Cyclohexylbenzene

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Recent and well documented study in according to OECD and GLP guidelines.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the 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: Charles River Laboratories, Research Models and services, Germany GmbH
- Age at study initiation: 10-11 weeks old
- Housing: Makrolon type M III cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15/hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

+ 1% carbocymethylcellulose with about 5mg/100ml Cremophor.EL

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Phenylcyclohexan was applied as a emulsion. To prepare this suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, drinking water containing 1% Carboxymethylcellulose with about 5 mg/100 mL Cremophor EL was filled up to the desired volume, subsequently released with a high speed homogenizer. During administration of the test substance preparations were kept homogeneous by stirring with a magnetic stirrer. The test substance preparations were produced at least once a week.

VEHICLE
- Concentration in vehicle: 0.4, 2.0 and 10.0 mg/100 mL
- Amount of vehicle: 10 mg/kg bw/d

Details on mating procedure:

On the day of arrival the animals were subjected to an acclimatization period during which they received ground diet and drinking water ad libitum. Prior to the first detailed clinical observation, the animals were distributed according to weight among the individual test groups, separated by sex. The weight variation of the animals used did not exceed 20 percent of the mean weight of each sex. The list of randomization instructions was compiled with a computer.

At the start of the administration period (study day 0) the rats were 11-12 weeks old.

After the acclimatization period, the test substance was administered orally via gavage to the F0 generation parental animals, daily at the same time in the morning (exception: no administration to animals being in labor). The treatment lasted up to one day prior to sacrifice. The animals of the control group were treated in the same way with the vehicle only (drinking water containing 1% Carboxymethylcellulose with about 5 mg/100 mL Cremophor EL). The calculation of the administered volume was generally based on the most recent individual body weights.

Two weeks after the beginning of treatment, males and females from the same test group were mated overnight in a ratio of 1:1. In general, each of the male and female animals was mated overnight in a 1:1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same test group.

The animals were paired by placing the female in the cage of the male mating partner from about 16.00 h until 07.00 - 09.00 h of the following morning. Deviations from the specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for the presence of sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted gestation day (GD) 0 and the following day "GD 1".

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Detail of analytical dose concentration carried out at the analytical chemistry laboratory of experimental toxicology and ecotoxicology of BASF SE.
The purity was performed by capillary GC with area % evaluation corrected with the content of water.
The concentration analyse of all concentration revealed that the value were in the expected range of the target concentration (about 90-110% of nominal concentration)

Duration of treatment / exposure:

for male: treatment started after acclimatisation (6 days) during 2 weeks before the mating, during the mating and 2 weeks after the end of the mating
for female: treatment started after acclimatisation (6 days) during 2 weeks before the mating, during the mating, during the gestation and 4 days after delivery.

Frequency of treatment:

Administrate every day at the same time in the morning

Remarks:

Doses / Concentrations:
40 mg/kg bw/d
Basis:
actual ingested

Remarks:

Doses / Concentrations:
200 mg/kg bw/d
Basis:
actual ingested

Remarks:

Doses / Concentrations:
1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

10 per dose per sex

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

This information is covered in the robust study summary under the endpoint "repeated dose toxicity".

Litter observations:

PUP NUMBER AND STATUS AT DELIVERY
All pups delivered from the F0 parents (F1 litter) were examined as soon as possible on the day of birth to determine the total number of pups, the sex and the number of liveborn and stillborn pups in each litter. At the same time, the pups were also being examined for macroscopically evident changes. Pups, which died before this initial examination, were defined as stillborn pups.

PUP VIABILITY / MORTALITY
In general, a check was made for any dead or moribund pups twice daily on workdays (once in the morning and once in the afternoon) or as a rule, only in the morning on Saturdays, Sundays or public holidays.
The number and percentage of dead pups on the day of birth (PND 0) and of pups dying between PND 1 - 4 (lactation period) were determined. Pups which died accidentally or were sacrificed due to maternal death were not included in these calculations. The number of live pups/litter was calculated on the day after birth, and on lactation day 4. The viability index was calculated according to the following formula:
Viability index (%) = number of live pups on day 4 after birth * 100 / number of live pups on the day of birth

SEX RATIO
On the day of birth (PND 0) the sex of the pups was determined by observing the distance between the anus and the base of the genital tubercle; normally, the anogenital distance is considerably greater in male than in female pups. The sex of the pups was finally confirmed at necropsy.
The sex ratio was calculated at day 0 and day 4 after birth according to the following formula:
Sex ratio = number of live male or female pups on da 0-4 * 100 / number of live male and female pups on day 0-4

PUP CLINICAL OBSERVATIONS
The live pups were examined daily for clinical symptoms (including gross-morphological findings) during the clinical inspection of the dams.

PUP BODY WEIGHT DATA
The pups were weighed on the day after birth (PND 1) and on PND 4. Pups' body weight change was calculated from these results.
The individual weights were always determined at about the same time of the day (in the morning).
In the summary tables pup body weights and pup body weight change are listed for males, females and males + females.
“Runts” were defined on the basis of the body weights on PND 1. "Runts" are pups that weigh less than 75% of the mean weight of the respective control pups.

Postmortem examinations (parental animals):

This information is covered in the robust study summary under the endpoint "repeated dose toxicity".

Postmortem examinations (offspring):

All pups with scheduled sacrifice on PND 4 were sacrificed under isoflurane anesthesia with CO2. All pups were examined externally and eviscerated; their organs were assessed macroscopically.
All stillborn pups and all pups that died before PND 4 were examined externally, eviscerated and their organs were assessed macroscopically.
All pups without notable findings or abnormalities were discarded after their macroscopic evaluation. Animals with notable findings or abnormalities were evaluated on a case-by- case basis, depending on the type of finding noted.

Statistics:

See "other information" section.

Reproductive indices:

Parameters examined in the F0 parental generation:
the pairing partners, the number of mating days until vaginal sperm was detected in and the gestation status were recorded for F0 females.

Calculation of inidces:

Female mating index (%) = number of females mated * 100 / number of females placed with males

with “females mated” defined as the number of females with vaginal sperm or with implants in utero

Female fertility index (%) = number of females pregnant * 100 / number of females mated

with “females pregnant” defined as the number of females with implants in utero, and “females mated” defined as above

Gestation index (%) = number of females with live pups on the day of birth * 100 / number of females pregnant

The total number of pups delivered and the number of liveborn and stillborn pups were noted, and the live birth index was calculated for F1 litters according to the following formula:

Live birth index (%) = number of liveborn pups at birth * 100 / total number of pups born

The implantations were counted and the post-implantation loss (in %) was calculated according to the following formula:

Post implantation loss (%) = [number of implantations – number of pups delivered] * 100 / number of implantations

Parameters examined in the F0 parental generation: the pairing partners, the number of mating days until vaginal sperm was detected in the female animals, and the gestation status of the females was recorded for F0 breeding pairs.

Calculation of mating and fertility inidces:

Male mating index (%) = number of males with confirmed mating * 100 / number of males placed with females

with "confirmed mating" defined by a female with vaginal sperm or implants in utero

Male fertility index (%) = number of males providing their fertility * 100 / number of males placed with females

with "providing their fertility" defined by a female with implants in utero

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

see repeated dose section

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

see repeated dose section

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

see repeated dose section

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

see repeated dose section

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

For a detailed description of the effects observed in the parental animals, please refer to the section on repeated dose toxicity.

MALE MATING INDEX
The male mating index was 100% in test groups 0, 1 and 3 and 90% in test group 2. This finding reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.

MALE FERTILITY INDEX
Fertility was proven for most of the F0 parental males within the scheduled mating interval to produce F1 litter.
One male of test group 2 (No. 24 mated with female No. 124) did not generate F1 pups.
The male fertility index was 90% in test group 2 and 100% in test groups 0, 1 and 3.
This finding reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data

FEMALE MATING INDEX
The female mating index calculated after the mating period for F1 litter was 100% in test groups 0, 1 and 3 and 90% in test group 2. The mean duration until sperm was detected (GD 0) was 3.0, 3.0, 1.8 and 2.7 days in test groups 0-3. This finding reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.

FEMALE FERTILITY INDEX
All sperm positive rats delivered pups.
Female animal No. 124 (test group 2) which was mated with male No. 24 did not get sperm in vaginal smear.
The female fertility index was 100% in in all test groups. Female animal No. 124, which delivered no pups, showed no implantation sites.
The mean duration of gestation was similar in all test groups (i.e. between 22.0 and 22.2 days). This finding reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.

GESTATION INDEX
The gestation index was 100% in test group 0, 1 and 2 and 80% in test group 3. The value of test group 3 was not in the historical control data and therefore assessed as being substance-related and as an adverse effect.

LIVE BIRTH INDEX
The rate live birth indices were 99% in test group 0, 98.4% in test group 1, 99.1% in test group 2 and 87.6% in test group 3. The value of test group 3 was not in the historical control data and therefore assessed as being substance-related and as an adverse effect.

POST-IMPLANTATION LOSS
The postimplantation loss was 3.21 % in test group 0, 3.1 % in test group 1, 4.3 % in test group 2 and 15.93 % in test group 3.
These findings were assessed as being substance-related and as an adverse effect. The postimplantation loss of 15.93% in test group 3 was increased mainly because of the high postimplantation loss found in one animal (No. 131).

Dose descriptor:

NOAEL

Remarks:

parental toxicity - systemic effects

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Clinical findings, clinical pathology, pathology.

Dose descriptor:

NOAEL

Remarks:

fertility and reproductive performance

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed at highest tested dose

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

PUP NUMBER AND STATUS AT DELIVERY
The mean number of delivered F1 pups per dam was evenly distributed about the groups.

PUP VIABILITY / MORTALITY
The viability index indicating pup mortality during lactation (PND 0 - 4) was 98.3% (test group 0), 100.0% (test group 1), 99.2% (test group 2), 84.6% (test group 3). Due to a dose dependency, this finding was assessed as being substance-related and as an adverse effect.
One male pup of control group and one female pup of test group 2, two male pups of test group 1, six male pups and 5 female pups of test group 3 were found stillborn.
One male pup of test group 2, seven male pups and five female pups of test group 3 were cannibalized.
These findings were assessed as being substance-related however no final conclusion can be drawn concerning whether this is an adverse finding or not.

SEX RATIO
The sex distribution and sex ratios of live F1 pups on the day of birth and PND 4 did not show substantial differences between the control and the test substance-treated groups; slight differences were regarded to be spontaneous in nature.

PUP CLINCAL OBSERVATIONS
The surviving F1 pups of any test group did not show adverse clinical signs up to scheduled sacrifice on PND 4.

PUP BODY WEIGHT DATA
Mean pup body weights was significantly decreased in males of test group 3 (1000 mg/kg bw/d) on PND 1 and 4 and in females on PND 4. Pup body weight changes were significantly decreased in both gender of test group 3 (1000 mg/kg bw/d).
Mean pup body weights was significantly decreased in males and females of test group 2 (200 mg/kg bw/d) on PND 4. Pup body weight changes were significantly decreased in males of test group 2 (200 mg/kg bw/d) and in females of test group 1 (40 mg/kg bw/d).
Mean pup body weights/ pup body weight changes of all pups in all other test groups were comparable to the control group.
These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
One male and one female runt were seen in test group 2 (200 mg/kg bw/d). Nine male and five female runts were seen in test group 3 (1000 mg/kg bw/d).
These findings were assessed as being substance-related however no final conclusion can be drawn concerning whether this is an adverse finding or not.

PUP NECROPSY OBSERVATIONS
In test group 3 (1000 mg/kg bw/d) five pups showed post mortem autolysis, one pup was partly cannibalized and one pup showed empty stomach. These findings were assessed as being spontaneous in nature and without biological relevance.

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Generation:

F1

Effect level:

200 mg/kg bw (total dose)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: gestation index, live birth index, postimplantation loss

Reproductive effects observed:

not specified

Systemic toxicity effects are described under Section 7.5.1, therefore they are not repeated in this section. The NOAEL for general systemic toxicity was 200 mg/kg bw/d for the parental rats because of the major clinical findings, clinical pathology and pathology findings. Here below further details are given on the clinical observations and body weights in parents in terms of relation between maternal and litter toxicity.

 

In the male parents (Table 1), salivation was observed at 200 and 1000 mg/kg bw during all phases, which was considered to be due to local irritation in the stomach, therefore it was not of systemic nature. Poor conditions was seen pre-mating in one animal at 1000 mg/kg bw. There were no relevant effects on body weight during various phases.

 

Table 1. Clinical observations & body weights in male parents

Parameter	Group:	I	II	III	IV
	Dose mg/kg:	0	40	200	1000
No. of parents	total No.	10	10	10	10
Mortality	incidence	0	0	0	0
Clinical observations
Salivation - premating	incidence	0	0	8	10
Salivation - mating	incidence	0	0	10	10
Salivation - postmating	incidence	0	0	8	9
Poor condition - premating	incidence	0	0	0	1
Mean bw day 0 - premating	g	318,9	316,2	315,9	312,8
Mean bw day 7 - premating	g	338,1	340,1	338,5	327,1
Mean bw day 13 - premating	g	357,2	358,6	354,7	338,8
Mean bw day 0 - mating	g	369,3	367,3	364,5	352,2
Mean bw day 0 - postmating	g	377,1	379,2	371,2	358,7

 

In the female parents (Table 2), salivation was observed at all dose levels during all phases, which was considered to be due to local irritation in the stomach, therefore it was not of systemic nature. Poor conditions and related findings (e.g. fur piloerection, nose encrusted) were seen during gestation and lactation in two animals at 1000 mg/kg bw. There were no statistically significant effects on body weight premating and during gestation, however there was a statistically significant decrease in mean body weight during lactation (-8.3 and -6% versus control on day 1 and 4, respectively), which was already preceded by a non-significant decrease in mean body weight towards the end of gestation.

 

Table 2. Clinical observations & body weights in female parents

Parameter	Group:	I	II	III	IV
	Dose mg/kg:	0	40	200	1000
Maternal findings
No. of dams	total No.	10	10	10	10
Mortality	incidence	0	0	0	0
Clinical observations
Salivation - premating	incidence	0	0	6	10
Salivation - mating	incidence	0	0	8	9
Salivation - gestation	incidence	0	0	8	9
Poor condition - gestation	incidence	0	0	0	2
Fur piloerection - gestation	incidence	0	0	0	2
All pups stillborn - gestation	incidence	0	0	0	2
Apathy - gestation	incidence	0	0	0	1
Nose encrusted - gestation	incidence	0	0	0	1
Salivation - lactation	incidence	0	2	8	10
Poor condition - lactation	incidence	0	0	0	2
All pups stillborn - lactation	incidence	0	0	0	2
Complete litter loss - lactation	incidence	0	0	0	1
Fur piloerection - lactation	incidence	0	0	0	1
Skin ulceration - lactation	incidence	0	1	0	0
Reproduction - lactation	incidence	0	0	0	3
Mean bw day 0 - premating	g	216,5	215,5	213,8	215,2
Mean bw day 7 - premating	g	219,6	221,3	218	218,1
Mean bw day 13 - premating	g	223,4	228,5	223,4	232,3
Mean bw day 0 - gestation	g	224,1	228,2	221,7	227,9
Mean bw day 7 - gestation	g	257,6	257,2	253,6	260,9
Mean bw day 14 - gestation	g	286,4	287,5	283,4	285,6
Mean bw day 20 - gestation	g	343,9	351,6	347	325,9
	% vs Control	100	2,2	0,9	-5,2
Mean bw day 0 - lactation	g	274,9	268,3	267,9	252,2*
	% vs Control	100	-2,4	-2,5	-8,3
Mean bw day 4 - lactation	g	280,2	277,1	273,2	263,5*
	% vs Control	100	-1,1	-2,5	-6,0

* Dunnet test (two-sided): * p =<0,05 

 

Conclusions:

Under the conditions of the present reproduction/developmental toxicity screening test the NOAEL for fertility and reproductive performance the NOAEL was 1000 mg/kg bw/d.
 The NOAEL for developmental toxicity in the F1 progeny of the test substance-treated group was found to be 200 mg/kg bw/d.

Executive summary:

Cyclohexylbenzene was administered daily as an aqueous suspension to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 40, 200 and 1000 mg/kg body weight/day. Control animals were dosed daily with the vehicle only (drinking water containing 1% Carboxymethylcellulose with about 5 mg/100 mL Cremophor EL).

The duration of treatment covered a 2 week premating period and mating in both sexes (mating pairs were from the same dose group) as well as entire gestation and 4 days of lactation period in females up to one day prior to the day of schedule sacrifice of the animals. The effects related to repeated-dose toxicity to parental animals are described under the repeated-dose toxicity endpoint Section 7.5, however it was clear that general systemic toxicity was evident at 1000 mg/kg bw as demonstrated by clnical, clinical pathology and pathological changes. The NOAEL for systemic toxicity is 200 mg/kg bw/day.

Evident systemic toxicity was seen in two mother animals dosed at 1000 mg/kg bw/day, expressed by poor general condition towards the end of pregancy, leading to stillborn pups in these animals (partly due to post-implantation loss). Another animal at this dose group delivered 16 pups with smaller size, of which most were canniblised by the mother on PND 1 -2. When these outlier animals were not taken into account, litter sizes at birth were comparable between groups, whereas litter size on day 4 was slightly lower at 1000 mg/kg bw/day compared to control.

The findings seen in the litters at 1000 mg/kg bw were assumed to be secondary to maternal toxicity and stress and/or coincidental outranging high litter size in a few dams. No other relevant findings were retained between groups for reproductive/developmental changes in parents and litters.

Under the conditions of the present reproduction/developmental toxicity screening test the NOAEL for fertility and reproductive performance the NOAEL was 1000 mg/kg bw/d.
 The NOAEL for developmental toxicity in the F1 progeny of the test substance-treated group was found to be 200 mg/kg bw/d.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Reliable

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 key study was conducted for combined repeated dose toxicity study with reproduction/developmental toxicity screening test according to OECD guideline 422 (BASF SE, 2013).

Cyclohexylbenzene was administered daily as an aqueous suspension to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 40, 200 and 1000 mg/kg body weight/day. Control animals were dosed daily with the vehicle only (drinking water containing 1% Carboxymethylcellulose with about 5 mg/100 mL Cremophor EL).

The duration of treatment covered a 2 week premating period and mating in both sexes (mating pairs were from the same dose group) as well as entire gestation and 4 days of lactation period in females up to one day prior to the day of schedule sacrifice of the animals.The effects related to repeated-dose toxicity to parental animals are described under the repeated-dose toxicity endpoint Section 7.5, however it was clear that general systemic toxicity was evident at 1000 mg/kg bw as demonstrated by clinical, clinical pathology and pathological changes. The NOAEL for systemic toxicity is 200 mg/kg bw/day,

Evident systemic toxicity was seen in two mother animals dosed at 1000 mg/kg bw/day, expressed by poor general condition and less weight gain towards the end of pregancy, leading to stillborn pups in these animals (partly due to post-implantation loss). Another animal at this dose group delivered 16 pups, which exceeds the historical range for litter sizes (9.3 - 14.1), resulting in lower pup body weight, of which most were cannibalised by the mother on PND 1 -2. When these 3 outlier dams were not taken into account, litter sizes at birth were comparable between groups, and litter size on day 4 was only slightly lower at 1000 mg/kg bw/day compared to control.

The findings seen in the litters at 1000 mg/kg bw were assumed to be secondary to maternal toxicity and stress and/or coincidental outranging high litter size in a few dams.No other relevant findings were retained between groups for reproductive/developmental changes in parents and litters.

Under the conditions of the present reproduction/developmental toxicity screening test the NOAEL for fertility and reproductive performance was 1000 mg/kg bw/d.


Short description of key information:
A key combined repeated dose toxicity study with reproduction/developmental toxicity screening test was conducted for Cyclohexylbenzene according to OECD guideline 422 by oral gavage at doses of 40, 200 and 1000 mg/kg body weight/day. General systemic toxicity was evident at 1000 mg/kg bw as demonstrated by clinical, clinical pathology and pathological changes; the NOAEL for systemic toxicity is 200 mg/kg bw/day. Evident systemic toxicity was seen in two mother animals dosed at 1000 mg/kg bw/day. The findings seen in the litters at 1000 mg/kg bw were assumed to be secondary to maternal toxicity and stress and/or coincidental outranging high litter size in a few dams. No other relevant findings were retained between groups for reproductive/developmental changes in parents and litters. Under the conditions of the present reproduction/developmental toxicity screening test the NOAEL for fertility and reproductive performance the NOAEL was 1000 mg/kg bw/d.
 The NOAEL for developmental toxicity in the F1 progeny of the test substance-treated group was found to be 200 mg/kg bw/d.

Justification for selection of Effect on fertility via oral route:
Key study

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

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

The above-mentioned OECD 422 study (BASF SE, 2013) that addresses repeated dose toxicity together with toxicity to reproduction, equally provides some information on developmental toxicity.

Evident systemic toxicity was seen in two mother animals dosed at 1000 mg/kg bw/day, expressed by poor general condition and less weight gain towards the end of pregancy, leading to stillborn pups in these animals (partly due to post-implantation loss). Another animal at this dose group delivered 16 pups which exceeds the historical range for litter sizes (9.3 - 14.1), resulting in lower pup body weights, of which most were cannibalised by the mother on PND 1 -2. When these 3 outlier dams were not taken into account, litter sizes at birth were comparable between groups, and litter size on day 4 was only slightly lower at 1000 mg/kg bw/day compared to control.

The findings seen in the litters at 1000 mg/kg bw were assumed to be secondary to maternal toxicity and stress and/or coincidental outranging high litter size in a few dams.No other relevant findings were retained between groups for reproductive/developmental changes in parents and litters.

The NOAEL for developmental toxicity in the F1 progeny of the test substance-treated group was found to be 200 mg/kg bw/d.

Justification for selection of Effect on developmental toxicity: via oral route:
The dose descriptor is based on information available from the OECD 422 study (Stark, 2013) regarding observed developmental effects.

Justification for classification or non-classification

At the dose of 1000 mg/kg body weight, maternal toxicity was observed. There were three dams (Nos. 131, 135, 139) which showed more excessive maternal toxicity and stress and/or outranging large litter size, associated with stillborn pups and litter loss.

There were no other relevant litter findings. As a consequence, the study is considered conclusive but not sufficient for classification according to the criteria set out in Annex I to EU Regulation n° 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP) and Annex VI to Council Directive 67/548/EEC on the Classification, Packaging and Labelling of Dangerous Substances (DSD).