Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
In reprotox studies, the dye 4-chlororesorcinol was administered by gavage to Sprague-Dawley rats on days 6 through 15 of gestation at the following dose levels: at 50, 100, and 200 mg/kg and the effects were noted.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Age at study initiation: (P) x wks; mature (F1) x wks : No data available
- Weight at study initiation: 225 and 250 grams
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow .ad libitum

- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Constant
- Humidity (%): Constant
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The solutions were prepared fresh daily and administered at a rate of 10 ml/kg.

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: to get a dose of 0, 50, 100 and 200 mg/kg body weight/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required):
- Purity:
Details on mating procedure:
- M/F ratio per cage: 1:2 ratio
- Length of cohabitation: No data available
- Proof of pregnancy: Sperm in vaginal smear is referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.: No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No data available
- After successful mating each pregnant female was caged (how): Once mating was determined, each female was separated, housed, and identified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
10 days (gestation day 6-15)
Frequency of treatment:
Daily
Details on study schedule:
no details available
Remarks:
Doses / Concentrations:
0, 50, 100, and 200 mg/kg body weight/day
Basis:
nominal conc.
No. of animals per sex per dose:
0 mg/kg bw/day: 22 female
50 mg/kg bw /day: 7 female
100 mg/kg bw /day: 7 female
200 mg/kg bw/day: 8 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels for the dyes were determined by previous range finding studies to estimate the maximum tolerated dosages. The dose levels were as follows: 50, 100, and 200 mg/kg for 4-chlororesorcinol.
- Rationale for animal assignment (if not random): Mature male and female Sprague-Dawley rats were chosen for the study. Pregnant females were assigned on a random basis to a high, medium, or low dosage group for 4-chlororesorcinol.
- Other:
On day 20 of gestation, estimated as 24 hours preparturition, the dams were sacrificed by carbon dioxide inhalation. The viability of each foetus was determined. The metrial glands were counted, identifying original implantation sites. An implantation site not occupied by a foetus was designated a resorption site. Each fetus was sexed and weighed to the nearest 0.1 gram. Any fetal external malformations were recorded after gross examination of the head, trunk and limbs.
Positive control:
Positive controls were included in the study. Vitamin A (Aquasol A Drops, USV Laboratories, N.Y.) was.dosed at a rate of 100,000 I.U. per animal on day 9 of gestation only. Aspirin (Fisher Scientific Company, N.J.) was dosed at a rate of 350 mg/kg on days 6-15 of gestation.
Parental animals: Observations and examinations:
Survival, clinical sign and body weight were examined.
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated
Sperm parameters (parental animals):
No data available
Litter observations:
Survival, sex ratio, Number of Litters, No. Abnormal Fetuses and body weight of fetus were examined.
Postmortem examinations (parental animals):
Gross abnormalities and histopathology were examined.
Number of implantation sites and resorption site was examined.
Postmortem examinations (offspring):
Gross abnormalities, visceral anomalies and skeletal anomalies/ variations were examined.
Statistics:
Statistical analysis was performed by using Student’s T-test for comparison of maternal weight changes, the number of fetal implantations, fetal weight and fetal sex ratio. Chi square analysis were used to compared the number of fetal resorptions and abnormal fetuses. A “naive” model trend analysis was conducted according to Johnson and Siskin. For all statistical analyses, a level of probability of p = 0.05 was used for significance. When lower levels of probability were observed, these were noted.
Reproductive indices:
Fertility index, gestation index and implantation index were examined.
Offspring viability indices:
Yes, viability of each fetus was determined
Clinical signs:
no effects observed
Description (incidence and severity):
All dams appeared normal upon gross observation throughout the studies
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
when treated with 200 mg/kg bw/day, on day 6-16 significant decrease in weight gains were observed in females as compared to control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
when treated with 200 mg/kg bw/day, on day 6-16 significant decrease in weight gains were observed in females as compared to control.
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effect were observed on reproductive function of treeated rat as compared to control.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect were observed on reproductive performance of treated rat as compared to control.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight , Gross abnormalities, histopathology and reproductive performance.
Clinical signs:
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 200 mg/kg bw/day, open eye, Gastromegaly and Wavy Rib were observed in fetaus of treated rat. Although abnormalities were observed but they are not statistically significant as compared to control.
Histopathological findings:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival and gross pathology of foetus
Reproductive effects observed:
not specified

Exposure to the positive control agents, Vitamin A and aspirin,resulted in a statistically significant increase in abnormal fetuses with a broad spectrum of gross visceral and skeletal anomalies ranging from a frequency of 18-60%.

Conclusions:
NOAEL of 4-Chlororesorcinol in female Sprague-Dawley rats was considered to be 100 mg/kg body weight /day for F0 and F1 generation.
Executive summary:

In a reproductive toxicity study, Sprague-Dawley female rat were exposed to 4-Chlororesorcinol in the concentration of 0, 50, 100 and 200 mg/kg body weight /day on day 6 -15 of gestation.

A significant reduction in mean maternal weight gain and significant decrease in total resorpton of 200 mg/kg body weight /day treated rat were observed as compared to control.

On fetal evaluation open eye, gastromegaly and wavy rib were observed but the effect is not statistically significant as compared to contol.

Therefore NOAEL was considered to be 100 mg/kg body weight/day for F0 and F1 genearation when rats are exposed to 4-Chlororesorcinol orally for 10 days.

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
T he hair dye formulation was tested for teratologic effects following topical applications to groups of 20 pregnant Charles River CDrats on days I, 4, 7, 10, 13, 16, and 19 of gestation. The oxidation dye was mixed 1:1 with 6% hydrogen peroxide just prior to application, as in normal use.
GLP compliance:
not specified
Species:
rat
Strain:
other: Charles River CD
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data available
- Age at study initiation: (P) x wks; (F1) x wks: No data available
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Ralston Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): Water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
Route of administration:
dermal
Vehicle:
other: Hydrogen peroxide
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 4-Chlororesorcinol was mix with equal volume of 6% Hydrogen peroxide in the concentration of 2 ml/kg on every third day of the gestation period.

TEST SITE
- Area of exposure: On dorso-scapular area.
- % coverage: No data available
- Type of wrap if used: No data available
- Time intervals for shavings or clipplings \: No data available
Details on mating procedure:
Mated Charles River CD female rats (presence of sperm in the vagina considered day 0 of gestation) were used.
The mated females were housed individually.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
20 days
Frequency of treatment:
Every third day of gestation period.( 1, 4, 7, 10, 13, 16, and 19 of gestation).
Details on study schedule:
The hair dye formulation was tested for teratologic effects following topical applications to groups of 20 pregnant Charles River CDrats on days I, 4, 7, 10, 13, 16, and 19 of gestation. The oxidation dye was mixed 1:1 with 6% hydrogen peroxide just prior to application, as in normal use.
Remarks:
Doses / Concentrations:
2 ml/kg (equivalent to 680 mg/kg bw/day)
Basis:
nominal conc.
No. of animals per sex per dose:
2 ml/kg : 20 female
Control 1 untreated: 20 female
Control 2 untreated: 20 female
Control 3 untreated: 20 female
Acetylsalicylic acid (250 mg/kg-day) positive control: 20 female
Control animals:
yes, concurrent no treatment
Positive control:
The positive control group received acetylsalicylic acid by gavage at a dose of 250 mg/kg on days 6 through 16 of gestation.
Parental animals: Observations and examinations:
Clinical sign, body weight and weight gain and food consumption were observed.
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated.
Sperm parameters (parental animals):
No data available
Litter observations:
Live fetus, sex ratio and fetal weight were observed.
Postmortem examinations (parental animals):
Gross abnormalities were examined.
Number of corpora lutea, implantation sites, live fetuses and resorption sites was examined.
Postmortem examinations (offspring):
Gross abnormalities, number of fetuses with soft-tissue or skeletal anomalies and accessory ribs were examined.
Statistics:
Statistical analyses for the number of females exhibiting resorption sites, number of females exhibiting two or more resorptions, number of dead or resorbed fetuses, and the number of fetuses with soft-tissue or skeletal anomalies and accessory ribs was compared by using chi-square test criterion with Yates' correction on 2 X 2 contingency tables as described by Steel and Torrie (1960) or Fisher's exact probability test. The mean number of corpora lutea, implantation sites, live fetuses, and resorption sites and live fetal weights was compared by using analysis of variance (one-way classification) as described by Steel and Torrie (1960) using Dunnett's (1964) multiple comparison tables to judge the significance of differences
Reproductive indices:
Fertility index, gestation index and implantation index were examined
Offspring viability indices:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Changes in color of skin and hair at the site of application were observed in treated rat as compared to control. No other signs of toxicity were observed in treated rat.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No changes were observed in body weight of treated rat. Food consumption: No change was observed on mean food consumption of treated rat as compared to control
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No changes were observed in body weight of treated rat. Food consumption: No change was observed on mean food consumption of treated rat as compared to control
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No significant effect was observed on mean number of corpora lutea, implantation sites, resorption sites or mean resorptions per pregnancy of treated rat as compared to control.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect was observed on number of live fetus and sex retio of treated rat as copmared to control.
Dose descriptor:
NOAEL
Effect level:
680 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effect on clinical sign, body weight and weight gain, food consumption, gross pathology and reproductive performance.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect was observed on live fetal weight of treated rat.
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Significant change in number of fetuses with accessory ribs were observed as compared to control 2. But it is not significant as compared to all three controls.
Histopathological findings:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
680 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on body weight and gross pathology of foetus.
Reproductive effects observed:
not specified
Conclusions:
NOAEL of 4-Chlororesorcinol when applied topically to Charles River CD female rat was considered to be 680 mg/kg bw/day for F0 and F1 generation.
Executive summary:

In a dermal reproductive toxicity study, Charles River CD female rat were exposed to 4-Chlororesorcinol in the concentration of 0 and 2 ml/kg (equivalent to 680 mg/kg) on day in 1, 4, 7, 10, 13, 16, and 19 day of gestation by dermal application.

No significant effect were observed on clinical signs, body weight and food consumption of treated rat. In addition, no effect were observed on numbers of corpora lutea, implantation sites, live fetuses, and resorptions per pregnancy, as well as numbers of litters with resorptions. On fetal evaluation no effect were observed on body weight and on gross pathology. This indicates that the compound is non embryotoxic.

Therefore, NOAEL was considered to be 680 mg/kg/day for F0 and F1 genearation when rats are exposed to 4-Chlororesorcinol for 20 days.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is of K2 level and is obtained from peer reviewed publications.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
680 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is of K2 level and is obtained from peer reviewed publications.
Additional information

Variuos studies of 4-Chlororesorcinol were reviewed for reproductive toxicity from reliable sources having Klimisch rating 2

The summary of the results is presented below:

Sr. No

End point

Value

Species

Route

Effects

Remarks

1.     

NOAEL

100 mg/ kg bw/ d

Rat

Oral: gavage

No adverse effect on survival, clinical sign, body weight, Gross abnormalities, histopathology and reproductive performance.

No adverse effect on survival and gross pathology of foetus

Experimental data for target chemical

2.     

NOAEL

680 mg/kg bw/day

Rat

Dermal

No adverse effect on clinical sign, body weight and weight gain, food consumption, gross pathology and reproductive performance.

No adverse effect on body weight and gross pathology of foetus.

Experimental data for target chemical

Based on the studies summarized in the above table it can be observed that NOAEL value in rats is in the range 100-680 mg/kg/day. The effects observed on these doses was listed as follows:

 

·          No adverse effect on clinical sign, body weight and weight gain, food consumption, gross pathology and reproductive performance.

·          No adverse effect on body weight and gross pathology of foetus

Based on these results, it is concluded that the substance is likely to be non toxic to reproduction.

Short description of key information:
In a oral reproductive toxicity study, Sprague-Dawley female rat were exposed to 4-Chlororesorcinol in the concentration of 0, 50, 100 and 200 mg/kg body weight /day on day 6 -15 of gestation. NOAEL was considered to be 100 mg/kg body weight /day for F0 and F1 generation.

In a dermal reproductive toxicity study, Charles River CD female rat were exposed to 4-Chlororesorcinol in the concentration of 0 and 2 ml/kg (equivalent to 680 mg/kg bw/day) on day in 1, 4, 7, 10, 13, 16, and 19 day of gestation by dermal application. NOAEL was considered to be 680 mg/kg for F0 and F1 generation.

Justification for selection of Effect on fertility via oral route:
NOAEL of 4-Chlororesorcinol in female Sprague-Dawley rats was considered to be 100 mg/kg body weight /day for F0 and F1 generation.

Justification for selection of Effect on fertility via dermal route:
NOAEL of 4-Chlororesorcinol when applied topically to Charles River CD female rat was considered to be 680 mg/kg bw/day for F0 and F1 generation.

Effects on developmental toxicity

Description of key information
Oral route: NOAEL was considered to be 100 mg/kg body weight/day  for F0 and 50 mg/kg body weight/day for F1 genearation when rats are exposed to 4-Chlororesorcinol orally for 10 days
Dermal route: NOAEL was considered to be 680 mg/kg bw/day for F0 and F1 generation when Charles River CD female rat were exposed topically to 4-Chlororesorcinol.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Teratogenicity study of 4 -Chlororesorcinol administered orally to rat on days 6-15 of gestation period is carried out.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Sex: Female
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Age at study initiation: mature
- Weight at study initiation: For P generation :225 and 250 grams
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow .ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Constant
- Humidity (%): Constant
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The solutions were prepared fresh daily and administered at a rate of 10 ml / kg.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Propylene glycol was used.
- Concentration in vehicle: 0, 50, 100 and 200 mg/kg body weight/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: Males were housed with the females at a ratio of 1 male: 2 females per cage.
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Day 0 of pregnancy was defined as the day on which a sperm plug or sperm in a vaginal smear was detected.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility.: No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No data available
- After successful mating each pregnant female was caged (how): Once mating was determined, each female was separated, housed, and identified.
- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
Days 6-15 of gestation period
Frequency of treatment:
Daily
Duration of test:
20 days of gestation period
Remarks:
Doses / Concentrations:
0, 50, 100, and 200 mg/kg body weight/day
Basis:
nominal conc.
No. of animals per sex per dose:
0 mg/kg bw/day: 22 female
50 mg/kg bw /day: 7 female
100 mg/kg bw /day: 7 female
200 mg/kg bw/day: 8 female
Control animals:
yes, concurrent vehicle
Details on study design:
Further details on study design
- Dose selection rationale: Dose levels were determined by previous range finding studies to estimate the maximum tolerated dosages. The dose levels were selected for the present study is 0, 50, 100 and 200 mg/kg for 4-chlororesorcinol.
- Rationale for animal assignment (if not random): Animal was assigned once mating was determined in female.
Maternal examinations:
Survival, clinical sign and body weight, Gross abnormalities and histopathology were examined.
Ovaries and uterine content:
Number of live fetuses, Number of implantation sites and resorption site was examined.
Fetal examinations:
Survival, sex ratio, Number of Litters, Number of Abnormal Fetuses, body weight of fetus, Gross abnormalities, visceral anomalies and skeletal anomalies/ variations were examined.
Statistics:
Statistical analysis was performed by using Student’s T-test for comparison of maternal weight changes, the number of fetal implantations, fetal weight and fetal sex ratio. Chi square analysis were used to compared the number of fetal resorptions and abnormal fetuses. A “naive” model trend analysis was conducted according to Johnson and Siskin. For all statistical analyses, a level of probability of p = 0.05 was used for significance. When lower levels of probability were observed, these were noted.
Indices:
Viability indices for fetus, fertility index, gestation index and implantation index were examined.
Historical control data:
No data available
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: At 200 mg/kg (high dose) significant decrease in maternal weight gains and embryolethal (increase in resorptions) were observed in females.

Details on maternal toxic effects:
Mortality: No effect were observed on survival of treated rat as compared to control.

Body weight: When treated with 200 mg/kg bw/day, on day 6-16 significant decrease in weight gains were observed in females as compared to control.

Reproductive function: No effect was observed on reproductive function of treated rat as compared to control.

Reproductive performance: No effect were observed on reproductive performance of treated rat as compared to control.

Gross pathology: When treated with 200 mg/kg bw/day, significant decrease were observed in total resorption of treated rat as compared to control.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mortality: No data available
Body weight: No significant change was observed in both male and female fetuses’ body weight.
Gross pathology:
When treated with 200 mg/kg bw/day, open eye, gastromegaly and wavy rib were observed in fetus of treated rat.
Although abnormalities were observed but they are not statistically significant as compared to control.
Abnormalities:
not specified
Developmental effects observed:
not specified

Exposure to the positive control agents, Vitamin A and aspirin, resulted in a statistically significant increase in abnormal fetuses with a broad spectrum of gross visceral and skeletal anomalies ranging from a frequency of 18-60%.

Conclusions:
NOAEL was considered to be 100 mg/kg body weight/day for F0 and 50 mg/kg body weight/day for F1 genearation when rats are exposed to 4-Chlororesorcinol orally for 10 days
Executive summary:

In a Teratogenicity study, Sprague-Dawley female rat were exposed to 4-Chlororesorcinol in the concentration of 0, 50, 100 and 200 mg/kg body weight /day.

A significant reduction in mean maternal weight gain and significant decrease in total resorpton of 200 mg/kg body weight /day treated rat were observed as compared to control. On fetal evaluation open eye, gastromegaly and wavy rib were observed but the effect is not statistically significant as compared to contol. Evaluation of skeletal preparations revealed either minor anomalies (wavy ribs) or variations (incomplete ossification of the sternebrae, rudimentary and bilateral 14th ribs). 

However ,4-Chlororesorcinol not exhibited teratogenic responses although maternally toxic levels were utilized.

Therefore, NOAEL was considered to be 100 mg/kg body weight/day for F0 and 50 mg/kg body weight/day for F1 genearation when rats are exposed to 4-Chlororesorcinol orally for 10 days.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Dermal Teratogenicity study of 4 -Chlororesorcinol on rat
GLP compliance:
not specified
Species:
rat
Strain:
other: Charles River CD
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Sex: Female
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals was housed in cages.
- Diet (e.g. ad libitum): Ralston Purina Laboratory Chow, ad libitum.
- Water (e.g. ad libitum): Water, ad libitum.
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled
- Humidity (%): Controlled
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available
Route of administration:
dermal
Vehicle:
other: Hydrogen peroxide
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 2 ml/kg of 4 -Chlororesorcinol mix with an equal volume of 6% hydrogen peroxide just prior to use and applied topically.

TEST SITE
- Area of exposure: Dorsolateral aspects of thoracic-lumbar area (one on each side of the midline) were exposed.
- % coverage: No data available
- Type of wrap if used: No data available
- Time intervals for shavings or clipplings: Animals were shaved a day before the solution was applied

VEHICLE
- Justification for use and choice of vehicle (if other than water): Hydrogen peroxide
- Concentration in vehicle: 0 and 2 ml/kg
- Amount of vehicle (if gavage): 6 % Hydrogen peroxide were used.
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: No data available
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Presence of sperm in the vagina considered day 0 of gestation.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility.: No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No data available
- After successful mating each pregnant female was caged (how): The mated females were housed individually.
- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
20 days of gestation.
Frequency of treatment:
On day 1, 4, 7, 10, 13, 16 and 19 of gestation
Duration of test:
20 days of gestation.
Remarks:
Doses / Concentrations:
2 ml/kg (equivqlent to 680 mg/kg bw/day)
Basis:
nominal conc.
No. of animals per sex per dose:
2 ml/kg : 20 female
Control 1 untreated: 20 female
Control 2 untreated: 20 female
Control 3 untreated: 20 female
Acetylsalicylic acid (250 mg/kg-day) positive control: 20 female
Control animals:
yes, concurrent no treatment
Details on study design:
- Other: The negative control animals were untreated but were shaved. Three separate and discrete negative control groups were maintained in order to determine the degree of variability among small groups of control animals and to utilize this information in assessing treatment effects.
The positive control group received acetylsalicylic acid by gavage at a dose of 250 mg/kg on days 6 through 16 of gestation
Maternal examinations:
Clinical sign, body weight and weight gain and food consumption and Gross abnormalities was examined.
Ovaries and uterine content:
Number of corpora lutea, implantation sites, live fetuses and resorption sites was examined.
Fetal examinations:
Live fetus, sex ratio and fetal weight, gross abnormalities, number of fetuses with soft-tissue or skeletal anomalies and accessory ribs were examined.
Statistics:
Statistical analyses for the number of females exhibiting resorption sites, number of females exhibiting two or more resorptions, number of dead or resorbed fetuses, and the number of fetuses with soft-tissue or skeletal anomalies and accessory ribs was compared by using chi-square test criterion with Yates' correction on 2 X 2 contingency tables as described by Steel and Torrie (1960) or Fisher's exact probability test. The mean number of corpora lutea, implantation sites, live fetuses, and resorption sites and live fetal weights was compared by using analysis of variance (one-way classification) as described by Steel and Torrie (1960) using Dunnett's (1964) multiple comparison tables to judge the significance of differences.
Indices:
Fertility index, gestation index and implantation index were examined.
Historical control data:
No data available
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Mortality: No data available

Clinical signs: Changes in color of skin and hair at the site of application were observed in treated rat as compared to control.
No other signs of toxicity were observed in treated rat.

Body weight: No changes were observed in body weight of treated rat.

Food consumption: No change was observed on mean food consumption of treated rat as compared to control.

Reproductive function: No significant effect was observed on mean number of corpora lutea, implantation sites, resorption sites or mean resorptions per pregnancy of treated rat as compared to control.

Reproductive performance: No effect was observed on number of live fetus and sex retio of treated rat as copmared to control.

Gross pathology: No data available
Dose descriptor:
NOEL
Effect level:
680 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
680 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Mortality :
No effect was observed on number of live fetus and sex retio of treated rat as copmared to control.

Body weight:
No effect was observed on live fetal weight of treated rat.

Gross pathology:
Significant change in number of fetuses with accessory ribs were observed as compared to control 2.
But it is not significant as compared to all three controls.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
NOAEL was considered to be 680 mg/kg bw/day for F0 and F1 generation when Charles River CD female rat were exposed to 4-Chlororesorcinol.
Executive summary:

In a reproductive dermal toxicity study, Charles River CD female rat were exposed to4-Chlororesorcinol in the concentration of 0 and 2 ml/kg/day (equivalent to 680 mg/kg bw/day) on day 1, 4, 7, 10, 13, 16, and 19 day of gestation by dermal application.

No significant effect were observed on clinical signs, body weight and food consumption of treated rat. In addition, no effect were observed on numbers of corpora lutea, implantation sites, live fetuses, and resorptions per pregnancy, as well as numbers of litters with resorptions. On fetal evaluation no effect were observed on body weight and on gross pathology.

This indicates that the compound is non embryotoxic. Therefore, NOAEL was considered to be 680 mg/kg bw/day for F0 and F1 genearation when rats are exposed to 4-Chlororesorcinol dermally.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is of K2 level and is obtained from publication.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
680 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is of K2 level and is obtained from publication.
Additional information

Various studies of 4-Chlororesorcinol were reviewed for developmental toxicity from reliable sources having Klimisch rating 2

The summary of the results is presented below:

Sr. No

End point

Value

Species

Route

Effects

Remarks

1.     

NOAEL

(maternal toxicity)

 

 

 

 

 

NOAEL

(developmental toxicity)

100 mg/ kg bw/ d

 

 

 

 

 

 

50 mg/ kg bw/ d

Rat

Oral: gavage

No adverse effect on survival, clinical sign, body weight, Gross abnormalities, histopathology and reproductive performance. 

 

No adverse effect on survival and gross pathology of foetus. 

Experimental data for target chemical

2.     

NOEL

(maternal toxicity)

 

 

 

 

 

NOAEL

(developmental toxicity)

 

680 mg/kg bw/day

 

 

 

 

 

 

 

680 mg/kg bw/day

Rat

Dermal

No adverse effect on clinical sign, body weight and weight gain, food consumption, gross pathology and reproductive performance.

 

No embryotoxic effect on body weight and gross pathology of foetus

Experimental data for target chemical

Based on the studies summarized in the above table it can be observed that the NOAEL value in rats is in the range 100 -680 mg/kg/day. The effects observed on these doses was listed as follows:

 

·         No adverse effect on clinical sign, body weight and weight gain, food consumption, gross pathology and reproductive performance.

·         No adverse effect on body weight and gross pathology of foetus

Based on these results, it is concluded that the substance is not likely to be teratogenic.

Justification for selection of Effect on developmental toxicity: via oral route:
NOAEL was considered to be 100 mg/kg body weight/day for F0 and 50 mg/kg body weight/day for F1 genearation when rats are exposed to 4-Chlororesorcinol orally for 10 days

Justification for selection of Effect on developmental toxicity: via dermal route:
NOAEL was considered to be 680 mg/kg for F0 and F1 generation when Charles River CD female rat were exposed to 4-Chlororesorcinol.

Justification for classification or non-classification

Based on the available studies, the substance 4 -Chlororesorcinol is likely to be non toxic to reproduction and non teratogenic by oral and dermal route of exposure within the dose levels mentioned.

Additional information