Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
- Effects upon reproductive function (including two-generation reproductive toxicity)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
As explained in a separate document (Read Across Justification, Sadler, 2017; attached to this dossier, Chapter 13) both paraffin oils, sulfochlorinated, saponified and the read across substance are very similarly composed secondary alkane sulfonates (UVCBs); slight differences are caused by the production processes - for the paraffin oils, sulfochlorinated, saponified the sulfochlorination and for the read across substance the sulfoxidation. A comparative assessment of the available toxicological in formations confirms that there is no reason to deviate from the read across approach from a toxicological view. This assessment is contained in a separate document (Supporting information on human health assessment, Karthaus, 2017; attached to this dossier, Chapter 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Informations given in (a) Read Across Justification, Sadler, 2017 and (b) Supporting information on human health assessment, Karthaus, 2017, both attached to this dossier, Chapter 13.

3. ANALOGUE APPROACH JUSTIFICATION
Informations given in (a) Read Across Justification, Sadler, 2017 and (b) Supporting information on human health assessment, Karthaus, 2017, both attached to this dossier, Chapter 13.

4. DATA MATRIX
Informations given in (a) Read Across Justification, Sadler, 2017 and (b) Supporting information on human health assessment, Karthaus, 2017, both attached to this dossier, Chapter 13.
Reason / purpose:
read-across source
Dose descriptor:
NOAEL
Remarks:
General toxicity
Effect level:
ca. 270 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Slight depression of somatic growth in next higher dose group
Dose descriptor:
NOAEL
Remarks:
Fertility
Effect level:
ca. 900 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No dose related effect on fertility consistent over two generations reported
Dose descriptor:
NOAEL
Remarks:
General toxicity
Effect level:
ca. 270 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Slight depression of somatic growth in next higher dose group
Dose descriptor:
NOAEL
Remarks:
Fertility
Effect level:
ca. 900 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No dose related effect on fertility consistent over two generations reported
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 270 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Slight depression of somatic growth in next higher dose group
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
ca. 270 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Slight depression of somatic growth in next higher dose group
Reproductive effects observed:
no
Executive summary:

Based on read across this result of a reproductive toxicity study is relevant for paraffin oils, sulfochlorinated, saponified. As explained in a separate document (Read Across Justification, Sadler, 2017; attached to this dossier, Chapter 13) both paraffin oils, sulfochlorinated, saponified and the read across substance are very similarly composed secondary alkane sulfonates (UVCBs); slight differences are caused by the production processes - for the paraffin oils, sulfochlorinated, saponified the sulfochlorination and for the read across substance the sulfoxidation. A comparative assessment of the available toxicological informations confirms that there is no reason to deviate from the read across approach from a toxicological view. This assessment is also contained in a separate document (Supporting information on human health assessment, Karthaus, 2017; attached to this dossier, Chapter 13).

Here is the result of the reproductive toxicity study with the read across substance:

The influence of the test material upon reproductive function and fertility was assessed over two generations in rats of the Charles River CD strain. For this purpose, the substance was administered in the diet to both the F0 and F1 generations at levels of 1000, 3000 or 10000 ppm. Treatment was given either continuously to both sexes for 60 days prior to mating and throughout three successive pregnancies (F1A, F1B, F1C, F2A, F2B and F2C) or to females only during the organogenesis stage of three successive pregnancies. Animals were randomly selected from the F1B litters to form the second generation.

In both the F0 and F1 generations, haematological investigations were carried out after 60 days of treatment on five males and five females in each group, prior to carbon dioxide asphyxiation and subsequent macroscopic and histopathological examination. The remaining animals were paired, within groups, on a one to one basis on three consecutive occasions. After the first two matings (F1A, F1B, F2A, F2B) the females were allowed to litter naturally and rear their young to weaning. Following the third mating (F1C, F2C) half of the dams in each group were killed on day 13 of gestation, and the remainder were killed on day 21 of gestation, to permit examination of their uterine contents.

After termination of each generation, all parent animals were examined macroscopically. Five males and five females from each of the continuously treated groups, together with five females only from each of the groups treated during organogenesis, were randomly selected for histopathological evaluation.

In both generations prior to mating, food intake, haematological parameters, absolute and relative organ weights and histopathological evaluation of tissues showed no adverse treatment-related effects.

In the F0 generation, slight depression of bodyweight gain was observed in males treated continuously with the substance at 10,000 ppm. A similar reduction was observed in F0 females treated prior to mating. During the three subsequent pregnancies, some fluctuation in bodyweight gain was recorded in treated females, but no significant inter-group variation was observed.

In the F1 generation, a slight depression of bodyweight gain was observed in males treated continuously with 3,000 or 10,000 ppm; those treated with 1,000 ppm were only marginally affected.

Because of a depressed rate of bodyweight gain during lactation, the mean bodyweight of female offspring from the group treated continuously with 10,000 ppm was significantly depressed at weaning. Subsequently however, the rate of bodyweight gain in this group was comparable with that of the controls. With the exception of females receiving 10,000 ppm during organogenesis, in which a significant reduction in bodyweight was recorded in the third pregnancy, no significant inter-group variations in bodyweight gain were observed.

Neither generation, during the first two pregnancies (F1A, F1B, F2A, F2B), showed any treatment-related effects in the number of litters containing at least one viable young, the litter size at birth, or the live birth index.

The viability index was significantly depressed in the F1A litters of females receiving 3000 or 10000 ppm continuously, and in the F2B litters of the females receiving 3000 ppm continuously. These observations are not regarded as compound related adverse effects because no consistent dose response or consistent effect over generations is observed. The observation on the F1A litter is due to a single dam that failed to lactate. In all other groups, the viability index was comparable with that of the control group.

The bodyweight of offspring at Day 1 post partum, showed no significant inter-group variations. However, the bodyweight gain of offspring from females receiving 10,000 ppm was depressed in the F1A, F1B and F2B litters, achieving statistical significance. All other treated offspring gained weight at a similar rate to the controls.

In both generations, the sex ratio at Day 4 post partum and at weaning were unaffected by treatment. A marginal delay in physical development of F2B offspring was recorded in all treated groups with unknown biological significance.

There was no consistent effect on pre-implantation loss, litter parameters or foetal development. Macroscopic examination, absolute and relative organ weights and histopathological evaluation of Fa and FI parent animals showed no adverse treatment-related effects.

It was concluded from these investigations that continuous treatment with the test material at a level of 10,000 ppm gave rise to a slight depression of somatic growth in parent animals and offspring in both generations. There were no indications for an embryotoxic or teratogenic effect related to treatment in any dose groups.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
900 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The influence of SAS upon reproductive function and fertility was assessed over two generations in rats of the Charles River CD strain. For this purpose, SAS was administered in the diet to both the F0 and F1 generations at levels of 1000, 3000 or 10000 ppm. Treatment was given either continuously to both sexes for 60 days prior to mating and throughout three successive pregnancies (F1A, F1B, F1C, F2A, F2B and F2C) or to females only during the organogenesis stage (gestational days 6 to 15) of three successive pregnancies. Animals were randomly selected from the F1B litters to form the second generation.

In both the F0 and F1 generations, haematological investigations were carried out after 60 days of treatment on five males and five females in each group, prior to carbon dioxide asphyxiation and subsequent macroscopic and histopathological examination. The remaining animals were paired, within groups, on a one to one basis on three consecutive occasions. After the first two matings (F1A, F1B, F2A, F2B) the females were allowed to litter naturally and rear their young to weaning. Following the third mating (F1C, F2C) half of the dams in each group were killed on day 13 of gestation, and the remainder were killed on day 21 of gestation, to permit examination of their uterine contents.

After termination of each generation, all parent animals were examined macroscopically. Five males and five females from each of the continuously treated groups, together with five females only from each of the groups treated during organogenesis, were randomly selected for histopathological evaluation.

In both generations prior to mating, food intake, haematological parameters, absolute and relative organ weights and histopathological evaluation of tissues showed no adverse treatment-related effects.

In the F0 generation, slight depression of bodyweight gain was observed in males treated continuously with SAS at 10,000 ppm. A similar reduction was observed in F0 females treated prior to mating. During the three subsequent pregnancies, some fluctuation in bodyweight gain was recorded in treated females, but no significant inter-group variation was observed.

In the F1 generation, a slight depression of bodyweight gain was observed in males treated continuously with 3,000 or 10,000 ppm; those treated with 1,000 ppm were only marginally affected.

Because of a depressed rate of bodyweight gain during lactation, the mean bodyweight of female offspring from the group treated continuously with 10,000 ppm was significantly depressed at weaning. Subsequently however, the rate of bodyweight gain in this group was comparable with that of the controls. With the exception of females receiving 10,000 ppm during organogenesis, in which a significant reduction in bodyweight was recorded in the third pregnancy, no significant inter-group variations in bodyweight gain were observed.

Neither generation, during the first two pregnancies (F1A, F1B, F2A, F2B), showed any treatment-related effects in the number of litters containing at least one viable young, the litter size at birth, or the live birth index.

The viability index was significantly depressed in the F1A litters of females receiving 3000 or 10000 ppm continuously, and in the F2B litters of the females receiving 3000 ppm continuously. These observations are not regarded as compound related adverse effects because no consistent dose response or consistent effect over generations is observed. The observation on the F1A litter is due to a single dam that failed to lactate. In all other groups, the viability index was comparable with that of the control group.

Bodyweight of offspring at Day 1 post partum, showed no significant inter-group variations. However, the bodyweight gain of offspring from females receiving 10,000 ppm was depressed in the F1A, F1B and F2B litters. All other treated offspring gained weight at a similar rate to the controls.

In both generations, the sex ratio at Day 4 post partum and at weaning were unaffected by treatment.

A marginal delay in physical development of F2B offspring was recorded in all treated groups with unknown biological significance.

There was no consistent effect on pre-implantation loss, litter parameters or foetal development. Macroscopic examination, absolute and relative organ weights and histopathological evaluation of Fa and FI parent animals showed no adverse treatment-related effects.

It was concluded from these investigations that continuous treatment with SAS at a level of 10000 ppm (corresponding to 900 mg/kg bw/day) gave rise to a slight depression of somatic growth in parent animals and offspring in both generations. There were no indications for an embryotoxic or teratogenic effect related to treatment in any dose groups (Tesh 1978).

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
As explained in a separate document (Read Across Justification, Sadler, 2017; attached to this dossier, Chapter 13) both paraffin oils, sulfochlorinated, saponified and the read across substance are very similarly composed secondary alkane sulfonates (UVCBs); slight differences are caused by the production processes - for the paraffin oils, sulfochlorinated, saponified the sulfochlorination and for the read across substance the sulfoxidation. A comparative assessment of the available toxicological in formations confirms that there is no reason to deviate from the read across approach from a toxicological view. This assessment is contained in a separate document (Supporting information on human health assessment, Karthaus, 2017; attached to this dossier, Chapter 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Informations given in (a) Read Across Justification, Sadler, 2017 and (b) Supporting information on human health assessment, Karthaus, 2017, both attached to this dossier, Chapter 13.

3. ANALOGUE APPROACH JUSTIFICATION
Informations given in (a) Read Across Justification, Sadler, 2017 and (b) Supporting information on human health assessment, Karthaus, 2017, both attached to this dossier, Chapter 13.

4. DATA MATRIX
Informations given in (a) Read Across Justification, Sadler, 2017 and (b) Supporting information on human health assessment, Karthaus, 2017, both attached to this dossier, Chapter 13.
Reason / purpose:
read-across source
Dose descriptor:
NOAEL
Effect level:
ca. 360 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEL
Effect level:
ca. 1 200 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: No teratogenic effect observed at any dose tested.
Developmental effects observed:
no
Executive summary:

Based on read across this result of a developmental toxicity study is relevant for paraffin oils, sulfochlorinated, saponified. As explained in a separate document (Read Across Justification, Sadler, 2017; attached to this dossier, Chapter 13) both paraffin oils, sulfochlorinated, saponified and the read across substance are very similarly composed secondary alkane sulfonates (UVCBs); slight differences are caused by the production processes - for the paraffin oils, sulfochlorinated, saponified the sulfochlorination and for the read across substance the sulfoxidation. A comparative assessment of the available toxicological informations confirms that there is no reason to deviate from the read across approach from a toxicological view. This assessment is also contained in a separate document (Supporting information on human health assessment, Karthaus, 2017; attached to this dossier, Chapter 13).

Here is the result of the developmental toxicity study with the read across substance:

The influence of the test material upon reproductive function and fertility was assessed over two generations in rats of the Charles River CD strain. For this purpose, the substance was administered in the diet to both the F0 and F1 generations at levels of 1000, 3000 or 10000 ppm. Treatment was given either continuously to both sexes for 60 days prior to mating and throughout three successive pregnancies (F1A, F1B, F1C, F2A, F2B and F2C) or to females only during the organogenesis stage of three successive pregnancies. Animals were randomly selected from the F1B litters to form the second generation.

In both the F0 and F1 generations, haematological investigations were carried out after 60 days of treatment on five males and five females in each group, prior to carbon dioxide asphyxiation and subsequent macroscopic and histopathological examination. The remaining animals were paired, within groups, on a one to one basis on three consecutive occasions. After the first two matings (F1A, F1B, F2A, F2B) the females were allowed to litter naturally and rear their young to weaning. Following the third mating (F1C, F2C) half of the dams in each group were killed on day 13 of gestation, and the remainder were killed on day 21 of gestation, to permit examination of their uterine contents.

After termination of each generation, all parent animals were examined macroscopically. Five males and five females from each of the continuously treated groups, together with five females only from each of the groups treated during organogenesis, were randomly selected for histopathological evaluation.

In both generations prior to mating, food intake, haematological parameters, absolute and relative organ weights and histopathological evaluation of tissues showed no adverse treatment-related effects.

In the F0 generation, slight depression of bodyweight gain was observed in males treated continuously with the substance at 10,000 ppm. A similar reduction was observed in F0 females treated prior to mating. During the three subsequent pregnancies, some fluctuation in bodyweight gain was recorded in treated females, but no significant inter-group variation was observed.

In the F1 generation, a slight depression of bodyweight gain was observed in males treated continuously with 3,000 or 10,000 ppm; those treated with 1,000 ppm were only marginally affected.

Because of a depressed rate of bodyweight gain during lactation, the mean bodyweight of female offspring from the group treated continuously with 10,000 ppm was significantly depressed at weaning. Subsequently however, the rate of bodyweight gain in this group was comparable with that of the controls. With the exception of females receiving 10,000 ppm during organogenesis, in which a significant reduction in bodyweight was recorded in the third pregnancy, no significant inter-group variations in bodyweight gain were observed.

Neither generation, during the first two pregnancies (F1A, F1B, F2A, F2B), showed any treatment-related effects in the number of litters containing at least one viable young, the litter size at birth, or the live birth index.

The viability index was significantly depressed in the F1A litters of females receiving 3000 or 10000 ppm continuously, and in the F2B litters of the females receiving 3000 ppm continuously. These observations are not regarded as compound related adverse effects because no consistent dose response or consistent effect over generations is observed. The observation on the F1A litter is due to a single dam that failed to lactate. In all other groups, the viability index was comparable with that of the control group.

The bodyweight of offspring at Day 1 post partum, showed no significant inter-group variations. However, the bodyweight gain of offspring from females receiving 10,000 ppm was depressed in the F1A, F1B and F2B litters, achieving statistical All other treated offspring gained weight at a similar rate to the controls.

In both generations, the sex ratio at Day 4 post partum and at weaning were unaffected by treatment.

A marginal delay in physical development of F2B offspring was recorded in all treated groups with unknown biological significance.

There was no consistent effect on pre-implantation loss, litter parameters or foetal development. Macroscopic examination, absolute and relative organ weights and histopathological evaluation of Fa and FI parent animals showed no adverse treatment-related effects.

It was concluded from these investigations that continuous treatment with the test material at a level of 10,000 ppm gave rise to a slight depression of somatic growth in parent animals and offspring in both generations. There were no indications for an embryotoxic or teratogenic effect related to treatment in any dose groups.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

In the study discussed above the influence of SAS upon reproductive function was assessed over two generations in rats of the Charles River CD strain. For this purpose, SAS was administered in the diet to both the F0 and F1 generations at levels of 1000, 3000 or 10000 ppm. Treatment was given either continuously to both sexes for 60 days prior to mating and throughout three successive pregnancies (F1A, F1B, F1C, F2A, F2B and F2C) or to females only during the organogenesis stage of three successive pregnancies. Animals were randomly selected from the F1B litters to form the second generation.

In both the F0 and F1 generations, haematological investigations were carried out after 60 days of treatment on five males and five females in each group, prior to carbon dioxide asphyxiation and subsequent macroscopic and histopathological examination. The remaining animals were paired, within groups, on a one to one basis on three consecutive occasions. After the first two matings (F1A, F1B, F2A, F2B) the females were allowed to litter naturally and rear their young to weaning. Following the third mating (F1C, F2C) half of the dams in each group were killed on day 13 of gestation, and the remainder were killed on day 21 of gestation, to permit examination of their uterine contents.

After termination of each generation, all parent animals were examined macroscopically. Five males and five females from each of the continuously treated groups, together with five females only from each of the groups treated during organogenesis, were randomly selected for histopathological evaluation.

In both generations prior to mating, food intake, haematological parameters, absolute and relative organ weights and histopathological evaluation of tissues showed no adverse treatment-related effects.

In the F0 generation, slight depression of bodyweight gain was observed in males treated continuously with the substance at 10,000 ppm. A similar reduction was observed in F0 females treated prior to mating. During the three subsequent pregnancies, some fluctuation in bodyweight gain was recorded in treated females, but no significant inter-group variation was observed.

In the F1 generation, a slight depression of bodyweight gain was observed in males treated continuously with 3,000 or 10,000 ppm; those treated with 1,000 ppm were only marginally affected.

Because of a depressed rate of bodyweight gain during lactation, the mean bodyweight of female offspring from the group treated continuously with 10,000 ppm was significantly depressed at weaning. Subsequently however, the rate of bodyweight gain in this group was comparable with that of the controls. With the exception of females receiving 10,000 ppm during organogenesis, in which a significant reduction in bodyweight was recorded in the third pregnancy, no significant inter-group variations in bodyweight gain were observed.

Neither generation, during the first two pregnancies (F1A, F1B, F2A, F2B), showed any treatment-related effects in the number of litters containing at least one viable young, the litter size at birth, or the live birth index.

The viability index was significantly depressed in the F1A litters of females receiving 3000 or 10000 ppm continuously, and in the F2B litters of the females receiving 3000 ppm continuously. These observations are not regarded as compound related adverse effects because no consistent dose response or consistent effect over generations is observed. The observation on the F1A litter is due to a single dam that failed to lactate. In all other groups, the viability index was comparable with that of the control group.

The bodyweight of offspring at Day 1 post partum, showed no significant inter-group variations. However, the bodyweight gain of offspring from females receiving 10,000 ppm was depressed in the F1A, F1B and F2B litters, achieving statistical All other treated offspring gained weight at a similar rate to the controls.

In both generations, the sex ratio at Day 4 post partum and at weaning were unaffected by treatment.

A marginal delay in physical development of F2B offspring was recorded in all treated groups with unknown biological significance.

There was no consistent effect on pre-implantation loss, litter parameters or foetal development. Macroscopic examination, absolute and relative organ weights and histopathological evaluation of Fa and FI parent animals showed no adverse treatment-related effects.

It was concluded from these investigations that continuous treatment with the test material at a level of 10,000 ppm (corresponding to 1200 mg/kg) gave rise to a slight depression of somatic growth in parent animals and offspring in both generations. There were no indications for an embryotoxic or teratogenic effect related to treatment in any dose groups.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex I, no classification is required for toxicity to reproduction (fertility and developmental toxicity).