Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: this study was planned and executed in accordance with relevant guidelines as well as the requirements of the GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Atlen SK

IUPAC Name:

Atlen SK

Details on test material:

- Name of test material (as cited in study report): Atlen SK
- Substance type: organic, UVCB
- Physical state: liquid
- Lot/batch No.:2/3
- Expiration date of the lot/batch: 2009-06-06
- Stability under test conditions: stable

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: conventional husbandry of Institute of Occupational Medicine, Lodz, Poland
- Age at study initiation: (P) 11 weeks; (F1) - not applicable
- Weight at study initiation: (P) Males: 267.8-290.0 g; Females: 185.7-204.1 g; (F1) not applicable
- Fasting period before study: the animals were not fasted before the study
- Housing: Females and males during pre-mating period, males after mating and females during gestation and up to the 4th day after parturition were kept individually in plastic cages of dimensions (length x width x height): 39 x 25 x 16 cm, with wired lid. During period of mating one female was kept with one male in cages of dimensions (length x width x height): 58 x 37 x 21 cm with wired lid. UV-sterilised wooden shavings were used as bedding.
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): ad libitum, the animals were given standard granulated laboratory fodder Murigran produced by Wytwornia Koncentratow i Mieszanek Paszowych AGROPOL, Motycz, Poland
- Water (e.g. ad libitum): ad libitum, the animals were given tap water
- Acclimation period: the animals were quarantined for 6 days before the start of the experiment (under the same conditions as during the test)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23
- Humidity (%): 45 - 60
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: not reported
- % coverage: 10
- Type of wrap if used: elastic band and plaster
- Time intervals for shavings or clipplings: shavings were performed 24 hrs before the start of the experiment and then in a week-long periods

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residues of the test item were removed with the aid of a tampon with oil
- Time after start of exposure: each day after termination of the 6 hours daily exposure period

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000 mg/kg bw
- Constant volume or concentration used: in order to keep constant level of dosage the amounts of the test item were adjusted to body weight changes on days of weighing

USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: not reported
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

The test item was applied to the skin of males during the period of preliminary treatment, during mating and after mating, together for 28 days. The
test item was applied to the skin of females during the period of preliminary treatment, during mating and up to the 19th day of gestation.

Frequency of treatment:

once a day for 6 hrs

Doses / concentrations

Remarks:

Doses / Concentrations:
1000 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

14 animals per sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale:The dose of 1000 mg/kg b.w. was used in the study on the ground of results obtained in the 28-day dermal toxicity study. Since there were no changes dependent on the test item, no lower doses were used (limit test).

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in Table 1 in the section Any other infromation on materials and methods incl. tables were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on days of weighing of animals

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight and food consumption of males were controlled once a week. Body weight of females and their food consumption were controlled once a week during pre-mating period and on 0, 5th, 10th, 15th and 20th day of gestation as well as on 4th day after delivery. Furthermore, body weight of females was controlled also on day of parturition. All parental animals were weighed on the day of gross necropsy

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

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 and behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS: yes

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals, after termination of observation
- Maternal animals: All surviving animals, after termination of observation

GROSS NECROPSY
- Gross necropsy consisted of thorough examination of external body surface, all apertures, cranial cavity, thoracic and abdominal cavity with content. Special attention was paid to the reproductive system. Number of implantation sites was determined in uteruses of females.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 2 in the section Any other infromation on materials and methods incl. tables were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- All F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of thorough examination of external body surface, all apertures, cranial cavity, thoracic and abdominal cavity with content. Special attention was paid to the reproductive system. Number of implantation sites was determined in uteruses of females.

Statistics:

Results were elaborated statistically with the use of one-way variance analysis and t test for independent variables (body weight of animals, food consumption, length of gestation, indices connected with survival of offspring) as well as Dunnet’s test (weight of internal organs) with p ≤ 0.05. Elaborated results were tabulated in the form of average values and standard deviation.
Weight of organs is presented in absolute values as well as relative values referring to the body weight of live animals.

Reproductive indices:

-Mating index for males:
number of males with confirmed copulation/total number of mated males x 100
-Mating index for females:
number of sperm-positive females /total number of mated females x 100
-Fertility index for males:
number of males that impregnating females/total number of mated males x 100
-Fertility index for females:
number of pregnant females/total number of sperm-positive females x 100
-Pregnancy index:
number of litters with live births/number of pregnant females x 100.

Offspring viability indices:

-Index of live births:
total number of live newborns/total number of newborns x 100
-Index of 4-day survival:
number of live sucklings after 4 days/number of live newborns x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

for details see section Details on results (parental animals)

Body weight and weight changes:

no effects observed

Description (incidence and severity):

for details see section Details on results (parental animals)

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

for details see section Details on results (parental animals)

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

for details see section Details on results (parental animals)

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

for details see section Details on results (parental animals)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
During the entire experiment parental animals of treated group did not differ in appearance and behaviour from animals of control group. Transient respiratory murmurs (lasting 2 days) were observed in two males of treated group: in male No 10 during the 3rd week and in male No 8 during the 4th week of the experiment. Transient body weight losses were observed in control group – in four males (No 8, 10, 11 and 13) and in one female (No 9); whereas in treated group – in seven males (No 3, 6, 9, 10, 12, 13 and 14) and in one female (No 1).
Clinical signs observed in parental animals are presented in detail in Table 1.

All parental animals survived the experiment.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)

Average body weights of parental males during period of pre-mating and after mating are presented in Table 3.
No statistically significant differences in average body weight of parental males were stated in treated group compared with the control.
Average body weights of parental females during period of pre-mating are presented in Table 4.
No statistically significant differences in average body weight of parental females during period of pre-mating were stated in treated group compared with control group.
Average body weights of parental females during gestation are presented in Table 5.
No statistically significant differences in average body weights of parental females during gestation were stated in treated group compared with control group.
Average body weights of females on 0 and 4th day of feeding are presented in Table 6.
No statistically significant differences in average body weight of parental females on the 0 and the 4th day of feeding were stated in treated group compared with control group.

The average food consumption of parental males during period of pre-mating is presented in Table 8.
The average food consumption of treated males was level with the average food consumption of control males.
The average food consumption of parental females during period of pre-mating is presented in Table 9.
The average food consumption of parental females of treated group during period of pre-mating was level with food consumption of females of control group.
The average food consumption of females during gestation is presented in Table 10.
The average food consumption of females of treated group during gestation was level with food consumption of females of control group.
The average food consumption of females during period of feeding is presented in Table 11.
The average food consumption of females of treated group during the period of feeding was level with food consumption of control females during the period of feeding.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS) - not examined
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS) - not examined
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS) - not examined

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
List of results of mating of parental animals are presented in Table 17.
14 females were mated with 14 males in both control and treated group. All females were mated by males during scheduled period of mating. Average number of days needed for copulation (counting day of placing one male and one female together in cage as day 0)
was 2.5 day in control group and 2.1 day in treated group. 12 females were fertilized in control group. 11 females delivered. Only one resorption
without any fetus was stated in one female (No 8). Two females (No 4 and 6) were not pregnant. 13 females were fertilized in treated group. 13 females delivered. One female (No 8) was not pregnant.
Values of indices connected with fertility of parental animals and length of gestation are presented in Table 18.
Mating index for males and mating index for females in control and treated group amounted 100. Fertility index for males and fertility index for females were lower in control group, and amounted 85.7 in control group and 92.9 in treated group. Pregnancy index was lower in control group, and amounted 91.7 in control group and 100.0 in treated group. Length of gestation in treated group was comparable with length of gestation in
control group and amounted 22.1 day in treated group and 22.0 day in control group.
List of average number of pups in litter is presented in Table 19.
11 females of control group delivered live births. Average number of pups in litter amounted 10.1: 46.9% were males and 53.1% were females. Number of pups in litter was from 6 to 14. 13 females of treated group delivered live births. Average number of pups in litter was 8.3: 41.7% were males and 58.3% were females. Number of pups in litter ranged from 3 to 14.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Average absolute weights of testes and epididymides are presented in Table 14, average relative weights of testes and epididymides are presented in Table 15. No statistically significant differences in absolute and relative weights of testes and epididymides were stated between treated and control group.

GROSS PATHOLOGY (PARENTAL ANIMALS)
List of gross changes observed in parental animals is presented in Table 12.
The following pathological changes were stated at necropsy:
- in uterus: presence of one fetus in late stage of resorption in female No 8 of group 0;
- right-sided cryptorchism in male No 8 of group 1 (female mated with this male was not pregnant);
- enlargement of lungs and purulent pneumonia as well as enlargement of spleen were stated in male No 13 of group 1.
At necropsy of females implantation sites in uteruses and number of corpora lutea in ovaries were counted. Results are presented in Table 13.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Histopathological changes in parental animals are presented in detail in Table 16.
The following changes were stated:
- partial atrophy of germinal epithelium of right testicle and presence of spermatogenetic cells in duct of right epididymis in male (No 8) of group 1 (female mated with this male was not pregnant);
- purulent pneumonia and overgrowth of white pulp in spleen in male (No 13) of group 1;
- congestion of ovaries in two females (No 9 and No 10) of group 0 as well as in two females (No 1 and No 2) of group 1.

OTHER FINDINGS (PARENTAL ANIMALS) - none were reported

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Description (incidence and severity):

for details see section Details on results (offspring)

Mortality / viability:

no mortality observed

Description (incidence and severity):

for details see section Details on results (offspring)

Body weight and weight changes:

no effects observed

Description (incidence and severity):

for details see section Details on results (offspring)

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

for details see section Details on results (offspring)

Histopathological findings:

not examined

Details on results (F1)

VIABILITY (OFFSPRING)
Three pups died in control group: 1 female (with blood extravasation on snout) died on 3rd day after birth; lack of one male in one litter and one female in another were stated on 4th day after birth (pups died and were eaten by mothers). Mortality of offspring is presented in Table 2.
Indices connected with survival of offspring are presented in Table 20.
3 pups of control group (1 male and 2 females) did not survive up to the 4th day of life. In treated group all pups survived up to the 4th day of life. Survival index up to the 4th day of life was 96.9% in the control group and 100.0 in the treated group. Mortality of pups was 2.7% in the control group and 0.0% in the treated group.

CLINICAL SIGNS (OFFSPRING)
Pups in treated group did not differ in appearance and behaviour from pups of control group from birth to the 4th day of life.
Some pathological changes were observed in pups of control and treated group after birth. Subcutaneous extravasation on snout was stated in one female pup of control group on first day after birth (female died on the 3rd day of life). Lack of milk in stomach was stated in one female pup of control group. Transient blood extravasations on snout were observed in two male pups of treated group on the first day after birth.
Clinical signs observed in offspring are presented in detail in Table 2.

BODY WEIGHT (OFFSPRING)
Average body weights of pups on 0 and 4th day of life are presented in Table 7.
Average body weight of pups of treated group on 0 and 4th day of life did not differ statistically significantly from average body weight of control pups on the 0 and the 4th day of life.

SEXUAL MATURATION (OFFSPRING) - not examined
ORGAN WEIGHTS (OFFSPRING) - not examined

GROSS PATHOLOGY (OFFSPRING)
No differences were found between treated and control groups.

HISTOPATHOLOGY (OFFSPRING) - not examined
OTHER FINDINGS (OFFSPRING) - none were reported

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

INTERPRETATION OF RESULTS

No differences in appearance, behaviour, body weight, food consumption and reproductive functions in parental animals of treated group were stated in comparison with control group. Respiratory murmurs stated in two males of treated group were transient. Respiratory system disturbances occur often in laboratory rats and should not be connected with the test item.

Pups of treated group did not differ in appearance and behaviour from pups of control group. Blood extravasations observed in two male pups of treated group were transient and this sign occurred also in control group and should not be connected with the administered item. Subcutaneous blood extravasations visible in pups after birth were observed also in pups, including the control ones, in other reproduction toxicity studies performed in Institute of Industrial Organic Chemistry, Branch Pszczyna.

Values of indices connected with fertility of parental animals including mating index for males and females, fertility index for males and females and pregnancy index obtained in treated and control group were on similar level what suggests that Atlen SK given to rats in dose of 1000 mg/kg b.w. did not negatively influence fertility of parental animals. The test item did not negatively influence total number of pups in litter, number of live births and stillbirths in litter and percentage of males and females in litter of treated group compared with the control. It is the evidence for lack of harmful influence of test item on fetuses.

Analysis of values of indices connected with survival of offspring of parents treated with test item shows lack of its negative influence on indices of live births and 4 -day survival in comparison with control group.

Morphological studies of offspring of treated group did not reveal any visible deviations in body structure, what suggests lack of infavorable influence of Atlen SK on offspring under the conditions of the experiment. It is additionally confirmed by lack of mortality of pups of the treated group.

Some unspecific pathological changes not connected with the test item were stated at gross necropsy and histopathological examination. Purulent pneumonia and overgrowth of white pulp in spleen (male No 13 in group 1) could be result of microbial infection. Atrophy of germinal epithelium in right testicle as well as presence of spermatogenetic cells in duct of right epididymis could be caused by right-sided cryptorchism (male No 8 in group 1).

Cryptorchism is observed in males of laboratory animals and is not connected with administered item. Congestion of ovaries in two females of group 0 (No 9 and No 10) and in two females of group 1 (No 1 and No 2) could be connected with physiological function of these organs.

No statistically significant differences were stated within relative and absolute weight of testes and epididymides.

Results of post mortem examination show that the test item – Atlen SK – given dermally to rats in dose 1000 mg/kg b.w. for a period of two months did not cause any specific pathological changes in parental animals and their offspring and it did not harmfully influence function of gonads in parental males and females.

Tables:

Table 1

ATLEN SK. Reproduction/developmental toxicity screening test

Clinical signs – parental animals

Clinical signs	Group/sex/number of animals
	0		1
	males	females	males	females
RESPIRATORY SYSTEM
Respiratory murmurs	-	-	2 [8,10]*	-
OTHER
Body weight loss	4 [8, 10, 11, 13]*	1 [9]*	7 [3, 6, 9, 10, 12, 13, 14]*	1 [1]*

[ ] computer numbers of animals in which clinical signs were observed

* clinical signs which were observed transiently

 

 

Table 2

ATLEN SK. Reproduction/developmental toxicity screening test

Clinical signs and mortality – offspring

Clinical signs	Group/sex/number of animals
	0		0
	males	males	males	males
Lack of milk in stomach	-	1 [11]*	-	-
Blood extravasation on snout	-	1 [7]**	2 [6, 14]*	-
Death of animal	-	3 [7]**[11, 14]***	-	-

[ ] computer numbers of mothers of animals in which clinical signs were observed

* clinical signs, which were observed transiently

** pups which died on 3rd day of feeding

*** pups eaten by female

 

Table 3

ATLEN SK. Reproduction/developmental toxicity screening test

Body weight[g]– period of pre-mating and after mating – parental males

Week of treatment	GROUP
	0	1
0	278,9 ± 11,1	278,9 ± 10,6
1	283,1 ± 19,2	285,9 ± 17,1
2	295,9 ± 21,6	296,9 ± 22,5
3	307,3 ± 19,2	308,4 ± 22,1
4	307,1 ± 20,7	300,4 ± 26,6

 

Table 4

ATLEN SK. Reproduction/developmental toxicity screening test

Body weight[g]– period of pre-mating – parental females

Week of treatment	GROUP
	0	1
0	194,9 ± 8,6	194,9 ± 9,2
1	197,7 ± 7,2	197,3 ± 11,7
2	202,6 ± 9,3	205,6 ± 12,1

 

Table 5

ATLEN SK. Reproduction/developmental toxicity screening test

Body weight[g]– period of gestation – parental females

Day of gestation	GROUP
	0	1
0	202,9 ± 10,5	202,6 ± 12,3
5	224,1 ± 10,1	222,7 ± 12,2
10	236,0 ± 13,8	235,6 ± 13,8
15	251,9 ± 18,3	254,2 ± 14,2
20	286,1 ± 29,9	286,6 ± 22,9

 

Table 6

ATLEN SK. Reproduction/developmental toxicity screening test

Body weight[g]– period of feeding up to 4th day of life – parental females

Day of feeding	GROUP
	0	1
0	237,3 ± 11,5	235,5 ± 11,7
4	245,2 ± 8,5	243,3 ± 18,1

 

Table 7

ATLEN SK. Reproduction/developmental toxicity screening test

Body weight[g]of pups on 0 and 4th day of life

Age of pups (days of life)	GROUP
	0	1
0	6,0 ± 0,6	6,3 ± 0,7
4	9,4 ± 1,2	9,8 ± 1,3

 

Table 8

ATLEN SK. Reproduction/developmental toxicity screening test

Food consumption [g/rat/day] – period of pre-mating – parental males

Week of treatment	GROUP
	0	1
1	22,2 ± 3,2	22,5 ± 2,8
2	22,4 ± 2,4	23,2 ± 2,2

 

Table 9

ATLEN SK. Reproduction/developmental toxicity screening test

Food consumption [g/rat/day] – period of pre-mating – parental females

Week of treatment	GROUP
	0	1
1	17,8 ± 1,0	17,9 ± 2,0
2	17,7 ± 1,4	18,2 ± 2,0

 

Table 10

ATLEN SK. Reproduction/developmental toxicity screening test

Food consumption [g/rat/day] – period of gestation – parental females

Day of gestation	GROUP
	0	1
0	-	-
5	21,4 ± 2,0	22,4 ± 2,4
10	21,9 ± 1,7	22,5 ± 2,3
15	23,1 ± 2,2	23,6 ± 2,5
20	23,7 ± 2,1	24,1 ± 2,6

 

Table 11

ATLEN SK. Reproduction/developmental toxicity screening test

Food consumption [g/rat/day] – period of feeding – parental females

Day of feeding	GROUP
	0	1
4	21,7 ± 6,0	24,4 ± 5,3

 

Table 12

ATLEN SK. Reproduction/developmental toxicity screening test

Gross changes – parental animals

Group	Sex	Number of animals	Numer of animals/ computer numbers of animals
			Uterus	Testes	Lungs		Spleen
0	Males	14	-	-	-	-	-
	Females	14	1 [8]	-	-	-	-
1	Males	14	-	1 [8]	1 [13]	1 [13]	1 [13]
	Females	14	-	-	-	-	-

[ ] computer numbers of animals in which gross changes were stated

 

Table 13

ATLEN SK. Reproduction/developmental toxicity screening test

Number of implantation sites and number of corpora lutea – parental females

 

Group	Computer No	Registry No	Number of implantation sites	Number of corpora lutea
0	1	14	11	12
	2	22	14	14
	3	57	12	13
	4	10	-	-
	5	34	10	12
	6	3	-	-
	7	58	9	11
	8	41	1	5
	9	24	10	10
	10	49	14	14
	11	12	11	12
	12	38	7	12
	13	15	13	13
	14	63	8	9
1	1	43	10	10
	2	13	8	12
	3	1	3	11
	4	8	7	13
	5	36	11	11
	6	31	11	17
	7	60	6	15
	8	45	-	-
	9	52	13	13
	10	21	10	12
	11	5	10	11
	12	7	9	11
	13	61	14	14
	14	2	5	9

 

Table 14

ATLEN SK. Reproduction/developmental toxicity screening test

Absolute weight of testes and epididymides [mg] – parental males

Day of feeding	GROUP
	0	1
Epididymides	0,368 ± 0,027	0,371 ± 0,043
Testes	1,129 ± 0,098	1,141 ± 0,117

 

Table 16

ATLEN SK. Reproduction/developmental toxicity screening test

Histopathological changes in internal organs – parental animals

Group	Sex	Number of animals	Number of animals
			Ovaries	Epididymides	Testes	Lungs	Spleen
			Congestion	Spermatogenetic cells in duct of epididymis	Partial atrophy of germinal epithelium	Purulent pneumonia	Overgrowth of white pulp
0	Males	14	-	-	-	-	-
	Females	14	2 [9,10]	-	-	-	-
1	Males	14	-	1 [8]	1 [8]	1 [13]	1 [13]
	Females	14	2 [1,2]	-	-	-	-

 

Table 17

ATLEN SK. Reproduction/developmental toxicity screening test

Mating of parental animals – list of results

Parameter	GROUP
	0	1
Number of males to mating	14	14
Number of females to mating	14	14
Number of males which copulated	14	14
Number of females which were mated	14	14
Average number of days to copulation	2,5	2,1
Number of fertilized females	12	13
Number of pregnant females	12	13
Number of females which delivered	11	13
Number of not pregnant females	2	1
Number of females with resorption of fetus	1	-

 

Table 18

ATLEN SK. Reproduction/developmental toxicity screening test

Indices concerning fertility of parental animals

Parameter	GROUP
	0	1
Mating index for males	100,0	100,0
Mating index for females	100,0	100,0
Fertility index for males	85,7	92,9
Fertility index for females	85,7	92,9
Pregnancy index	91,7	100,0
Length of gestation	22,0 ± 0,4	22,1 ± 0,5

 

Table 19

ATLEN SK. Reproduction/developmental toxicity screening test

Average number of pups in litter

Parameter	GROUP
	0	1
Total number of pups in litter	10,1 ± 2,5	8,3 ± 3,6
Number of live births in litter	10,1 ± 2,5	8,3 ± 3,6
Number of pups in litter, min.– max.	6 – 14	3 – 14
Percentage of males in litter	46,9	41,7
Percentage of females in litter	53,1	58,3

 

Table 20

ATLEN SK. Reproduction/developmental toxicity screening test

Indices connected with survival of offspring

Parameter	GROUP
	0	1
Index of live births	100,0 ± 0,0	100,0 ± 0,0
Index of 4-day survival	96,9 ± 5,3	100,0 ± 0,0
Mortality [%]	2,7	0,0

 

 

Applicant's summary and conclusion

Conclusions:

Results of Reproduction/Developmental toxicity screening test of Atlen SK indicate that dose od 1000 mg/kg bw/day can be considered a NOAEL for this endpoint.

Executive summary:

Presented results originate from a guideline study conducted in accordance with the requirements of the GLP. Hence, this information can be considered reliable and suitable for use as the key study for this endpoint.