Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
no further studies available/known
Link to relevant study records
Reference
Endpoint:
multi-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
before 1970
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well documented study. Short comings are: small animal number, no definite data on actual intake of L-Cysteine hydrochloride monohydrate, no purity and no impurities given for the test substance. In results: only means given; no min/max no standard deviation given (thus, results are not presented in very detail). It is important to mention that the substance was applied within the bread baking procedure and heated up to 227°C for 1/2 hour. This may have influenced the stability of the test substance especially as there are comments declaring a decomposition temperature of 175-177.8 °C for L-Cysteine hydrochloride. Nevertheless the documentation is complete enough, so that the influence of the baking process could be evaluated by an additional test if needed. Therefore the study can be jugded as a valid screening test for the evaluation of toxic effects on fertility.
Principles of method if other than guideline:
L-Cysteine hydrochloride monohydrate was added to flour at levels of 0, 35, 350 and 3500 ppm. Bread was baked from this flour, dried and milled to a powder, which was added to the rats diet.
Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation only 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same procedure as before was adopted for the sixth generation, using all four dosages, and during the breeding of the seventh generation the experiment was terminated.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: C.D. Norwegian Hooded of an inbred Middle Aston strain
Sex:
female
Details on test animals and environmental conditions:
Starting with pregnant C.D. Norwegian Hooded rats of an inbred Middle Aston strain.
Route of administration:
oral: feed
Details on exposure:
The substance was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight
No feed intake is reported. An animal weight of 100 g and a feed intake of 10 g diet per animal and day is used for estimation of the doses. 77% of milled bread was added to the diet. This resulted in an estimated daily intake of L-Cysteine of 0, 2.7, 27 and 270 mg/kg bw..
Details on mating procedure:
For the first generation pregnant rats were used. No data on mating procedure available. 11 weeks after birth the next generation females were mated with males from the same litter. During the breeding of the seventh generation the experiment was terminated.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 generations
Frequency of treatment:
daily
Details on study schedule:
L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking a powder was produced and mixed to a diet. The test article intake is estimated: An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is presumed. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-Cysteine hydrochoride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..
For the first generation pregnant rats were used. Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
11 weeks after birth the next generation females were mated with males from the same litter.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation only 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.
Remarks:
Doses / Concentrations:
0 ppm
Basis:
other: flour weight
Remarks:
Doses / Concentrations:
35 ppm
Basis:
other: flour weight
Remarks:
Doses / Concentrations:
350 ppm
Basis:
other: flour weight
Remarks:
Doses / Concentrations:
3500 ppm
Basis:
other: flour weight
No. of animals per sex per dose:
4
Control animals:
yes
Details on study design:
Estimation of the actual intake of L-Cysteine hydrochloride monohydrate:
feed intake: animal weight: 100g, 10 g diet per animal and day. 77% of milled bread was added to the diet. This resulted in an estimated daily intake of L-Cysteine of 0, 0.27, 2.7 and 27 mg per animal.
Positive control:
Controls: yes
Solvent control: not applicable
Positive control: no
Postmortem examinations (parental animals):
examinations for gross lesions
Postmortem examinations (offspring):
examinations for gross lesions
Reproductive indices:
Number born, litter weight at birth, numbers weaned and litter weight at weaning, carcass, liver and kidney weights of all slaughtered aninmals, post mortem examination for gross lesions.
In the 0 and 3500 ppm groups the principal characteristics of the response to the treatment were measured: rate of change per generation in litter size and weight at birth and at weaning, and the rate of change in the size of the carcasses, livers and kidneys of both adults and weanling rats.
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive performance:
no effects observed
Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest L-cysteine hydrochloride monohydrate treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age.
Clinical signs:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Reproductive effects observed:
not specified

As results only means given; no min/max no standard deviation given.

No treatment related effects were observed (authors: "no obvious adverse effect").

Conclusions:
L-Cysteine hydrochloride monohydrate was added to flour. With this flour bread was baked and from this bread a powder was produced and mixed to the diet. A daily intake of 0, 2.7, 27 and 270 mg/kg bw. was estimated..
Starting with 4 pregnant rats in the control and the highest dosage group a study over 7 generations was conducted.

Although quite well documented the study has short comings as there are: small animal number, no definite data on actual intake of L-cysteine hydrochloride monohydrate, no purity and no impurities given for the test substance and in results: only means, no min/max no standard deviation are given. Nevertheless the study can be jugded as a valid screening test for the evaluation of the reproduction toxicity.

Up to and including dosages of 270 mg/kg bw. no adverse effects on fertility occurred in the rats during the experiment even at the high level of L-cysteine hydrochloride monohydrate treatment.
Executive summary:

L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight.

Estimation of doses: An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..

For the first generation pregnant rats were used.

Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.

11 weeks after birth the next generation females were mated with males from the same litter.

This procedure was continued in the second and third generations, but at the weaning of the fourth generation 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.

Recorded are number born, litter weight at birth, numbers weaned and litter weight at weaning, carcass, liver and kidney weights of all slaughtered aninmals, post mortem examination for gross lesions. In the 0 and 3500 ppm groups the principal characteristics of the response to the treatment were measured: rate of change per generation in litter size and weight at birth and at weaning, and the rate of change in the size of the carcasses, livers and kidneys of both adults and weanling rats.

Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest

L-cysteine hydrochloride monohydrate

treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age.

No adverse effects on fertility occurred in the rats during the experiment even at the high level of L-cysteine hydrochloride monohydrate treatment.

It is important to mention that the substance was applied within the bread baking procedure and heated up to 227°C for 1/2 hour. This may have influenced the stability of the test substance especially as there are comments declaring a decomposition temperature of 175-177.8 °C for l-cysteine hydrochloride. Nevertheless the documentation is complete enough, so that the influence of the baking process could be evaluated by an additional test if needed.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
270 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Klimisch 2: reliable with restrictions
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight. An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw.. All in all 7 generations were studied.

Recorded are number born, litter weight at birth, numbers weaned and litter weight at weaning, carcass, liver and kidney weights of all slaughtered aninmals, post mortem examination for gross lesions. In the 0 and 3500 ppm groups the principal characteristics of the response to the treatment were measured: rate of change per generation in litter size and weight at birth and at weaning, and the rate of change in the size of the cracasses, livers and kidneys of both adults and weaning rats.

Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age.

No obvious adverse effects on fertility occurred in the rats during the experiment even at the high level of L-cysteine hydrochloride monohydrate treatment.


Short description of key information:
In a combined study with Norwegian rats over 6 generations possible effects on fertility and developmental toxicity of L-Cysteine hydrochloride monohydrate were tested. The substance was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking a powder was produced and was mixed to a diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..

No adverse effects on fertility occurred in the rats during the experiment even at the high level of L-cysteine hydrochloride monohydrate treatment.
NOEL (fertility) 270 mg/kg b.w./ day.

In accordance with article 2(7)(b) and Annex V 6., REACH the hydrate free form of L-Cysteine hydrochloride is registered. L-Cysteine hydrochloride monohydrate (CAS 7048-04-6, hydrate part of the molecule = 10.25 %) is the manufactured and imported substance and was used for testing.
It is generally accepted that water and especially water of crystallisation has no toxicologically relevant effects. Therefore, the effect levels of L-Cysteine hydrochloride monohydrate can be used to calculate the corresponding dosages of L-Cysteine hydrochloride (anhydrous (free of water of crystallisation)). Thus, the conclusion on hazard assessment and classification holds true for the anhydrous form as well.

Justification for selection of Effect on fertility via oral route:
Well documented study. Short comings are: small animal number, no definite data on actual intake of L-Cysteine hydrochloride monohydrate,
no purity and no impurities given for the test substance. In results: only means given; no min/max no standard deviation given (thus, results are not presented in very detail). Nevertheless the study can be jugded as a valid screening test for the evaluation of the fertility.

Effects on developmental toxicity

Description of key information
In a combined study with rats over 6 generations the fertility developmental toxicity of L-Cysteine hydrochloride monohydrate was tested. The substance was added to flour and with this flour bread was baked. After the baking a powder was produced and was mixed to a diet. This resulted in an estimated daily intake of  L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..
Starting with 4 pregnant rats in the control and the highest dosage group the mothers of 7 generations were studied.
Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest L-cysteine hydrochloride monohydrate treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age.
No developmental effects were seen. NOEL for developmental toxicity = 270 mg/kg bw./ day.
In accordance with article 2(7)(b) and Annex V 6., REACH the hydrate free form of L-Cysteine hydrochloride is registered. L-Cysteine hydrochloride monohydrate (CAS 7048-04-6, hydrate part of the molecule = 10.25 %) is the manufactured and imported substance and was used for testing.
It is generally accepted that water and especially water of crystallisation has no toxicologically relevant effects. Therefore, the effect levels of L-Cysteine hydrochloride monohydrate can be used to calculate the corresponding dosages of L-Cysteine hydrochloride (anhydrous (free of water of crystallisation)). Thus, the conclusion on hazard assessment and classification holds true for the anhydrous form as well.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1971
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
well documented. Short comings are: small animal number, no definite data on actual intake of L-Cysteine hydrochloride monohydrate, no purity and no impurities given for the test substance and in results only means given; no min/max no standard deviation given (thus, results are not presented in very detail). It is important to mention that the substance was applied within the bread baking procedure and heated up to 227°C for 1/2 hour. This may have influenced the stability of the test substance especially as there are comments declaring a decomposition temperature of 175-177.8 °C for L-Cysteine hydrochloride. Nevertheless the documentation is complete enough, so that the influence of the baking process could be evaluated by an additional test if needed. All in all the study can be jugded as a screening test for the evaluation of the deveolppmental toxicity.
Reason / purpose:
reference to same study
Principles of method if other than guideline:
L-Cysteine hydrochloride monohydrate was added to flour at levels of 0, 35, 350 and 3500 ppm. Bread was baked from this flour, dried and milled to a powder, which was added to the rats diet.
Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation only 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all four dosages, and during the breeding of the seventh generation the experiment was terminated.
GLP compliance:
no
Species:
rat
Strain:
other: C.D. Norwegian Hooded of an inbred Middle Aston strain
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Middle Aston
- Housing: on wood shavings
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 21
Route of administration:
oral: feed
Vehicle:
other: baked bread cooled, sliced, freeze-dried, crushed and passed through a hammer mill
Details on exposure:
DIET PREPARATION
The substance was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight
No feed intake is reported. An animal weitht of 100 g and a feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to the diet. This resulted in an estimated daily intake of L-Cysteine of 0, 2.7, 27 and 270 mg/kg bw..
Analytical verification of doses or concentrations:
no
Details on mating procedure:
For the first generation pregnant rats were used. No data on mating procedure are available. 11 weeks after birth the next generation females were mated with males from the same litter. During the breeding of the seventh generation the experiment was terminated.
Duration of treatment / exposure:
Details on doses (preparation)/ Duration:
L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dryed, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight. No feed intake is reported.
Estimation: A daily feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..
For the first generation pregnant rats were used. No data on mating procedure are available.
Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
11 weeks after birth the next generation females were mated with males from the same litter.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation only 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.
Frequency of treatment:
daily
Duration of test:
6 generations
No. of animals per sex per dose:
4
Control animals:
yes
Details on study design:
Estimation of the actual intake of L-cysteine hydrochloride monohydrate:
Estimated feed intake: 10 g diet per animal and day, animal weight 100 g. 77% of milled bread was added to the diet. This resulted in an estimated daily intake of l-cysteine of 0, 2.7, 27 and 270 mg/kg bw..
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 270 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
L-Cysteine hydrochloride monohydrate was added to flour from which bread was baked, milled to a powder. This powder was added to the diet.
A daily intake of 0, 2.7, 27 and 270 mg/kg bw. can be estimated.
Starting with 4 pregnant rats in the control and the highest dosage group the study was conduced over 7 generations.
Especially the data on litter weight at weaning and the post mortem examination for gross lesions of both adults and weanling rats reveal and the histopathologic examination of the fifth generation can reveal devolopmental toxicity.
No developmental toxicity was observed.
Executive summary:

L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight.

Estimation: An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..

For the first generation pregnant rats were used.

Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.

11 weeks after birth the next generation females were mated with males from the same litter.

This procedure was continued in the second and third generations, but at the weaning of the fourth generation 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.

Recorded are number born, litter weight at birth, numbers weaned and litter weight at weaning, carcass, liver and kidney weights of all slaughtered aninmals, post mortem examination for gross lesions. In the 0 and 3500 ppm groups the principal characteristics of the response to the treatment were measured: rate of change per generation in litter size and weight at birth and at weaning, and the rate of change in the size of the cracasses, livers and kidneys of both adults and weanling rats.

Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest L-cysteine hydrochloride monohydrate treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age.

Especially parameters as litter weight at weaning and the post mortem examination for gross lesions of the pups after weaning and the histopathological examination of the rats of the fifth generation can reveal a possible devolpmental toxicity.

No developmental toxicity was observed in this study.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
270 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
reliable with restirictions
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

L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to the diet. The diets contained about 77% of bread crumbs on dry weight. An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..

Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.

11 weeks after birth the next generation females were mated with males from the same litter.

This procedure was continued in the second and third generations, at the weaning of the fourth generation 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.

Parameters as litter weight at weaning and the post mortem examination for gross lesions of the pups after weaning and the histopathological examination of the rats of the fifth generation can reveal a possible developmental toxicity.

No developmental toxicity was observed.


Justification for selection of Effect on developmental toxicity: via oral route:
Well documented study. Short comings are: small animal number, no definite data on actual intake of L-Cysteine hydrochloride monohydrate,
no purity and no impurities given for the test substance. In results: only means given; no min/max no standard deviation given (thus, results are not presented in very detail). Nevertheless the study can be jugded as a valid screening test for the evaluation of the developmental toxicity.

Justification for classification or non-classification

From the detailed evaluation of the available reliable data in comparison with the criteria set out in the CLP-regulation (see table below) it is concluded that L-cysteine hydrochloride monohydrate as well as the anhydrous form does not need to be classified with regard to reproduction toxicity.

Table: Criteria of CLP Regulation (EC) 1272/2008 and basis for classification for reproductive toxicants in comparison with

L-cysteine hydrochloride monohydrate data

Categories/ sections in CLP-Regulation Criteria in CLP-Regulation Comment for

L-cysteine hydrochloride monohydrate

Category 1 Known or presumed human reproductive toxicant Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).
Human data: criteria are not fulfilled.
Animal data: criteria are not fulfilled.
Category 1A Known human reproductive toxicant
The classification of a substance in Category 1A is largely based on evidence from humans.
There is no evidence from humans available.
Category 1B Presumed human reproductive toxicant
The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.
No effects on fertility were seen.
CATEGORY 2 Suspected human reproductive toxicant Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification. Such effects shall have been observed in the absence of other toxic effects, or if occurring
together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.
No effects of reproduction toxicity were observed.
3.7.2.2. Basis of classification
3.7.2.2.1. Classification is made on the basis of the appropriate criteria, outlined above, and an assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances shall not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.
The classification of a substance is derived from the hazard categories in the following order of precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lactation. If a substance meets the criteria for classification into both of the main categories (for example Category 1B for
effects on sexual function and fertility and also Category 2 for development) then both hazard differentiations shall be communicated by the respective hazard statements. Classification in the additional category for effects on or via lactation will be considered irrespective of a classification into Category 1A, Category 1B or Category 2.
not fulfilled.
3.7.2.2.2. In the evaluation of toxic effects on the developing offspring, it is
important to consider the possible influence of maternal toxicity (see
section 3.7.2.4).
One screening study with restricted reliability on embryotoxicity is published. No effects were observed
3.7.2.2.3. For human evidence to provide the primary basis for a Category 1A
classification there must be reliable evidence of an adverse effect on
reproduction in humans. Evidence used for classification shall
ideally be from well conducted epidemiological studies which include the use of appropriate controls, balanced assessment, and
due consideration of bias or confounding factors. Less rigorous data from studies in humans shall be supplemented with adequate data
from studies in experimental animals and classification in Category 1B shall be considered.

There is no evidence of an adverse effect on
reproduction.