 40 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2012-07-14 to 2012-xx-xx

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study according to OECD guideline 421

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 421 reproduction/developmental toxicity screening test

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories, BV, Kreuzelweg 53, 5961 NM Horst / Netherlands
- Age at study initiation: (P) x 10 wks
- Weight at study initiation: (P) Males: 339-385 g; Females: 203-236 g; (F1)
- Fasting period before study: no
- Housing: Individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding (‘Lignocel’ J.Rettenmaier & Söhne GmbH & CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba SA, 4303 Kaiseraugst / Switzerland; batch/lot no. 02105120301) with paper enrichment (Envirodri from Lillico, Biotechnology, Surrey / UK), batch/lot no. 100099). During the pre-pairing period, cages with males were interspersed amongst those
holding females to promote the development of regular estrus cycles.
- Diet (e.g. ad libitum): Pelleted standard Harlan Teklad 2914C (batch no. 73/11) rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst / Switzerland) was available ad libitum.
- Water (e.g. ad libitum): Community tap-water from Itingen was available ad libitum in water bottles.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): for stability of the test item
- Concentration in vehicle: o, 1.25, 3.75 and 10.0 mg/mL/day
- Amount of vehicle (if gavage): 4 mL/kg bw
- Lot/batch no. (if required): Charge 260156161

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The dose formulations were analyzed by an HPLC method adapted at Harlan Laboratories. The samples (approximately 2 g each) were delivered to the analytical laboratory.

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 14 days maximum
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): no data

Duration of treatment / exposure:

males: 4 weeks, females: 7 to 9 weeks

Frequency of treatment:

once daily

Duration of test:

Males were sacrificed after they had been treated for at least 28 days, when no longer needed for the assessment of reproductive effects. Dams and pups were sacrificed on day 4 post partum. If birth did not occur on the expected date (day 21 post coitum), the dam was sacrificed on
day 25 post coitum.

No. of animals per sex per dose:

11

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The highest dose level was chosen with the aim of inducing toxic effects but not death or severe suffering. A descending sequence of dose levels was selected with a view to demonstrating any dose related response. 2.67 to 3 fold intervals were chosen for the descending dose levels.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Males: Recorded on the first day of dosing, once weekly thereafter and at termination. Females: Recorded on the first day of dosing, once weekly thereafter and on days 0, 7, 14 and 20 post coitum, on days 0, 1 and 4 post partum.

Ovaries and uterine content:

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

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed, respectively: in females (ovaries) that did not give birth and liver of all animals. In addition, microscopic examination of the reproductive organs of all infertile males was made.

Fetal examinations:

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: for any structural changes

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGTHS
no data

Statistics:

The following statistical methods were used to analyze food consumption, body weights and reproduction data:
• Means and standard deviations of various data were calculated.
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test was applied if the variables could be dichotomized without loss of information.

Indices:

ERproductive indices:
Percentage mating = ( Females mated / Females paired) * 100
Fertility index = ( Females achieving a pregnancy / Females paired) * 100
Conception rate = ( Females achieving a pregnancy / Females mated) * 100
Gestation index = ( Number of females with living pups / Females pregnant) * 100

Offspring viability indices:
Viability index = (pups alive before culling on day 4 p.p. / pups born alive) * 100

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: LOAEL = 40 mg/kg bw/d

Details on maternal toxic effects:
Abnormal posture or gait, body weight loss and lower food consuption, clay- or tan-colored livers (for more details see RSS Braun 2012 in section 7.8.1 Toxicity to reproduction).

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In an OECD 421 Reproduction / Developmental Toxicity Screening Study no teratogenic effects observed up to the highest dose level tested of 40 mg/kg bw/d (NOEL).

Executive summary:

In a Klimisch-1 -rated OECD 421 Reproduction / Developmental Toxicity Screening Study no teratogenic effects were being observed up to the highest dose level tested of 40 mg/kg bw/d (NOEL).

The NOAEL for systemic toxicity in liver has to be based on the gross lesions that were recorded only in a few high dose animals. A correlating increase in glycogen contents was noted in these few males and females although the body weights were decreased in high dose animals. Therefore, a relation to an effect of the test item cannot be excluded definitely at 40 mg/kg bw/day and the NOAEL was established at 15 mg/kg bw/day based on the livers with gross lesions.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP study, Klimisch 1

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A Klimisch-1-rated OECD 421 reproduction/development toxicity screening study has been conducted in the year 2012 on the substance. The substance did not show any teratogenic effects in this study up to the highest applied dose of 40 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:
The selected study was performed under GLP and in accordance with OECD TG 421. No other studies are available.

Justification for classification or non-classification

The substance did not give any indication of reprotoxic potential at the highest test dose level of 40 mg/kg bw/day, while the LOAEL for systemic toxicity was established at 40 mg/kg bw/d. Based on these grounds no classification of the test item as to its reprotoxicity properties required.